Repeated restraint stress lowers the threshold for response to third ventricle CRF administration.

PubMed

Harris, Ruth B S

2017-03-01

Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague-Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0-3.0μg). The lowest dose of CRF (0.25μg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period. Copyright © 2016 Elsevier Inc. All rights reserved.

Corticotropin releasing factor influences aggression and monoamines: Modulation of attacks and retreats

PubMed Central

Carpenter, Russ E.; Korzan, Wayne J.; Bockholt, Craig; Watt, Michael J.; Forster, Gina L.; Renner, Kenneth J.; Summers, Cliff H.

2009-01-01

Salmonids establish social hierarchies as a result of aggressive social interactions. The establishment of dominant or subordinate status is strongly linked to neuroendocrine responses mediated through the stress axis. In this study, we tested the effects of icv CRF on the behavioral outcome, plasma cortisol and monoamine function in trout subjected to a socially aggressive encounter. Rainbow trout were treated with an icv injection of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Fish were allowed to interact with a similarly sized conspecific for 15 minutes. Following the behavioral interaction, plasma cortisol and central monoamine concentrations were analyzed. Trout treated with CRF were victorious in approximately 60% of the aggressive encounters against aCSF treated opponents. Trout injected with CRF exhibited a reduction in the total number of attacks and decreased latency to attack. When trout were divided winners and losers, only victorious CRF-treated fish exhibited a reduced latency to attack and fewer retreats. Social stress increased cortisol levels in both winners and losers of aggressive interaction. This effect was enhanced with the additional stress incurred from icv injection of aCSF. However, icv CRF in addition to social stress decreased plasma cortisol in both winners and losers. While aggression stimulated significant changes in serotonergic and dopaminergic activity, the magnitude and direction were dependent on limbic brain region, CRF dose, and outcome of social aggression. With broad effects on aggressive behavior, anxiety, stress responsiveness, and central monoaminergic activity, CRF plays an important role modulating the behavioral components of social interaction. PMID:18992791

Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress.

PubMed

Varodayan, F P; Khom, S; Patel, R R; Steinman, M Q; Hedges, D M; Oleata, C S; Homanics, G E; Roberto, M; Bajo, M

2018-01-04

Stress induces neuroimmune responses via Toll-like receptor 4 (TLR4) activation. Here, we investigated the role of TLR4 in the effects of the stress peptide corticotropin-releasing factor (CRF) on GABAergic transmission in the central nucleus of the amygdala (CeA) following restraint stress. Tlr4 knock out (KO) and wild-type rats were exposed to no stress (naïve), a single restraint stress (1 h) or repeated restraint stress (1 h per day for 3 consecutive days). After 1 h recovery from the final stress session, whole-cell patch-clamp electrophysiology was used to investigate the effects of CRF (200 nM) on CeA GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs). TLR4 does not regulate baseline GABAergic transmission in the CeA of naive and stress-treated animals. However, CRF significantly increased the mean sIPSC frequencies (indicating enhanced GABA release) across all genotypes and stress treatments, except for the Tlr4 KO rats that experienced repeated restraint stress. Overall, our results suggest a limited role for TLR4 in CRF's modulation of CeA GABAergic synapses in naïve and single stress rats, though TLR4-deficient rats that experienced repeated psychological stress exhibit a blunted CRF cellular response. TLR4 has a limited role in CRF's activation of the CeA under basal conditions, but interacts with the CRF system to regulate GABAergic synapse function in animals that experience repeated psychological stress. © The Author(s) 2018. Medical Council on Alcohol and Oxford University Press. All rights reserved.

The effect of non-diabetic chronic renal failure on olfactory function.

PubMed

Koseoglu, S; Derin, S; Huddam, B; Sahan, M

2017-05-01

In chronic renal failure (CRF), deterioration of glomerular filtration results in accumulation of metabolites in the body which affect all organs. This study was performed to investigate the olfactory functions, and determine if hemodialysis or peritoneal dialysis improves olfactory function in non-diabetic CRF patients. The olfactory functions were analyzed in CRF patients not on a dialysis program and had a creatinine level≥2mg/dL, in CRF patients on hemodialysis or peritoneal dialysis, and in healthy controls. Diabetic patients were excluded since diabetes alone is a cause of olfactory dysfunction. The study group consisted of a total of 107 individuals including 38CRF patients on a hemodialysis program, 15 CRF patients on peritoneal dialysis, 30 patients with a creatinine level ≥ 2mg/dL without any need for dialysis, and 24 healthy controls with normal renal functions. Olfactory functions were analyzed with "Sniffin' sticks" test, and the groups were compared for the test results. All test parameters were impaired in patients with CRF. The median TDI scores of the patients with CRF and the healthy subjects were 24.75 (13-36) and 32.5 (27.75-37.75), respectively, with a statistically significant difference in between (P<0.001). The olfactory functions for the dialysis patients were better than those for the CRF patients not on a dialysis program (P=0.020). Non-diabetic CRF affects olfactory functions negatively. Dialysis improves olfactory functions in those patients. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine.

PubMed

Giardino, William J; Mark, Gregory P; Stenzel-Poore, Mary P; Ryabinin, Andrey E

2012-02-01

Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants. We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg). These results contrasted with previous studies implicating CRF-R1 in the locomotor effects of psychostimulants. Since the majority of previous studies focused on cocaine, rather than methamphetamine, we set out to test the hypothesis that these drugs differentially engage CRF-R1 and CRF-R2. We expanded our earlier findings by first replicating our previous experiments at a higher dose of methamphetamine (2 mg/kg), and by assessing the effects of the CRF-R1-selective antagonist CP-376,395 (10 mg/kg) on methamphetamine-induced locomotor activity. Next, we used both genetic and pharmacological tools to examine the specific components of the CRF system underlying the acute locomotor response to cocaine (5-10 mg/kg). While genetic deletion of CRF-R2 dampened the locomotor response to methamphetamine (but not cocaine), genetic deletion and pharmacological blockade of CRF-R1 dampened the locomotor response to cocaine (but not methamphetamine). These findings highlight the differential involvement of CRF receptors in acute sensitivity to two different stimulant drugs of abuse, providing an intriguing basis for the development of more targeted therapeutics for psychostimulant addiction.

Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria

There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated bymore » naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone-precipitated morphine withdrawal increases PKA expression in the heart. • CRF1 receptor is implicated in the sympathetic activity induced by morphine withdrawal.« less

Microinjection of urocortin into the rat nucleus tractus solitarii decreases arterial blood pressure.

PubMed

Yamazaki, Toshiya; Waki, Hidefumi; Kohsaka, Akira; Nakamura, Takeshi; Cui, He; Yukawa, Kazunori; Maeda, Masanobu

2008-11-03

Systemic administration of urocortin I (Ucn I), a member of the corticotrophin-releasing factor (CRF) peptide family, modulates cardiovascular system. In the central nervous system, Ucn I is found in the nucleus tractus solitarii (NTS), which plays an important role in regulating arterial blood pressure (ABP) and heart rate (HR) in response to activation of the baroreceptor afferents. In this study, we examined the effects of Ucn I, which has a high affinity for both type 1 and type 2 CRF receptors (i.e. CRF-R1 and -R2), on cardiovascular functions at the level of the NTS. A specific agonist of CRF-R1 (i.e. CRF) and a specific agonist of CRF-R2 (i.e. Urocortin II) were also tested to identify the specific cardiovascular effects induced by individual activation of either CRF-R1 or -R2. We found that Ucn I microinjected into the rat NTS produced a significant reduction in both ABP and HR. Both agonists for CRF-R1 and -R2 microinjected into the NTS also reduced ABP and HR. Our results suggest that Ucn I in the NTS may play an important role in cardiovascular regulation and the cardiovascular effects of Ucn I may be mediated by activation of both CRF-R1 and -R2, which are known to be present in the NTS.

Peptide YY, neuropeptide Y and corticotrophin-releasing factor modulate gastrointestinal motility and food intake during acute stress.

PubMed

Forbes, Sarah C; Cox, Helen M

2014-11-01

Peripheral neuropeptide Y (NPY) provides protection against the endocrine, feeding and gastrointestinal (GI) responses to stress; however, it is not yet established how it interacts with corticotrophin-releasing factor (CRF) to mediate these effects. Peptide YY (PYY) also has significant roles in GI motility and food intake but little is known about its role in stress responses. Upper GI transit, fecal pellet output (FPO) and feeding responses, and the role of CRF1 receptors, during restraint or a novel environment stress, were ascertained in PYY-/-, NPY-/- and wild type (WT) mice, with CRF and the CRF1 antagonist, antalarmin, injected intraperitoneally. Upper GI transit and FPO were significantly increased in PYY-/- mice during restraint stress. Exogenous CRF increased defecation during placement in a novel environment in WT mice through CRF1 , while CRF1 blockade reduced defecation in WT and NPY-/- mice but had no effect in PYY-/- mice. In addition, CRF1 blockade had no effect on upper GI transit in WT mice, or on food intake in PYY-/- or NPY-/- mice, but it significantly increased food intake in WT mice. Endogenous NPY appears to inhibit the colonic motor response induced by CRF1 activation, unlike PYY, while both peptides are required for CRF1 modulation of feeding behavior during stress. Overall, these results provide new insights into the mechanism by which PYY and NPY affect stress responses. © 2014 John Wiley & Sons Ltd.

Synaptic and Network Mechanisms of Sparse and Reliable Visual Cortical Activity during Nonclassical Receptive Field Stimulation

PubMed Central

Haider, Bilal; Krause, Matthew R.; Duque, Alvaro; Yu, Yuguo; Touryan, Jonathan; Mazer, James A.; McCormick, David A.

2011-01-01

SUMMARY During natural vision, the entire visual field is stimulated by images rich in spatiotemporal structure. Although many visual system studies restrict stimuli to the classical receptive field (CRF), it is known that costimulation of the CRF and the surrounding nonclassical receptive field (nCRF) increases neuronal response sparseness. The cellular and network mechanisms underlying increased response sparseness remain largely unexplored. Here we show that combined CRF + nCRF stimulation increases the sparseness, reliability, and precision of spiking and membrane potential responses in classical regular spiking (RSC) pyramidal neurons of cat primary visual cortex. Conversely, fast-spiking interneurons exhibit increased activity and decreased selectivity during CRF + nCRF stimulation. The increased sparseness and reliability of RSC neuron spiking is associated with increased inhibitory barrages and narrower visually evoked synaptic potentials. Our experimental observations were replicated with a simple computational model, suggesting that network interactions among neuronal subtypes ultimately sharpen recurrent excitation, producing specific and reliable visual responses. PMID:20152117

Corticotropin-releasing factor: effect on cerebral blood flow in physiologic and ischaemic conditions.

PubMed

De Michele, Manuela; Touzani, Omar; Foster, Alan C; Fieschi, Cesare; Sette, Giuliano; McCulloch, James

2005-09-01

The expression of corticotrophin-releasing factor (CRF) receptors in cerebral arteries and arterioles suggests that CRF may modulate cerebral blood flow (CBF). In the present study, the effects of CRF, CRF-like peptides and the CRF broad spectrum antagonist DPhe-CRF on CBF have been investigated under normal physiologic conditions and in the margins of focal ischaemic insult. The experiments were carried out in anaesthetised and ventilated rats. Changes in CBF after subarachnoid microapplication of CRF and related peptides were assessed with a laser-Doppler flowmetry (LDF) probe. In the ischaemic animals, agents were injected approximately 60 minutes after permanent middle cerebral artery occlusion (MCAo). Microapplication of CRF and related peptides in normal rats into the subarachnoid space produced sustained concentration-dependent increases in CBF. This effect was attenuated by co-application with DPhe-CRF, which did not alter CBF itself. A second microapplication of CRF 30 min after the first failed to produce increases in CBF in normal animals. Microapplication of CRF in the subarachnoid space overlying the ischaemic cortex effected minor increases in CBF whereas D-Phe-CRF had no significant effect on CBF. Activation of the CRF peptidergic system increases CBF in the rat. Repeated activation of CRF receptors results in tachyphylaxis of the vasodilator response. CRF vasodilator response is still present after MCAo in the ischaemic penumbra, suggesting that the CRF peptidergic system may modulate CBF in ischaemic stroke.

Icariin combined with human umbilical cord mesenchymal stem cells significantly improve the impaired kidney function in chronic renal failure.

PubMed

Li, Wen; Wang, Li; Chu, Xiaoqian; Cui, Huantian; Bian, Yuhong

2017-04-01

At present, the main therapy for chronic renal failure (CRF) is dialysis and renal transplantation, but neither obtains satisfactory results. Human umbilical cord mesenchymal stem cells (huMSCs) are isolated from the fetal umbilical cord which has a high self-renewal and multi-directional differentiation potential. Icariin (ICA), a kidney-tonifying Chinese Medicine can enhance the multipotency of huMSCs. Therefore, this work seeks to employ the use of ICA-treated huMSCs for the treatment of chronic renal failure. Blood urea nitrogen and creatinine (Cr) analyses showed amelioration of functional parameters in ICA-treated huMSCs for the treatment of CRF rats at 3, 7, and 14 days after transplantation. ICA-treated huMSCs can obviously increase the number of cells in injured renal tissues at 3, 7, and 14 days after transplantation by optical molecular imaging system. Hematoxylin-eosin staining demonstrated that ICA-treated huMSCs reduced the levels of fibrosis in CRF rats at 14 days after transplantation. Superoxide dismutase and Malondialdehyde analyses showed that ICA-treated huMSCs reduced the oxidative damage in CRF rats. Moreover, transplantation with ICA-treated huMSCs decreased inflammatory responses, promoted the expression of growth factors, and protected injured renal tissues. Taken together, our findings suggest that ICA-treated huMSCs could improve the kidney function in CRF rats.

Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

PubMed Central

Gurbuz, Nilgun; Kol, Arif; Ipekci, Tumay; Ates, Erhan; Baykal, Asli; Usta, Mustafa F

2015-01-01

The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg−1 p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE's)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats. PMID:25652632

Differential neuroendocrine responses to chronic variable stress in adult Long Evans rats exposed to handling-maternal separation as neonates.

PubMed

Ladd, Charlotte O; Thrivikraman, K V; Huot, Rebecca L; Plotsky, Paul M

2005-07-01

Burgeoning evidence supports a preeminent role for early- and late-life stressors in the development of physio- and psychopathology. Handling-maternal separation (HMS) in neonatal Long Evans hooded rats leads to stable phenotypes ranging from resilient to vulnerable to later stressor exposure. Handling with 180 min of maternal separation yields a phenotype of stress hyper-responsiveness associated with facilitation of regional CRF neurocircuits and glucocorticoid resistance. This study assessed whether or not prolonged HMS (180 min/day, HMS180) on post-natal days 2-14 sensitizes the adult limbic hypothalamo-pituitary-adrenal (LHPA) axis to chronic variable stress (CS) compared to brief HMS (15 min/day, HMS15). We examined regional mRNA densities of corticotropin-releasing factor (CRF), its receptor CRF1, glucocorticoid receptor (GR), and mineralocorticoid receptor (MR); regional CRF1 and CRF2alpha binding, and pituitary-adrenal responses to an acute air-puff startle (APS) stressor in four groups: HMS15, nonstressed; HMS15, stressed; HMS180, nonstressed; HMS180, stressed. As expected we observed exaggerated pituitary-adrenal responses to APS, increased regional CRF mRNA density, decreased regional CRF1 binding, and decreased cortical GR mRNA density in nonstressed HMS180 vs. HMS15 animals. However, in contrast to our hypothesis, CS decreased pituitary-adrenal reactivity and central amygdala CRF mRNA density in HMS180 rats, while increasing cortical GR mRNA density and CRF1 binding. CS had no effect on the pituitary-adrenal response to APS in HMS15 rats, despite tripling hypothalamic paraventricular CRF mRNA density. The data suggest that many effects of prolonged HMS are reversible in adulthood by CS, while the neuroendocrine adaptations imbued by brief HMS are sufficiently stable to restrain pituitary-adrenal stress responses even following CS.

Activation of corticotropin-releasing factor receptors from the basolateral or central amygdala increases the tonic immobility response in guinea pigs: an innate fear behavior.

PubMed

Donatti, Alberto Ferreira; Leite-Panissi, Christie Ramos Andrade

2011-11-20

The tonic immobility (TI) behavior is an innate response associated with extreme threat situations such as a predator attack. Several studies have provided evidence suggesting an important role for corticotropin-releasing factor (CRF) in the regulation of the endocrine system, defensive behaviors and behavioral responses to stress. TI has been shown to be positively correlated with the basal plasma levels of corticosterone. CRF receptors and neurons that are immunoreactive to CRF are found in many cerebral regions, especially in the amygdaloid complex. Previous reports have demonstrated the involvement of the basolateral amygdaloid (BLA) and central amygdaloid (CeA) nuclei in the TI response. In this study, we evaluated the CRF system of the BLA and the CeA in the modulation of the TI response in guinea pigs. The activation of CRF receptors in the BLA and in the CeA promoted an increase in the TI response. In contrast, the inhibition of these receptors via alpha-helical-CRF(9-41) decreased the duration of the TI response. Moreover, neither the activation nor inhibition of CRF receptors in the BLA or the CeA altered spontaneous motor activity in the open-field test. These data suggest that the activation of the CRF receptors in the BLA or the CeA probably potentiates fear and anxiety, which may be one of the factors that promote an increase in the TI behavior. Therefore, these data support the role of the CRF system in the control of emotional responses, particularly in the modulation of innate fear. Copyright © 2011 Elsevier B.V. All rights reserved.

Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity.

PubMed

Howerton, Alexis R; Roland, Alison V; Fluharty, Jessica M; Marshall, Anikò; Chen, Alon; Daniels, Derek; Beck, Sheryl G; Bale, Tracy L

2014-06-01

Women are twice as likely as men to suffer from stress-related affective disorders. Corticotropin-releasing factor (CRF) is an important link between stress and mood, in part through its signaling in the serotonergic dorsal raphe (DR). Development of CRF receptor-1 (CRFr1) antagonists has been a focus of numerous clinical trials but has not yet been proven efficacious. We hypothesized that sex differences in CRFr1 modulation of DR circuits might be key determinants in predicting therapeutic responses and affective disorder vulnerability. Male and female mice received DR infusions of the CRFr1 antagonist, NBI 35965, or CRF and were evaluated for stress responsivity. Sex differences in indices of neural activation (cFos) and colocalization of CRFr1 throughout the DR were examined. Whole-cell patch-clamp electrophysiology assessed sex differences in serotonin neuron membrane characteristics and responsivity to CRF. Males showed robust behavioral and hypothalamic-pituitary-adrenal axis responses to DR infusion of NBI 35965 and CRF, whereas females were minimally responsive. Sex differences were also found for both CRF-induced DR cFos and CRFr1 co-localization throughout the DR. Electrophysiologically, female serotonergic neurons showed blunted membrane excitability and divergent inhibitory postsynaptic current responses to CRF application. These studies demonstrate convincing sex differences in CRFr1 activity in the DR, where blunted female responses to NBI 35965 and CRF suggest unique stress modulation of the DR. These sex differences might underlie affective disorder vulnerability and differential sensitivity to pharmacologic treatments developed to target the CRF system, thereby contributing to a current lack of CRFr1 antagonist efficacy in clinical trials. © 2013 Published by Society of Biological Psychiatry on behalf of Society of Biological Psychiatry.

The neuroanatomic complexity of the CRF and DA systems and their interface: What we still don't know.

PubMed

Kelly, E A; Fudge, J L

2018-07-01

Corticotropin-releasing factor (CRF) is a neuropeptide that mediates the stress response. Long known to contribute to regulation of the adrenal stress response initiated in the hypothalamic-pituitary axis (HPA), a complex pattern of extrahypothalamic CRF expression is also described in rodents and primates. Cross-talk between the CRF and midbrain dopamine (DA) systems links the stress response to DA regulation. Classically CRF + cells in the extended amygdala and paraventricular nucleus (PVN) are considered the main source of this input, principally targeting the ventral tegmental area (VTA). However, the anatomic complexity of both the DA and CRF system has been increasingly elaborated in the last decade. The DA neurons are now recognized as having diverse molecular, connectional and physiologic properties, predicted by their anatomic location. At the same time, the broad distribution of CRF cells in the brain has been increasingly delineated using different species and techniques. Here, we review updated information on both CRF localization and newer conceptualizations of the DA system to reconsider the CRF-DA interface. Copyright © 2018 Elsevier Ltd. All rights reserved.

A chronology of ratios between black smoke and PM10 and PM2.5 in the context of comparison of air pollution epidemiology concentration-response functions.

PubMed

Heal, Mathew R; Beverland, Iain J

2017-05-03

For many air pollution epidemiological studies in Europe, 'black smoke' (BS) was the only measurement available to quantify ambient particulate matter (PM), particularly for exposures prior to the mid-1990s when quantification via the PM 10 and/or PM 2.5 metrics was introduced. The aim of this work was to review historic BS and PM measurements to allow comparison of health concentration-response functions (CRF) derived using BS as the measure of exposure with CRFs derived using PM 10 or PM 2.5 . The literature was searched for quantitative information on measured ratios of BS:PM 10 , BS:PM 2.5 , and chemical composition of PM; with specific focus on the United Kingdom (UK) between 1970 and the early 2000s when BS measurements were discontinued. The average BS:PM 10 ratio in urban background air was just below unity at the start of the 1970s, decreased rapidly to ≈ 0.7 in the mid-1970s and to ≈ 0.5 at the end of the 1970s, with continued smaller declines in the 1980s, and was within the range 0.2-0.4 by the end of the 1990s. The limited data for the BS:PM 2.5 ratio suggest it equalled or exceeded unity at the start of the 1970s, declined to ≈ 0.7 by the end of the 1970s, with slower decline thereafter to a range 0.4-0.65 by the end of the 1990s. For an epidemiological study that presents a CRF BS value, the corresponding CRF PM10 value can be estimated as R BS:PM10  × CRF BS where R BS:PM10 is the BS:PM 10 concentration ratio, if the toxicity of PM 10 is assumed due only to the component quantified by a BS measurement. In the general case of some (but unknown) contribution of toxicity from non-BS components of PM 10 then CRF PM10  > R BS:PM10  × CRF BS , with CRF PM10 exceeding CRF BS if the toxicity of the other components in PM 10 is greater than the toxicity of the component to which the BS metric is sensitive. Similar analyses were applied to relationships between CRF PM2.5 and CRF BS . Application of this analysis to example published CRF BS values for short and long-term health effects of PM suggest health effects from other components in the PM mixture in addition to the fine black particles characterised by BS.

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor.

PubMed

Bryce, Courtney A; Floresco, Stan B

2016-07-01

Acute stress activates numerous systems in a coordinated effort to promote homeostasis, and can exert differential effects on mnemonic and cognitive functions depending on a myriad of factors. Stress can alter different forms of cost/benefit decision-making, yet the mechanisms that drive these effects, remain unclear. In the present study, we probed how corticotropin-releasing factor (CRF) may contribute to stress-induced alterations in cost/benefit decision-making, using an task where well-trained rats chose between a low effort/low reward lever (LR; two pellets) and a high effort/high reward lever (HR; four pellets), with the effort requirement increasing over a session (2, 5, 10, and 20 presses). One-hour restraint stress markedly reduced preference for the HR option, but this effect was attenuated by infusions of the CRF antagonist, alpha-helical CRF. Conversely, central CRF infusion mimicked the effect of stress on decision-making, as well as increased decision latencies and reduced response vigor. CRF infusions did not alter preference for larger vs smaller rewards, but did reduce responding for food delivered on a progressive ratio, suggesting that these treatments may amplify perceived effort costs that may be required to obtain rewards. CRF infusions into the ventral tegmental area recapitulated the effect of central CRF treatment and restraint on choice behavior, suggesting that these effects may be mediated by perturbations in dopamine transmission. These findings highlight the involvement of CRF in regulating effort-related decisions and suggest that increased CRF activity may contribute to motivational impairments and abnormal decision-making associated with stress-related psychiatric disorders such as depression.

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor

PubMed Central

Bryce, Courtney A; Floresco, Stan B

2016-01-01

Acute stress activates numerous systems in a coordinated effort to promote homeostasis, and can exert differential effects on mnemonic and cognitive functions depending on a myriad of factors. Stress can alter different forms of cost/benefit decision-making, yet the mechanisms that drive these effects, remain unclear. In the present study, we probed how corticotropin-releasing factor (CRF) may contribute to stress-induced alterations in cost/benefit decision-making, using an task where well-trained rats chose between a low effort/low reward lever (LR; two pellets) and a high effort/high reward lever (HR; four pellets), with the effort requirement increasing over a session (2, 5, 10, and 20 presses). One-hour restraint stress markedly reduced preference for the HR option, but this effect was attenuated by infusions of the CRF antagonist, alpha-helical CRF. Conversely, central CRF infusion mimicked the effect of stress on decision-making, as well as increased decision latencies and reduced response vigor. CRF infusions did not alter preference for larger vs smaller rewards, but did reduce responding for food delivered on a progressive ratio, suggesting that these treatments may amplify perceived effort costs that may be required to obtain rewards. CRF infusions into the ventral tegmental area recapitulated the effect of central CRF treatment and restraint on choice behavior, suggesting that these effects may be mediated by perturbations in dopamine transmission. These findings highlight the involvement of CRF in regulating effort-related decisions and suggest that increased CRF activity may contribute to motivational impairments and abnormal decision-making associated with stress-related psychiatric disorders such as depression. PMID:26830960

Validation of an Experimental Model to Study Less Severe Chronic Renal Failure.

PubMed

Fernandes-Charpiot, Ida Mária Maximina; Caldas, Heloisa Cristina; Mendes, Glória Elisa Florido; Gomes de Sá Neto, Luiz; Oliveira, Henrique Lacativa; Baptista, Maria Alice Sperto Ferreira; Abbud-Filho, Mario

2016-10-01

The 5/6 nephrectomy, mimics the stages of human chronic renal failure (CRF), but the procedure causes severe renal functional and morphological damage that could interfere with the evaluation of therapies for slowing the progression of the disease. This study summarizes the results of renal function, histology, and immunohistochemical findings in rats undergoing a 2/3 nephrectomy. The rats were distributed in groups according to the type of nephrectomy: CRF5/6: induced by a 5/6 renal mass reduction and CRF2/3: less severe CRF. The body weight and blood pressure were monitored, and the serum creatinine (SCr), creatinine clearance (CCr), urine osmolality, and 24-h proteinuria (PT24h) were measured. CRF progression was evaluated by the rate of decline of CCr (RCCr). Histology and immunohistochemistry were performed in the remnant kidneys. Statistical analysis was done by unpaired t-test, and a P-value < 0.05 was taken as a statistical significance. Compared to the CRF5/6 group, the CRF2/3 model had a lower SCr, PT24h, CCr, and variations of the SCr from baseline. The disease progression was also significantly slower. The renal histopathological findings revealed fewer chronic lesions in rats with CRF2/3. Similarly, we observed less macrophage accumulation as well as lower proliferative activity and expression of fibronectin and a-smooth muscle-actin in the CRF2/3 model. The CRF2/3 model presented with a pattern of less severe CRF, functionally and morphologically, compared to the classical CRF5/6 model, and the CRF2/3 model may be useful for evaluating therapeutic interventions that target the early stages of CRF.

Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.

PubMed

Kotenko, S V; Izotova, L S; Mirochnitchenko, O V; Esterova, E; Dickensheets, H; Donnelly, R P; Pestka, S

2001-01-26

Interleukin-10 (IL-10)-related T cell-derived inducible factor (IL-TIF; provisionally designated IL-22) is a cytokine with limited homology to IL-10. We report here the identification of a functional IL-TIF receptor complex that consists of two receptor chains, the orphan CRF2-9 and IL-10R2, the second chain of the IL-10 receptor complex. Expression of the CRF2-9 chain in monkey COS cells renders them sensitive to IL-TIF. However, in hamster cells both chains, CRF2-9 and IL-10R2, must be expressed to assemble the functional IL-TIF receptor complex. The CRF2-9 chain (or the IL-TIF-R1 chain) is responsible for Stat recruitment. Substitution of the CRF2-9 intracellular domain with the IFN-gammaR1 intracellular domain changes the pattern of IL-TIF-induced Stat activation. The CRF2-9 gene is expressed in normal liver and kidney, suggesting a possible role for IL-TIF in regulating gene expression in these tissues. Each chain, CRF2-9 and IL-10R2, is capable of binding IL-TIF independently and can be cross-linked to the radiolabeled IL-TIF. However, binding of IL-TIF to the receptor complex is greater than binding to either receptor chain alone. Sharing of the common IL-10R2 chain between the IL-10 and IL-TIF receptor complexes is the first such case for receptor complexes with chains belonging to the class II cytokine receptor family, establishing a novel paradigm for IL-10-related ligands similar to the shared use of the gamma common chain (gamma(c)) by several cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-15.

Oxidative stress in uremia: nature, mechanisms, and potential consequences.

PubMed

Vaziri, Nosratola D

2004-09-01

Oxidative stress has emerged as a constant feature of chronic renal failure (CRF). The presence of oxidative stress in CRF is evidenced by an overabundance of lipid, carbohydrate, and protein oxidation products in the plasma and tissues of uremic patients and animals. We recently have shown that oxidative stress in CRF animals is associated with and, in part, owing to up-regulation of superoxide-producing enzyme, nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase, and down-regulation of superoxide dismutase (SOD). The functional significance of these findings was confirmed by favorable response to administration of the cell-permeable SOD-mimetic agent, tempol, in CRF rats. Oxidative stress in CRF plays an important role in the pathogenesis of the associated hypertension (oxidation of NO and arachidonic acid and vascular remodeling), cardiovascular disease (oxidation of lipoproteins, atherogenesis), neurologic disorders (nitration of brain proteins, oxidation of myelin), anemia (reduction of erythrocyte lifespan), inflammation (nuclear factor kappa B activation), fibrosis, apoptosis, and accelerated aging. The CRF-induced oxidative stress is aggravated by diabetes, uncontrolled hypertension, and autoimmune diseases, which independently increase production of reactive oxygen intermediates, and frequently are associated with CRF. In addition, dialysis treatment (blood interaction with dialyzer membrane and dialysate impurities), acute and chronic infections (blood access infection, hepatitis, and so forth), and excessive parenteral iron administration intensify CRF-associated oxidative stress and its adverse consequences in patients with end-stage renal disease. The problem is compounded by limited intake of fresh fruits and vegetables (K(+) restriction), which contain numerous natural phytochemicals and antioxidant vitamins.

Role of Corticotropin Releasing Factor in Anxiety Disorders: A Translational Research Perspective

PubMed Central

Risbrough, Victoria B.; Stein, Murray B.

2007-01-01

Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety. PMID:16870185

The effect of competitive and non-competitive NMDA receptor antagonists, ACPC and MK-801 on NPY and CRF-like immunoreactivity in the rat brain amygdala.

PubMed

Wierońska, J M; Brański, P; Pałvcha, A; Smiałowska, M

2001-01-01

Amygdala is the brain structure responsible for integrating all behavior connected with fear, and in this structure two neuropeptides, neuropeptide Y (NPY), corticoliberin (CRF) and the most abundant excitatory neurotransmitter glutamate seem to take part in the regulation of anxiety behavior. Our previous studies showed the modulation of NPY and CRF expression by classical neurotransmitters in some brain structures, therefore in the present study we investigated the effect of NMDA receptor antagonists on the expression of NPY and CRF immunoreactivity in the rat brain amygdala. A non-competitive NMDA receptor antagonist, MK-801, or a functional NMDA antagonist, ACPC were used. Brains were taken out and processed by immunohistochemical method using specific NPY or CRF antibodies. The staining intensity and density of IR neurons were evaluated under a microscope in amygdala sections. It was found that both MK-801 and ACPC induced a significant decrease in NPY-immunoreactivity in amygdala nerve cell bodies and terminals, which may suggest an increased release of this peptide. CRF-IR was decreased after ACPC only. The obtained results indicate that in the amygdala, the NMDA receptors mediated glutamatergic transmission may regulate NPY neurons. Copyright 2001 Harcourt Publishers Ltd.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

PubMed Central

Blacktop, Jordan M.; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A.; Mantsch, John R.

2015-01-01

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 hrs/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 sec; range 10–70 sec) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 µg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. PMID:26596556

The Central Nucleus of the Amygdala and Corticotropin-Releasing Factor: Insights into Contextual Fear Memory

PubMed Central

Pitts, Matthew W.; Todorovic, Cedomir; Blank, Thomas; Takahashi, Lorey K.

2009-01-01

The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA prior to contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately prior to retention testing did not impair freezing, suggesting that the previously observed retention deficits were due to inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator. PMID:19494159

A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses.

PubMed

Shekhar, Anantha; Johnson, Philip L; Fitz, Stephanie D; Nakazato, Atsuro; Chaki, Shigeyuki; Steckler, Thomas; Schmidt, Mark

2011-04-01

Corticotropin releasing factor (CRF) is implicated in a variety of stress-related disorders such as depression and anxiety, and blocking CRF receptors is a putative strategy for treating such disorders. Using a well-studied animal model of panic, we tested the efficacy of JNJ19567470/CRA5626, a selective, non-peptidergic CRF type 1 receptor (CRF1) antagonist (3, 10 and 40 mg/kg intraperitoneal injection), in preventing the sodium lactate (NaLac)-induced panic-like behavioural and cardiovascular responses. Adult male rats with chronic reduction of GABA levels (by inhibition of GABA synthesis with l-allyglycine, a glutamic acid decarboxylase inhibitor) in the dorsomedial/perifornical hypothalamus are highly anxious and exhibit physiological and behavioural responses to intravenous NaLac infusions similar to patients with panic disorder. These 'panic-prone' rats pre-treated with vehicle injections displayed NaLac-induced increases in autonomic responses (i.e. tachycardia and hypertensive responses), anxiety-like behaviour in the social interaction test, and flight-like increases in locomotor activity. However, systemically injecting such panic-prone rats with the highest dose of CRF1 receptor antagonist prior to NaLac infusions blocked all NaLac-induced behaviour and cardiovascular responses. These data suggest that selective CRF1 receptor antagonists could be a novel target for developing anti-panic drugs that are as effective as benzodiazepines in acute treatment of a panic attack without the deleterious side-effects (e.g. sedation and cognitive impairment) associated with benzodiazepines.

Water-avoidance stress enhances gastric contractions in freely moving conscious rats: role of peripheral CRF receptors.

PubMed

Nozu, Tsukasa; Kumei, Shima; Takakusaki, Kaoru; Okumura, Toshikatsu

2014-05-01

Stress alters gastrointestinal motility through central and peripheral corticotropin-releasing factor (CRF) pathways. Accumulating evidence has demonstrated that peripheral CRF is deeply involved in the regulation of gastric motility, and enhances gastric contractions through CRF receptor type 1 (CRF1) and delays gastric emptying (GE) through CRF receptor type 2 (CRF2). Since little is known whether water-avoidance stress (WAS) alters gastric motility, the present study tried to clarify this question and the involvement of peripheral CRF receptor subtypes in the mechanisms. We recorded intraluminal gastric pressure waves using a perfused manometric method. The rats were anesthetized and the manometric catheter was inserted into the stomach 4-6 days before the experiments. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1 h before and after initiation of WAS in nonfasted conscious rats. Solid GE for 1 h was also measured. WAS significantly increased gastric contractions. Intraperitoneal (ip) administration of astressin (100 μg/kg, 5 min prior to stress), a nonselective CRF antagonist, blocked the response to WAS. On the other hand, pretreatment (5 min prior to stress) with neither astressin2-B (200 μg/kg, ip), a selective CRF2 antagonist, nor urocortin 2 (30 μg/kg, ip), a selective CRF2 agonist, modified the response to WAS. These drugs did not alter the basal MI. WAS did not change GE. WAS may activate peripheral CRF1 but not CRF2 signaling and stimulates gastric contractions without altering GE.

Fitness in Young Adulthood and Long-Term Cardiac Structure and Function: The CARDIA Study.

PubMed

Pandey, Ambarish; Allen, Norrina B; Ayers, Colby; Reis, Jared P; Moreira, Henrique T; Sidney, Stephen; Rana, Jamal S; Jacobs, David R; Chow, Lisa S; de Lemos, James A; Carnethon, Mercedes; Berry, Jarett D

2017-05-01

This study sought to evaluate the association between early-life cardiorespiratory fitness (CRF) and measures of left ventricular (LV) structure and function in midlife. Low CRF in midlife is associated with a higher risk of heart failure. However, the unique contributions of early-life CRF toward measures of LV structure and function in middle age are not known. CARDIA (Coronary Artery Risk Development in Young Adults) study participants with a baseline maximal treadmill test and an echocardiogram at year 25 were included. Associations among baseline CRF, CRF change, and echocardiographic LV parameters (global longitudinal strain [GLS] and global circumferential strain, E/e') were assessed using multivariable linear regression. The study included 3,433 participants. After adjustment for baseline demographic and clinical characteristics, lower baseline CRF was significantly associated with higher LV strain (standardized parameter estimate [Std β] = -0.06; p = 0.03 for GLS) and ratio of early transmitral flow velocity to early peak diastolic mitral annular velocity (E/e') (Std β = -0.10; p = 0.0001 for lateral E/e'), findings suggesting impaired contractility and elevated diastolic filling pressure in midlife. After additional adjustment for cumulative cardiovascular risk factor burden observed over the follow-up period, the association of CRF with LV strain attenuated substantially (p = 0.36), whereas the association with diastolic filling pressure remained significant (Std β = -0.05; p = 0.02 for lateral E/e'). In a subgroup of participants with repeat CRF tests at year 20, greater decline in CRF was significantly associated with increased abnormalities in GLS (Std β = -0.05; p = 0.02) and higher diastolic filling pressure (Std β = -0.06; p = 0.006 for lateral E/e') in middle age. CRF in young adulthood and CRF change were associated with measures of LV systolic function and diastolic filling pressure in middle age. Low CRF-associated abnormalities in systolic function were related to the associated higher cardiovascular risk factor burden. In contrast, the inverse association between CRF and LV diastolic filling pressure was independent of cardiovascular risk factor burden. Copyright © 2017. Published by Elsevier Inc.

CRF1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse

PubMed Central

Bruijnzeel, Adrie W.; Prado, Melissa; Isaac, Shani

2010-01-01

Background Tobacco addiction is a chronic brain disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that blockade of CRF receptors with a non-specific CRF1/CRF2 receptor antagonist prevents the deficit in brain reward function associated with nicotine withdrawal and stress-induced reinstatement of extinguished nicotine seeking in rats. The aim of these studies was to investigate the role of CRF1 and CRF2 receptors in the deficit in brain reward function associated with precipitated nicotine withdrawal and stress-induced reinstatement of nicotine seeking. Methods The intracranial self-stimulation (ICSS) procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. Stress-induced reinstatement of nicotine seeking was investigated in animals in which responding for intravenously infused nicotine was extinguished by substituting saline for nicotine. Results In the ICSS experiments, the nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine dependent rats but not those of the control rats. The CRF1 receptor antagonist R278995/CRA0450, but not the CRF2 receptor antagonist astressin-2B, prevented the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. Furthermore, R278995/CRA0450, but not astressin-2B, prevented stress-induced reinstatement of extinguished nicotine seeking. Neither R278995/CRA0450 nor astressin-2B affected operant responding for chocolate-flavored food pellets. Conclusions These studies indicate that CRF1 receptors, but not CRF2 receptors, play an important role in the anhedonic-state associated with acute nicotine withdrawal and stress-induced reinstatement of nicotine seeking. PMID:19217073

Enduring, Handling-Evoked Enhancement of Hippocampal Memory Function and Glucocorticoid Receptor Expression Involves Activation of the Corticotropin-Releasing Factor Type 1 Receptor

PubMed Central

Fenoglio, Kristina A.; Brunson, Kristen L.; Avishai-Eliner, Sarit; Stone, Blake A.; Kapadia, Bhumika J.; Baram, Tallie Z.

2011-01-01

Early-life experience, including maternal care, influences hippocampus-dependent learning and memory throughout life. Handling of pups during postnatal d 2–9 (P2–9) stimulates maternal care and leads to improved memory function and stress-coping. The underlying molecular mechanisms may involve early (by P9) and enduring reduction of hypothalamic corticotropin-releasing factor (CRF) expression and subsequent (by P45) increase in hippocampal glucocorticoid receptor (GR) expression. However, whether hypothalamic CRF levels influence changes in hippocampal GR expression (and memory function), via reduced CRF receptor activation and consequent lower plasma glucocorticoid levels, is unclear. In this study we administered selective antagonist for the type 1 CRF receptor, NBI 30775, to nonhandled rats post hoc from P10–17 and examined hippocampus-dependent learning and memory later (on P50–70), using two independent paradigms, compared with naive and vehicle-treated nonhandled, and naive and antagonist-treated handled rats. Hippocampal GR and hypothalamic CRF mRNA levels and stress-induced plasma corticosterone levels were also examined. Transient, partial selective blockade of CRF1 in nonhandled rats improved memory functions on both the Morris watermaze and object recognition tests to levels significantly better than in naive and vehicle-treated controls and were indistinguishable from those in handled (naive, vehicle-treated, and antagonist-treated) rats. GR mRNA expression was increased in hippocampal CA1 and the dentate gyrus of CRF1-antagonist treated nonhandled rats to levels commensurate with those in handled cohorts. Thus, the extent of CRF1 activation, probably involving changes in hypothalamic CRF levels and release, contributes to the changes in hippocampal GR expression and learning and memory functions. PMID:15932935

Radiometric calibration of wide-field camera system with an application in astronomy

NASA Astrophysics Data System (ADS)

Vítek, Stanislav; Nasyrova, Maria; Stehlíková, Veronika

2017-09-01

Camera response function (CRF) is widely used for the description of the relationship between scene radiance and image brightness. Most common application of CRF is High Dynamic Range (HDR) reconstruction of the radiance maps of imaged scenes from a set of frames with different exposures. The main goal of this work is to provide an overview of CRF estimation algorithms and compare their outputs with results obtained under laboratory conditions. These algorithms, typically designed for multimedia content, are unfortunately quite useless with astronomical image data, mostly due to their nature (blur, noise, and long exposures). Therefore, we propose an optimization of selected methods to use in an astronomical imaging application. Results are experimentally verified on the wide-field camera system using Digital Single Lens Reflex (DSLR) camera.

Neurobiological Substrates for the Dark Side of Compulsivity in Addiction

PubMed Central

Koob, George F.

2009-01-01

Drug addiction can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreases in dopamine and opioid peptide function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, increases in anxiety-like responses, and increases in extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of addiction. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least in part, the compulsivity of addiction. PMID:18725236

Differences in response to corticotropin-releasing factor after short- and long-term consumption of a high-fat diet.

PubMed

Legendre, Ariadne; Papakonstantinou, Emilia; Roy, Marie-Claude; Richard, Denis; Harris, Ruth B S

2007-09-01

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF(2) receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF(1) receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects

PubMed Central

Schwandt, Melanie L; Cortes, Carlos R; Kwako, Laura E; George, David T; Momenan, Reza; Sinha, Rajita; Grigoriadis, Dimitri E; Pich, Emilio Merlo; Leggio, Lorenzo; Heilig, Markus

2016-01-01

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21–65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse. PMID:27109623

Central neuropeptide Y plays an important role in mediating the adaptation mechanism against chronic stress in male rats.

PubMed

Yang, Yu; Babygirija, Reji; Zheng, Jun; Shi, Bei; Sun, Weinan; Zheng, Xiaojiao; Zhang, Fan; Cao, Yu

2018-02-07

Exposure to continuous life stress often causes gastrointestinal (GI) symptoms. Studies have shown that neuropeptide Y (NPY) counteracts the biological actions of corticotrophin-releasing factor (CRF), and is involved in the termination of the stress response. However, in chronic repeated restraint stress (CRS) conditions, the actions of NPY on GI motility remain controversial. To evaluate the role of NPY in mediation of the adaptation mechanism and GI motility in CRS conditions, a CRS rat model was set up. Central CRF and NPY expression levels were analyzed, serum corticosterone and NPY concentrations were measured, and GI motor function was evaluated. The NPY Y1 receptor antagonist BIBP-3226 was centrally administered before stress loading, and on days, 1-5, of repeated stress, the central CRF and the serum corticosterone concentrations were measured. In addition, gastric and colonic motor functions were evaluated. The elevated central CRF expression and corticosterone concentration caused by acute stress began to fall after 3 days of stress loading, while central NPY expression and serum NPY began to increase. GI dysmotility also returned to a normal level. Pretreatment with BIBP-3226 abolished the adaptation mechanism, and significantly increased CRF expression and the corticosterone concentration, which resulted in delayed gastric emptying and accelerated fecal pellet output. Inhibited gastric motility and enhanced distal colonic motility were also recorded. CRS-produced adaptation, over-expressed central CRF, and GI dysmotility observed in acute restraint stress were restored to normal levels. Central NPY via the Y1 receptor plays an important role in mediating the adaptation mechanism against chronic stress. Copyright © 2018 Endocrine Society.

Molecular Modeling of Structures and Interaction of Human Corticotropin-Releasing Factor (CRF) Binding Protein and CRF Type-2 Receptor

PubMed Central

Slater, Paula G.; Gutierrez-Maldonado, Sebastian E.; Gysling, Katia; Lagos, Carlos F.

2018-01-01

The corticotropin-releasing factor (CRF) system is a key mediator of the stress response and addictive behavior. The CRF system includes four peptides: The CRF system includes four peptides: CRF, urocortins I–III, CRF binding protein (CRF-BP) that binds CRF with high affinity, and two class B G-protein coupled receptors CRF1R and CRF2R. CRF-BP is a secreted protein without significant sequence homology to CRF receptors or to any other known class of protein. Recently, it has been described a potentiation role of CRF-BP over CRF signaling through CRF2R in addictive-related neuronal plasticity and behavior. In addition, it has been described that CRF-BP is capable to physically interact specifically with the α isoform of CRF2R and acts like an escort protein increasing the amount of the receptor in the plasma membrane. At present, there are no available structures for CRF-BP or for full-length CRFR. Knowing and studying the structure of these proteins could be beneficial in order to characterize the CRF-BP/CRF2αR interaction. In this work, we report the modeling of CRF-BP and of full-length CRF2αR and CRF2βR based on the recently solved crystal structures of the transmembrane domains of the human glucagon receptor and human CRF1R, in addition with the resolved N-terminal extracellular domain of CRFRs. These models were further studied using molecular dynamics simulations and protein–protein docking. The results predicted a higher possibility of interaction of CRF-BP with CRF2αR than CRF2βR and yielded the possible residues conforming the interacting interface. Thus, the present study provides a framework for further investigation of the CRF-BP/CRF2αR interaction. PMID:29515519

Antagonism of corticotropin-releasing factor CRF1 receptors blocks the enhanced response to cocaine after social stress.

PubMed

Ferrer-Pérez, Carmen; Reguilón, Marina D; Manzanedo, Carmen; Aguilar, M Asunción; Miñarro, José; Rodríguez-Arias, Marta

2018-03-15

Numerous studies have shown that social defeat stress induces an increase in the rewarding effects of cocaine. In this study we have investigated the role played by the main hypothalamic stress hormone, corticotropin-releasing factor (CRF), in the effects that repeated social defeat (RSD) induces in the conditioned rewarding effects and locomotor sensitization induced by cocaine. A total of 220 OF1 mice were divided into experimental groups according to the treatment received before each social defeat: saline, 5 or 10 mg/kg of the nonpeptidic corticotropin-releasing factor CRF 1 receptor antagonist CP-154,526, or 15 or 30 µg/kg of the peptidic corticotropin-releasing factor CRF 2 receptor antagonist Astressin 2 -B. Three weeks after the last defeat, conditioned place preference (CPP) induced by 1 mg/kg of cocaine was evaluated. Motor response to 10 mg/kg of cocaine was also studied after a sensitization induction. Blockade of corticotropin-releasing factor CRF 1 receptor reversed the increase in cocaine CPP induced by social defeat. Conversely, peripheral corticotropin-releasing factor CRF 2 receptor blockade produced similar effects to those observed in socially stressed animals. The effect of RSD on cocaine sensitization was again blocked by the corticotropin-releasing factor CRF 1 receptor antagonist, while peripheral CRF 2 receptor antagonist did not show effect. Acute administration of Astressin 2 -B induced an anxiogenic response. Our results confirm that CRF modulates the effects of social stress on reinforcement and sensitization induced by cocaine in contrasting ways. These findings highlight CRF receptors as potential therapeutic targets to be explored by research about stress-related addiction problems. Copyright © 2018 Elsevier B.V. All rights reserved.

Contribution of amygdala CRF neurons to chronic pain.

PubMed

Andreoli, Matthew; Marketkar, Tanvi; Dimitrov, Eugene

2017-12-01

We investigated the role of amygdala corticotropin-releasing factor (CRF) neurons in the perturbations of descending pain inhibition caused by neuropathic pain. Forced swim increased the tail-flick response latency in uninjured mice, a phenomenon known as stress-induced analgesia (SIA) but did not change the tail-flick response latency in mice with neuropathic pain caused by sciatic nerve constriction. Neuropathic pain also increased the expression of CRF in the central amygdala (CeAmy) and ΔFosB in the dorsal horn of the spinal cord. Next, we injected the CeAmy of CRF-cre mice with cre activated AAV-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) vectors. Activation of CRF neurons by DREADD/Gq did not affect the impaired SIA but inhibition of CRF neurons by DREADD/Gi restored SIA and decreased allodynia in mice with neuropathic pain. The possible downstream circuitry involved in the regulation of SIA was investigated by combined injections of retrograde cre-virus (CAV2-cre) into the locus ceruleus (LC) and cre activated AAV-diphtheria toxin (AAV-FLEX-DTX) virus into the CeAmy. The viral injections were followed by a sciatic nerve constriction ipsilateral or contralateral to the injections. Ablation of amygdala projections to the LC on the side of injury but not on the opposite side, completely restored SIA, decreased allodynia and decreased ΔFosB expression in the spinal cord in mice with neuropathic pain. The possible lateralization of SIA impairment to the side of injury was confirmed by an experiment in which unilateral inhibition of the LC decreased SIA even in uninjured mice. The current view in the field of pain research attributes the process of pain chronification to abnormal functioning of descending pain inhibition. Our results demonstrate that the continuous activity of CRF neurons brought about by persistent pain leads to impaired SIA, which is a symptom of dysregulation of descending pain inhibition. Therefore, an over-activation of amygdala CRF neurons is very likely an important contributing factor for pain chronification. Copyright © 2017 Elsevier Inc. All rights reserved.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats.

PubMed

Blacktop, Jordan M; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A; Mantsch, John R

2016-03-01

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 s; range 10-70 s) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 μg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. Copyright © 2015 Elsevier Ltd. All rights reserved.

Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit Disorder

PubMed Central

2012-01-01

Alcoholism can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Alcoholism impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of specific neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreased dopamine and γ-aminobutyric acid function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from chronic alcohol, sufficient to produce dependence, increases reward thresholds, increases anxiety-like responses, decreases dopamine system function, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. Other components of brain stress systems in the extended amygdala that interact with CRF and that may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least partially, the compulsivity of alcoholism. PMID:21744309

Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse.

PubMed

Bruijnzeel, Adrie W; Prado, Melissa; Isaac, Shani

2009-07-15

Tobacco addiction is a chronic brain disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that blockade of corticotropin-releasing factor (CRF) receptors with a nonspecific CRF1/CRF2 receptor antagonist prevents the deficit in brain reward function associated with nicotine withdrawal and stress-induced reinstatement of extinguished nicotine-seeking in rats. The aim of these studies was to investigate the role of CRF1 and CRF2 receptors in the deficit in brain reward function associated with precipitated nicotine withdrawal and stress-induced reinstatement of nicotine-seeking. The intracranial self-stimulation (ICSS) procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. Stress-induced reinstatement of nicotine-seeking was investigated in animals in which responding for intravenously infused nicotine was extinguished by substituting saline for nicotine. In the ICSS experiments, the nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-dependent rats but not those of the control rats. The CRF1 receptor antagonist R278995/CRA0450 but not the CRF2 receptor antagonist astressin-2B prevented the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. Furthermore, R278995/CRA0450 but not astressin-2B prevented stress-induced reinstatement of extinguished nicotine-seeking. Neither R278995/CRA0450 nor astressin-2B affected operant responding for chocolate-flavored food pellets. These studies indicate that CRF(1) receptors but not CRF(2) receptors play an important role in the anhedonic-state associated with acute nicotine withdrawal and stress-induced reinstatement of nicotine-seeking.

Urocortins of the South African clawed frog, Xenopus laevis: conservation of structure and function in tetrapod evolution.

PubMed

Boorse, Graham C; Crespi, Erica J; Dautzenberg, Frank M; Denver, Robert J

2005-11-01

Several corticotropin-releasing factor (CRF) family genes have been identified in vertebrates. Mammals have four paralogous genes that encode CRF or the urocortins 1, 2, and 3. In teleost fishes, a CRF, urotensin I (a fish ortholog of mammalian urocortin 1) and urocortin 3 have been identified, suggesting that at least three of the four mammalian lineages arose in a common ancestor of modern bony fishes and tetrapods. Here we report the isolation of genes orthologous to mammalian urocortin 1 and urocortin 3 from the South African clawed frog, Xenopus laevis. We characterize the pharmacology of the frog peptides and show that X. laevis urocortin 1 binds to and activates the frog CRF1 and CRF2 receptors at picomolar concentrations. Similar to mammals, frog urocortin 3 is selective for the CRF2 receptor. Only frog urocortin 1 binds to the CRF-binding protein, although with significantly lower affinity than frog CRF. Both urocortin genes are expressed in brain, pituitary, heart, and kidney of juvenile frogs; urocortin 1 is also expressed in skin. We also identified novel urocortin sequences in the genomes of pufferfish, zebrafish, chicken, and dog. Phylogenetic analysis supports the view that four paralogous lineages of CRF-like peptides arose before the divergence of the actinopterygian and sarcopterygian fishes. Our findings show that the functional relationships among CRF ligands and binding proteins, and their anorexigenic actions mediated by the CRF2 receptor, arose early in vertebrate evolution.

Intracerebroventricular urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats

PubMed Central

Yeh, Chun; Ting, Ching-Heng; Doong, Ming-Luen; Chi, Chin-Wen; Lee, Shou-Dong; Chen, Chih-Yen

2016-01-01

Purpose Urocortin 3 is a key neuromodulator in the regulation of stress, anxiety, food intake, gut motility, and energy homeostasis, while ghrelin elicits feeding behavior and enhances gastric emptying, adiposity, and positive energy balance. However, the interplays between urocortin 3 and ghrelin on food intake and gastric emptying remain uninvestigated. Methods We examined the differential effects of central O-n-octanoylated ghrelin, des-Gln14-ghrelin, and urocortin 3 on food intake, as well as on charcoal nonnutrient semiliquid gastric emptying in conscious rats that were chronically implanted with intracerebroventricular (ICV) catheters. The functional importance of corticotropin-releasing factor (CRF) receptor 2 in urocortin 3-induced responses was examined by ICV injection of the selective CRF receptor 2 antagonist, astressin2-B. Results ICV infusion of urocortin 3 opposed central acyl ghrelin-elicited hyperphagia via CRF receptor 2 in satiated rats. ICV injection of O-n-octanoylated ghrelin and des-Gln14-ghrelin were equally potent in accelerating gastric emptying in fasted rats, whereas ICV administration of urocortin 3 delayed gastric emptying. In addition, ICV infusion of urocortin 3 counteracted central acyl ghrelin-induced gastroprokinetic effects via CRF receptor 2 pathway. Conclusion ICV-infused urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats. Our results clearly showed that enhancing ghrelin and blocking CRF receptor 2 signaling in the brain accelerated gastric emptying, which provided important clues for a new therapeutic avenue in ameliorating anorexia and gastric ileus found in various chronic wasting disorders. PMID:27757017

Central effects of corticotropin releasing factor (CRF): evidence for similar interactions with environmental novelty and with caffeine.

PubMed

Britton, D R; Indyk, E

1990-01-01

Centrally administered rat/human corticotropin-releasing factor (rCRF) increases low levels of locomotor activity by rats tested in a familiar environment but suppresses the higher levels of activity associated with exposure of the animals to a novel environment. These opposing responses do not appear to be manifestations of a simple rate-dependent effect, since ICV-administered rCRF did not lower the higher levels of locomotor activity associated with the dark (active) phase of the animal's activity cycle. Caffeine, which has anxiogenic effects in man, produces effects in rats which are similar to those of rCRF. That is, both compounds elevate activity in a familiar environment but lower activity in a novel environment. Furthermore, caffeine appears to substitute for novelty in determining the direction of the locomotor effect of rCRF. Animals made hyperactive by caffeine show decreased activity when co-administered rCRF. These findings are consistent with the view that CRF acts through pathways which also subserve the responsiveness to novelty and to the anxiogenic compound caffeine.

Erhuang Formula ameliorates renal damage in adenine-induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses.

PubMed

Zhang, Chun-Yan; Zhu, Jian-Yong; Ye, Ying; Zhang, Miao; Zhang, Li-Jun; Wang, Su-Juan; Song, Ya-Nan; Zhang, Hong

2017-11-01

The present study aimed to evaluate the protective effects of Erhuang Formula (EHF) and explore its pharmacological mechanisms on adenine-induced chronic renal failure (CRF). The compounds in EHF were analyzed by HPLC/MS. Adenine-induced CRF rats were administrated by EHF. The effects were evaluated by renal function examination and histology staining. Immunostaining of some proteins related cell adhesion was performedin renal tissues, including E-cadherin, β-catenin, fibronectin and laminin. The qRT-PCR was carried out determination of gene expression related inflammation and fibrosis including NF-κB, TNF-α, TGF-β1, α-SMA and osteopontin (OPN). Ten compounds in EHF were identified including liquiritigenin, farnesene, vaccarin, pachymic acid, cycloastragenol, astilbin, 3,5,6,7,8,3',4'-heptemthoxyflavone, physcion, emodin and curzerene. Abnormal renal function and histology had significant improvements by EHF treatment. The protein expression of β-catenin, fibronectin and laminin were significantly increased and the protein expression of E-cadherin significantly decreased in CRF groups. However, these protein expressions were restored to normal levels in EHF group. Furthermore, low expression of PPARγ and high expression of NF-κB, TNF-α, TGF-β1, α-SMA and OPN were substantially restored by EHF treatment in a dose-dependent manner. EHF ameliorated renal damage in adenine-induced CRF rats, and the mechanisms might involve in the inhibition of inflammatory and fibrotic responses and the regulation of PPARγ, NF-κB and TGF-β signaling pathways. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cardiorespiratory Fitness Is Associated With Cognitive Performance in Older But Not Younger Adults.

PubMed

Hayes, Scott M; Forman, Daniel E; Verfaellie, Mieke

2016-05-01

Aging is associated with declines in executive function and episodic memory. Cardiorespiratory fitness (CRF) has been associated with enhanced executive function in older adults (OA), but the relationship with episodic memory remains unclear. The purpose of the study was to examine the relationship between CRF and cognition in young and OA and whether CRF mitigates age-related cognitive decline. Participants completed exercise testing to evaluate CRF (peak VO2) and neuropsychological testing to assess cognition. In OA, peak VO2 was positively related to executive function, as well as to accuracy on an experimental face-name memory task and visual episodic memory. In young adults (YA), a relationship between peak VO2 and cognition was not evident. High-fit OA performed as well as YA on executive function measures. On episodic memory measures, YA performed better than high-fit OA, who in turn performed better than low-fit OA. CRF is positively associated with executive function and episodic memory in OA and attenuates age-related cognitive decline. We provide preliminary support for the age-dependence hypothesis, which posits that cognition and CRF relationships may be most readily observed during lifetime periods of significant neurocognitive development. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

Recovery of stress-impaired social behavior by an antagonist of the CRF binding protein, CRF6-33, in the bed nucleus of the stria terminalis of male rats.

PubMed

Vasconcelos, Mailton; Stein, Dirson J; Albrechet-Souza, Lucas; Miczek, Klaus A; de Almeida, Rosa Maria M

2018-01-09

Social stress is recognized to promote the development of neuropsychiatric and mood disorders. Corticotropin releasing factor (CRF) is an important neuropeptide activated by social stress, and it contributes to neural and behavioral adaptations, as indicated by impaired social interactions and anhedonic effects. Few studies have focused on the role of the CRF binding protein (CRFBP), a component of the CRF system, and its activity in the bed nucleus of stria terminalis (BNST), a limbic structure connecting amygdala and hypothalamus. In this study, animals' preference for sweet solutions was examined as an index of stress-induced anhedonic responses in Wistar rats subjected to four brief intermittent episodes of social defeat. Next, social approach was assessed after local infusions of the CRFBP antagonist, CRF fragment 6-33 (CRF 6-33 ) into the BNST. The experience of brief episodes of social defeat impaired social approach behaviors in male rats. However, intra-BNST CRF 6-33 infusions restored social approach in stressed animals to the levels of non-stressed rats. CRF 6-33 acted selectively on social interaction and did not alter general exploration in nether stressed nor non-stressed rats. These findings suggest that BNST CRFBP is involved in the modulation of anxiety-like responses induced by social stress. Copyright © 2018 Elsevier B.V. All rights reserved.

Role of CRF Receptor Signaling in Stress Vulnerability, Anxiety, and Depression

PubMed Central

Hauger, Richard L.; Risbrough, Victoria; Oakley, Robert H.; Olivares-Reyes, J. Alberto; Dautzenberg, Frank M.

2011-01-01

Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF-related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF1 receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF1 receptors become rapidly desensitized by G protein-coupled receptor kinase (GRK) and β-arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress-induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and β-arrestin binding can shift a G protein-coupled receptor (GPCR) to signal selectively via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) or Akt pathways independent of G proteins. Also, Epac-dependent CRF1 receptor signaling via the ERK-MAPK pathway has been found to potentiate brain-derived neurotrophic factor (BDNF)-stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and β-arrestin function may be involved in the pathophysiology of stress-induced anxiety and depression. PMID:19906236

Don't stress about CRF: assessing the translational failures of CRF1antagonists.

PubMed

Spierling, Samantha R; Zorrilla, Eric P

2017-05-01

Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. We explore potential causes for the failure of CRF 1 antagonists and review recent findings concerning CRF-CRF 1 systems in psychopathology. Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF 1 activation not homologous to tested patients, (5) repeated CRF 1 activation-induced plasticity that reduces the importance of ongoing CRF 1 agonist stimulation, and (6) therapeutic silencing which may need to address CRF 2 receptor or CRF-binding protein molecules, constitutive CRF 1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF 1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF 1 antagonists in food craving and CRF-driven HPA-axis overactivation. The therapeutic scope of selective CRF 1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF's role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

The Effect of Citalopram on Midbrain CRF Receptors 1 and 2 in a Primate Model of Stress-Induced Amenorrhea

PubMed Central

Senashova, Olga; Reddy, Arubala P.; Cameron, Judy L.; Bethea, Cynthia L.

2012-01-01

We have demonstrated marked differences in the neurobiology of the serotonin system between stress-sensitive (SS) and stress-resilient (SR) cynomolgus macaques characterized in a model of stress-induced amenorrhea, also called functional hypothalamic amenorrhea (FHA). Dysfunction of the serotonin system in SS monkeys suggested that administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA. This study examines the effect of escitalopram (CIT) administration to SS and SR monkeys on corticotrophin-releasing factor (CRF) receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2) gene expression in the serotonin cell body region of the midbrain dorsal raphe. CRF-R1 was not significantly different between groups. There was a significant effect of treatment and a significant interaction between treatment and stress sensitivity on the average CRF-R2-positive pixel area (P < .004 and P < .006, respectively) and on the average number of CRF-R2-positive cells (P < .023 and P < .025, respectively). CIT significantly increased CRF-R2-positive pixel area and cell number in the SS group (pixel area P < .001; cell number P < .01; Bonferoni) but not in the SR group. In summary, CIT administration tended to decrease CRF-R1, but the small animal number precluded significance. CIT administration significantly increased CRF-R2 only in SS animals. These data suggest that the administration of CIT reduces anxiogenic components and increases anxiolytic components of the CRF system in the midbrain serotonin network, which in turn leads to improved ovarian function. Moreover, these data raise the possibility that SSRIs may be effective in the treatment of stress-induced infertility. PMID:22412189

The effect of short moderate stress on the midbrain corticotropin-releasing factor system in a macaque model of functional hypothalamic amenorrhea.

PubMed

Bethea, Cynthia L; Phu, Kenny; Reddy, Arubala P; Cameron, Judy L

2013-10-01

To study the effect of moderate stress on corticotropin-releasing factor (CRF) components in the serotonergic midbrain region in a monkey model of functional hypothalamic amenorrhea. After characterization of stress sensitivity, monkeys were moved to a novel room and given 20% less chow for 5 days before euthanasia. Primate research center. Female cynomolgus macaques (Macaca fascicularis) characterized as highly stress resilient (HSR, n = 5), medium stress resilient (n = 4), or stress sensitive (SS, n = 4). Five days of diet in a novel room with unfamiliar conspecifics. Density of CRF axons in the serotonergic dorsal raphe nucleus; the number of urocortin 1 (UCN1) cells; the density of UCN1 axons; the expression of CRF receptor 1 (CRF-R1) and CRF-R2 in the dorsal raphe nucleus. The CRF innervation was higher in HSR than in SS animals; UCN1 cell number was higher in HSR than in SS animals and UCN1 axon bouton density was not different; all opposite of nonstressed animals. The CRF-R1 was not different between the sensitivity groups, but CRF-R2 was higher in HSR than in SS animals. The relative expression of CRF-R1 and CRF-R2 was similar to nonstressed animals. The HSR animals respond to stress with an increase in CRF delivery to serotonin neurons. With stress, UCN1 transport decreases in HSR animals. The CRF receptor expression was similar with or without stress. These changes may contribute to resilience in HSR animals. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III.

PubMed

Pelleymounter, Mary Ann; Joppa, Margaret; Ling, Nick; Foster, Alan C

2004-04-01

We compared the in vivo efficacy of two selective CRF2 agonists, mouse urocortin II (mUcn II) and human urocortin III (hUcn III), using food intake, anxious behavior, or ACTH release in CD-1 or Balb/c mice as indices of biological stress responses. All three peptides produced anorexia (Minimal Effective Dose (M.E.D.) for CRF and mUcn II = 0.03 nmol; M.E.D. for hUcn III = 0.3 nmol). Only mUcn II and CRF appeared to increase anxious behaviors in the elevated plus maze test (M.E.D. = 0.3 and 0.01 nmol, respectively). CRF increased the release of plasma ACTH (M.E.D. of 0.3 nmol), while mUcn II and hUcn III had no effect on ACTH release. These data suggest that the CRF2 receptor subtype plays a primary role in the activation of behavioral, but not neuroendocrine, stress responses. Copyright 2004 Elsevier Inc.

Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro.

PubMed

Nicholson, S A; Adrian, T E; Gillham, B; Jones, M T; Bloom, S R

1984-02-01

The effect of six hypothalamic peptides on the basal release of ACTH and that induced by arginine vasopressin (AVP) or by ovine corticotrophin releasing factor (oCRF) from fragments of the rat anterior pituitary gland incubated in vitro was investigated. Dose-response curves to AVP and to oCRF were obtained, and the response to a low dose of oCRF was potentiated by a low dose of AVP. Basal release of ACTH was not affected by any of the peptides in concentrations in the range 10(-12) to 10(-6) mol/l, and only substance P (SP) and somatostatin (SRIF) inhibited significantly the response to oCRF in a dose-related manner. The responses to a range of doses of oCRF or AVP were reduced by 10(-8) and 10(-6) mol SP or SRIF/l, and to a greater extent by the higher dose. Except in the case of 10(-6) mol SRIF/l on the response to AVP, the response was not further diminished by preincubation of the tissue with the peptide before the stimulating agent was added. The inhibition of the responses to AVP or oCRF by 10(-9) mol SP/l was not potentiated by its combination with either 5 X 10(-10) or 10(-8) mol SRIF/l; the inhibitory effects were merely additive. The results suggest that although SRIF and SP are able to modulate the release of ACTH from the anterior pituitary gland, they do so only at a high concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala.

PubMed

Amat, J; Tamblyn, J P; Paul, E D; Bland, S T; Amat, P; Foster, A C; Watkins, L R; Maier, S F

2004-01-01

The intra dorsal raphe nucleus (DRN) administration of corticotropin releasing hormone (CRF) inhibits serotonergic (5-HT) activity in this structure, an effect blocked by antagonists selective for the type 1 CRF receptor (CRF1). The DRN has a high density of the type 2 receptor (CRF2), and so the present experiments explored the impact of CRF2 activation within the DRN on 5-HT function. The intra-DRN administration of the selective CRF2 agonist urocortin 2 (Ucn 2) dose dependently increased 5-HT efflux in the basolateral amygdala, a projection region of the DRN. Intra-DRN Ucn 2 also increased c-fos expression in labeled 5-HT neurons. Both of these effects of Ucn 2 were completely blocked by intra-DRN antisauvagine-30 (ASV-30), a relatively selective CRF2 antagonist. These data suggest that CRF1 and CRF2 activation within the DRN affect 5-HT neurons in opponent fashion. Implications of these results for understanding the behavioral effects of CRF and other CRF-like ligands are discussed.

Hedonic Homeostatic Dysregulation as a Driver of Drug-Seeking Behavior

PubMed Central

Koob, George F.

2009-01-01

Drug addiction can be defined by a compulsion to seek and take drug and loss of control in limiting intake, and the excessive drug taking derives from multiple motivational mechanisms. One such mechanism is the emergence of a negative emotional state when access to the drug is prevented, reflecting hedonic homeostatic dysregulation. Excessive drug taking then results in part via the construct of negative reinforcement. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in reward and stress within basal forebrain structures, including the ventral striatum and extended amygdala. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreases in dopamine and opioid peptide function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Chronic exposure or extended access to self-administration of all major drugs of abuse produces during abstinence increases in reward thresholds, increases in aversive anxiety-like responses, increases in extracellular levels of CRF in the central nucleus of the amygdala, and increases in drug self-administration. CRF receptor antagonists block excessive drug intake produced by dependence. A combination of decreased reward system function and increased brain stress response system function is hypothesized to be responsible for hedonic homeostatic dysregulation that drives drug seeking behavior in dependence. Such hedonic dysregulation is hypothesized to extend into protracted abstinence to provide a residual negative emotional state that enhances the salience of cues eliciting drug seeking and relapse. PMID:20054425

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

PubMed Central

Taché, Yvette; Million, Mulugeta

2015-01-01

The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF1 and CRF2. CRF binds with high and moderate affinity to CRF1 and CRF2 receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF2 agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF1 pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF1/CRF2 antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF2 signaling in the colon dampened the CRF1 mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF1 system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF1 antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF1 antagonists. Whether the existing or newly developed CRF1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress. PMID:25611064

Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice.

PubMed

Toth, Mate; Gresack, Jodi E; Bangasser, Debra A; Plona, Zach; Valentino, Rita J; Flandreau, Elizabeth I; Mansuy, Isabelle M; Merlo-Pich, Emilio; Geyer, Mark A; Risbrough, Victoria B

2014-05-01

Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure.

Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm.

PubMed

Fernández Macedo, Georgina Valeria; Cladouchos, María Laura; Sifonios, Laura; Cassanelli, Pablo Martín; Wikinski, Silvia

2013-02-01

Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.

Childhood cardiorespiratory fitness, muscular fitness and adult measures of glucose homeostasis.

PubMed

Fraser, Brooklyn J; Blizzard, Leigh; Schmidt, Michael D; Juonala, Markus; Dwyer, Terence; Venn, Alison J; Magnussen, Costan G

2018-02-14

To assess whether childhood cardiorespiratory fitness (CRF) and muscular fitness phenotypes (strength, power, endurance) predict adult glucose homeostasis measures. Prospective longitudinal study. Study examining participants who had physical fitness measured in childhood (aged 7-15 years) and who attended follow-up clinics approximately 20 years later and provided a fasting blood sample which was tested for glucose and insulin. Physical fitness measurements included muscular strength (right and left grip, shoulder flexion, shoulder and leg extension), power (standing long jump distance) and endurance (number of push-ups in 30s), and CRF (1.6km run duration). In adulthood, fasting glucose and insulin levels were used to derive glucose homeostasis measures of insulin resistance (HOMA2-IR) and beta cell function (HOMA2-β). A standard deviation increase in childhood CRF or muscular strength (males) was associated with fasting glucose (CRF: β=-0.06mmol/L), fasting insulin (CRF: β=-0.73mU/L; strength: β=-0.40mU/L), HOMA2-IR (CRF: β=-0.06; strength: β=-0.05) and HOMA2-β (CRF: β=-3.06%; strength: β=-2.62%) in adulthood, independent of the alternative fitness phenotype (all p<0.01). Adjustment for childhood waist circumference reduced the effect by 17-35% for CRF and 0-15% for muscular strength (males) and statistical significance remained for all associations expect between CRF, fasting glucose and HOMA2-β (p>0.06). CRF and muscular fitness in childhood were inversely associated with measures of fasting insulin, insulin resistance and beta cell function in adulthood. Childhood CRF and muscular fitness could both be potential independent targets for strategies to help reduce the development of adverse glucose homeostasis. Copyright © 2018 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment.

PubMed

Edwards, Thomas; Motl, Robert W; Pilutti, Lara A

2018-01-01

Exercise training is one strategy for improving cardiorespiratory fitness (CRF) in multiple sclerosis (MS); however, few modalities are accessible for those with severe mobility impairment. Functional electrical stimulation (FES) cycling is an adapted exercise modality with the potential for improving CRF in people with severe MS. The objective of this study was to characterize the cardiorespiratory response of acute voluntary cycling with FES in people with MS with severe mobility impairment, and to compare this response to passive leg cycling. Eleven participants with MS that required assistance for ambulation completed a single bout of voluntary cycling with FES or passive leg cycling. Oxygen consumption, heart rate (HR), work rate (WR), and ratings of perceived exertion (RPE) were recorded throughout the session. For the FES group, mean exercising oxygen consumption was 8.7 ± 1.8 mL/(kg·min) -1 , or 63.5% of peak oxygen consumption. Mean HR was 102 ± 9.7 bpm, approximately 76.4% of peak HR. Mean WR was 27.0 ± 9.2 W, or 57.3% of peak WR, and median RPE was 13.5 (interquartile range = 5.5). Active cycling with FES was significantly (p < 0.05) more intense than passive leg cycling based on oxygen consumption, HR, WR, and RPE during exercise. In conclusion, voluntary cycling with FES elicited an acute response that corresponded with moderate-to vigorous-intensity activity, suggesting that active cycling with FES can elicit a sufficient stimulus for improving CRF.

Persistent Adaptation by Chronic Alcohol is Facilitated by Neuroimmune Activation Linked to Stress and CRF

PubMed Central

Breese, George R.; Knapp, Darin J.

2016-01-01

This review updates the conceptual basis for the association of alcohol abuse with an insidious adaptation that facilitates negative affect during withdrawal from chronic intermittent alcohol (CIA) exposure – a change that later supports sensitization of stress-induced anxiety following alcohol abstinence. The finding that a CRF1-receptor antagonist (CRF1RA) minimized CIA withdrawal-induced negative affect supported an association of alcohol withdrawal with a stress mechanism. The finding that repeated stresses or multiple CRF injections into selected brain sites prior to a single 5-day chronic alcohol (CA) exposure induced anxiety during withdrawal provided critical support for a linkage of CIA withdrawal with stress. The determination that CRF1RA injection into positive CRF-sensitive brain sites prevented CIA withdrawal-induced anxiety provided support that neural path integration maintains the persistent CIA adaptation. Based upon reports that stress increases neuroimmune function, an effort was undertaken to test whether cytokines would support the adaptation induced by stress/CA exposure. Twenty-four hours after withdrawal from CIA, cytokine mRNAs were found to be increased in cortex as well as other sites in brain. Further, repeated cytokine injections into previously identified brain sites substituted for stress and CRF induction of anxiety during CA withdrawal. Discovery that a CRF1RA prevented the brain cytokine mRNA increase induced by CA withdrawal provided critical evidence for CRF involvement in this neuroimmune induction after CA withdrawal. However, the CRF1RA did not block the stress increase in cytokine mRNA increases in controls. The latter data supported the hypothesis that distinct mechanisms linked to stress and CA withdrawal can support common neuroimmune functions within a brain site. As evidence evolves concerning neural involvement in brain neuroimmune function, a better understanding of the progressive adaptation associated with CIA exposure will advance new knowledge that could possibly lead to strategies to combat alcohol abuse. PMID:27139233

Corticotropin releasing factor: a key role in the neurobiology of addiction.

PubMed

Zorrilla, Eric P; Logrip, Marian L; Koob, George F

2014-04-01

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body's response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction. The results support the hypothesis that brain CRF-CRF1 systems contribute to the etiology and maintenance of addiction. Copyright © 2014 Elsevier Inc. All rights reserved.

Corticotropin Releasing Factor: A Key Role in the Neurobiology of Addiction

PubMed Central

Zorrilla, Eric P.; Logrip, Marian L.; Koob, George F.

2014-01-01

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body’s response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction.. The results support the hypothesis that brain CRF-CRF1 systems contribute to the etiology and maintenance of addiction. PMID:24456850

Corticotropin-releasing factor overexpression in mice abrogates sex differences in body weight, visceral fat, and food intake response to a fast and alters levels of feeding regulatory hormones.

PubMed

Wang, Lixin; Goebel-Stengel, Miriam; Yuan, Pu-Qing; Stengel, Andreas; Taché, Yvette

2017-01-01

Corticotropin-releasing factor overexpressing (CRF-OE) male mice showed an inhibited feeding response to a fast, and lower plasma acyl ghrelin and Fos expression in the arcuate nucleus compared to wild-type (WT) mice. We investigated whether hormones and hypothalamic feeding signals are impaired in CRF-OE mice and the influence of sex. Male and female CRF-OE mice and WT littermates (4-6 months old) fed ad libitum or overnight fasted were assessed for body, adrenal glands and perigonadal fat weights, food intake, plasma hormones, blood glucose, and mRNA hypothalamic signals. Under fed conditions, compared to WT, CRF-OE mice have increased adrenal glands and perigonadal fat weight, plasma corticosterone, leptin and insulin, and hypothalamic leptin receptor and decreased plasma acyl ghrelin. Compared to male, female WT mice have lower body and perigonadal fat and plasma leptin but higher adrenal glands weights. CRF-OE mice lost these sex differences except for the adrenals. Male CRF-OE and WT mice did not differ in hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), while female CRF-OE compared to female WT and male CRF-OE had higher NPY mRNA levels. After fasting, female WT mice lost more body weight and ate more food than male WT, while CRF-OE mice had reduced body weight loss and inhibited food intake without sex difference. In male WT mice, fasting reduced plasma insulin and leptin and increased acyl ghrelin and corticosterone while female WT showed only a rise in corticosterone. In CRF-OE mice, fasting reduced insulin while leptin, acyl ghrelin and corticosterone were unchanged with no sex difference. Fasting blood glucose was higher in CRF-OE with female > male. In WT mice, fasting increased hypothalamic NPY expression in both sexes and decreased POMC only in males, while in CRF-OE mice, NPY did not change, and POMC decreased in males and increased in females. These data indicate that CRF-OE mice have abnormal basal and fasting circulating hormones and hypothalamic feeding-related signals. CRF-OE also abolishes the sex difference in body weight, abdominal fat, and fasting-induced feeding and changes in plasma levels of leptin and acyl ghrelin.

Review. Neurobiological mechanisms for opponent motivational processes in addiction.

PubMed

Koob, George F; Le Moal, Michel

2008-10-12

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

PubMed Central

Van'T Veer, Ashlee; Yano, Jessica M; Carroll, F Ivy; Cohen, Bruce M; Carlezon, William A

2012-01-01

Stress often disrupts behavior and can lead to psychiatric illness. Considerable evidence suggests that corticotropin-releasing factor (CRF) plays an important role in regulating the effects of stress. CRF administration produces stress-like effects in humans and laboratory animals, and CRF levels are elevated in individuals with stress-related illness. Recent work indicates that κ-opioid receptor (KOR) antagonists can block CRF effects, raising the possibility that at least some of the effects of stress are mediated via KORs. Here we examined the effects of CRF on performance in the 5-choice serial reaction time task (5CSRTT), a test used to quantify attention in rodents, as well as functional interactions between CRF and KORs. Male Sprague-Dawley rats were trained in the 5CSRTT and then each was implanted with an intracerebroventricular (ICV) cannula. After recovery and restabilization of performance, they received a single intraperitoneal (IP) injection of vehicle or JDTic (10 mg/kg), a KOR antagonist with long-lasting (>14 days) effects. In subsequent sessions, rats received ICV infusions of CRF (0.25–1.0 μg) or vehicle and were tested 60 min later. CRF dose-dependently disrupted performance as reflected by decreases in correct responding, increases in omission errors, increases in latencies to respond correctly, and increases in time to complete the session. JDTic attenuated each of these CRF-induced deficits while having no effects on its own. The persistent ability of JDTic to disrupt KOR function was confirmed using the tail immersion assay. These findings indicate that KOR antagonists can prevent acute stress-related effects that degrade performance in tasks requiring attention. PMID:22948977

Fitness and adiposity as predictors of functional limitation in adults.

PubMed

Maslow, Andréa L; Price, Anna E; Sui, Xuemei; Lee, Duck-chul; Vuori, Ikka; Blair, Steven N

2011-01-01

This study examined the associations of body mass index (BMI), waist circumference (WC), and cardiorespiratory fitness (CRF) with incident functional limitation (IFL) in adults. Patients (n = 2400), 30+ years [mean age, 45.2 (SD, 8.3); 12% women], completed a baseline health examination during 1979 to 1995. CRF was quantified by age-and sex-specific thirds for maximal treadmill exercise test duration. Adiposity was assessed by BMI and WC (grouped for analysis according to clinical guidelines). Incident IFL was identified from mail-back surveys during 1995, 1999, and 2004. After adjusting for potential confounders and either BMI or WC, CRF was inversely related to IFL (P trend < .001). The association between BMI and IFL was significant after adjusting for all confounders (P trend = .002), but not after additional adjustment for CRF (P trend = .23). After controlling for all confounders and CRF, high WC was associated with greater odds of IFL in those aged 30 to 49; normal WC was associated with greater odds of IFL in those aged 50+. CRF was a significant predictor of IFL in middle aged and older adults, independent of overall or abdominal adiposity. Clinicians should consider the importance of preserving functional capacity by recommending regular physical activity for normal-weight and overweight individuals. ©2011 Human Kinetics, Inc.

Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats.

PubMed

Rorato, Rodrigo; Menezes, Aline Motta; Giusti-Paiva, Alexandre; de Castro, Margaret; Antunes-Rodrigues, José; Elias, Lucila Leico Kagohara

2009-03-01

Corticotrophin-releasing factor (CRF) and alpha-melanocyte-stimulating hormone (alpha-MSH), both of which are synthesized by hypothalamic neurons, play an essential role in the control of energy homeostasis. Neuroendocrine and behavioural responses induced by lipopolyssacharide (LPS) have been shown to involve prostaglandin-mediated pathways. This study investigated the effects of prostaglandin on CRF and alpha-MSH neuronal activities in LPS-induced anorexia. Male Wistar rats were pretreated with indomethacin (10 mg kg(-1); i.p.) or vehicle; 15 min later they received LPS (500 microg kg(-1); i.p.) or saline injection. Food intake, hormone responses and Fos-CRF and Fos-alpha-MSH immunoreactivity in the paraventricular and arcuate nuclei, respectively, were evaluated. In comparison with saline treatment, LPS administration induced lower food intake and increased plasma ACTH and corticosterone levels, as well as an increase in Fos-CRF and Fos-alpha-MSH double-labelled neurons in vehicle-pretreated rats. In contrast, indomethacin treatment partly reversed the hypophagic effect, blunted the hormonal increase and blocked the Fos-CRF and Fos-alpha-MSH hypothalamic double labelling increase in response to the LPS stimulus. These data demonstrate that the activation of pro-opiomelanocortin and CRF hypothalamic neurons following LPS administration is at least partly mediated by the prostaglandin pathway and is likely to be involved in the modulation of feeding behaviour during endotoxaemia.

Improved contour detection model with spatial summation properties based on nonclassical receptive field

NASA Astrophysics Data System (ADS)

Lin, Chuan; Xu, Guili; Cao, Yijun; Liang, Chenghua; Li, Ya

2016-07-01

The responses of cortical neurons to a stimulus in a classical receptive field (CRF) can be modulated by stimulating the non-CRF (nCRF) of neurons in the primary visual cortex (V1). In the very early stages (at around 40 ms), a neuron in V1 exhibits strong responses to a small set of stimuli. Later, however (after 100 ms), the neurons in V1 become sensitive to the scene's global organization. As per these visual cortical mechanisms, a contour detection model based on the spatial summation properties is proposed. Unlike in previous studies, the responses of the nCRF to the higher visual cortex that results in the inhibition of the neuronal responses in the primary visual cortex by the feedback pathway are considered. In this model, the individual neurons in V1 receive global information from the higher visual cortex to participate in the inhibition process. Computationally, global Gabor energy features are involved, leading to the more coherent physiological characteristics of the nCRF. We conducted an experiment where we compared our model with those proposed by other researchers. Our model explains the role of the mutual inhibition of neurons in V1, together with an approach for object recognition in machine vision.

Co-localization of corticotropin-releasing factor and vesicular glutamate transporters within axon terminals of the rat dorsal raphe nucleus.

PubMed

Waselus, Maria; Van Bockstaele, Elisabeth J

2007-10-12

Electrophysiological, microdialysis and behavioral studies support a modulatory role for corticotropin-releasing factor (CRF) in regulating the dorsal raphe nucleus (DRN)-serotonin (5-HT) system. CRF and 5-HT are implicated in the pathophysiology of depression, thus neuroanatomical substrates of CRF-DRN-5-HT interactions are of interest. Identification of co-transmitters within DRN CRF axon terminals is important for elucidating the complex effects underlying CRF afferent regulation of DRN neurons. This study investigated whether CRF-labeled axon terminals within the DRN contain immunoreactivity for vesicular glutamate transporters (isoforms vGlut1 and vGlut2) indicative of the excitatory neurotransmitter glutamate. Dual immunohistochemistry for CRF and either vGlut1 or vGlut2 was conducted within the same tissue section and immunofluorescence results indicated patterns of immunoreactivity consistent with previous reports. Abundant vGlut1- and vGlut2-immunoreactivity was found in puncta exhibiting a largely uniform distribution, whereas CRF-immunoreactivity was localized to topographically distributed varicose processes within the DRN. Profiles containing both CRF- and either vGlut1- or vGlut2-immunoreactivity were apparent in the DRN. Electron microscopy confirmed that immunoreactivity for CRF and vGlut1 was localized primarily to separate axon terminals in the DRN, with a subset co-localizing CRF and vGlut1. Examination of CRF and vGlut2 immunoreactivities in the DRN indicated that CRF and vGlut2 were found within the same axon terminal more frequently than CRF and vGlut1. Overall, these anatomical findings suggest that CRF may function, in part, with the excitatory neurotransmitter glutamate in the modulation of neuronal activity in the DRN.

Disruption of the CRF(2) receptor pathway decreases the somatic expression of opiate withdrawal.

PubMed

Papaleo, Francesco; Ghozland, Sandy; Ingallinesi, Manuela; Roberts, Amanda J; Koob, George F; Contarino, Angelo

2008-11-01

Escape from the extremely aversive opiate withdrawal symptoms powerfully motivates compulsive drug-seeking and drug-taking behaviors. The corticotropin-releasing factor (CRF) system is hypothesized to mediate the motivational properties of drug dependence. CRF signaling is transmitted by two receptor pathways, termed CRF(1) and CRF(2). To investigate the role for the CRF(2) receptor pathway in somatic opiate withdrawal, in the present study we used genetically engineered mice deficient in the CRF(2) receptor (CRF(2)-/-). We employed a novel, clinically relevant mouse model of 'spontaneous' opiate withdrawal as well as a classical opioid receptor antagonist (naloxone)-precipitated opiate withdrawal paradigm. To induce opiate dependence, mice were treated with intermittent escalating morphine doses (20-100 mg/kg, i.p.). We found that 8-128 h after the last opiate injection, CRF(2)-/- mice showed decreased levels of major somatic signs of spontaneous opiate withdrawal, such as paw tremor and wet dog shake, as compared to wild-type mice. Similarly, challenge with naloxone 2 h after the last morphine injection induced lower levels of paw tremor and wet dog shake in CRF(2)-/- mice as compared to wild-type mice. Despite the differences in somatic signs, wild-type and CRF(2)-/- mice displayed similar plasma corticosterone responses to opiate dosing and withdrawal, indicating a marginal role for the hypothalamus-pituitary-adrenal axis in the CRF(2) receptor mediation of opiate withdrawal. Our results unravel a novel role for the CRF(2) receptor pathway in opiate withdrawal. The CRF(2) receptor pathway might be a critical target of therapies aimed at alleviating opiate withdrawal symptoms and reducing relapse to drug intake.

Disruption of the CRF2 Receptor Pathway Decreases the Somatic Expression of Opiate Withdrawal

PubMed Central

Papaleo, Francesco; Ghozland, Sandy; Ingallinesi, Manuela; Roberts, Amanda J; Koob, George F; Contarino, Angelo

2009-01-01

Escape from the extremely aversive opiate withdrawal symptoms powerfully motivates compulsive drug-seeking and drug-taking behaviors. The corticotropin-releasing factor (CRF) system is hypothesized to mediate the motivational properties of drug dependence. CRF signaling is transmitted by two receptor pathways, termed CRF1 and CRF2. To investigate the role for the CRF2 receptor pathway in somatic opiate withdrawal, in the present study we used genetically engineered mice deficient in the CRF2 receptor (CRF2−/−). We employed a novel, clinically relevant mouse model of ‘spontaneous’ opiate withdrawal as well as a classical opioid receptor antagonist (naloxone)-precipitated opiate withdrawal paradigm. To induce opiate dependence, mice were treated with intermittent escalating morphine doses (20–100 mg/kg, i.p.). We found that 8–128 h after the last opiate injection, CRF2−/− mice showed decreased levels of major somatic signs of spontaneous opiate withdrawal, such as paw tremor and wet dog shake, as compared to wild-type mice. Similarly, challenge with naloxone 2 h after the last morphine injection induced lower levels of paw tremor and wet dog shake in CRF2−/− mice as compared to wild-type mice. Despite the differences in somatic signs, wild-type and CRF2−/− mice displayed similar plasma corticosterone responses to opiate dosing and withdrawal, indicating a marginal role for the hypothalamus–pituitary–adrenal axis in the CRF2 receptor mediation of opiate withdrawal. Our results unravel a novel role for the CRF2 receptor pathway in opiate withdrawal. The CRF2 receptor pathway might be a critical target of therapies aimed at alleviating opiate withdrawal symptoms and reducing relapse to drug intake. PMID:18288089

Cytokine involvement in stress may depend on corticotrophin releasing factor to sensitize ethanol withdrawal anxiety

PubMed Central

Knapp, Darin J.; Whitman, Buddy A.; Wills, Tiffany A.; Angel, Robert A.; Overstreet, David H.; Criswell, Hugh E.; Ming, Zhen; Breese, George R.

2011-01-01

Stress has been shown to facilitate ethanol withdrawal-induced anxiety. Defining neurobiological mechanisms through which stress has such actions is important given the associated risk of relapse. While CRF has long been implicated in the action of stress, current results show that stress elevates the cytokine TNFα in the rat brain and thereby implicates cytokines in stress effects. In support of this view, prior TNFα microinjection into the central amygdala (CeA) of rats facilitated ethanol withdrawal-induced anxiety—a response that could not be attributed to an increase in plasma corticosterone. To test for a possible interaction between cytokines and CRF, a CRF1-receptor antagonist (SSR125543) administered prior to the repeated administration of TNFα or MCP-1/CCL2 reduced the magnitude of the withdrawal-induced anxiety. This finding provided evidence for cytokine action being dependent upon CRF. Additionally, the sensitizing effect of stress on withdrawal-induced anxiety was reduced by treating the repeated stress exposure prior to ethanol with the MEK inhibitor SL327. Consistent with cytokines having a neuromediator function distinct from a neuroimmune action, TNFα increased firing rate and GABA release from CeA neurons. Thus, an interaction of glial and neuronal function is proposed to contribute to the interaction of stress and chronic ethanol. Interrupting this potential glial-neuronal interaction could provide a novel means by which to alter the development of emotional states induced by stress that predict relapse in the alcoholic. PMID:21377524

The CRF system and social behavior: a review

PubMed Central

Hostetler, Caroline M.; Ryabinin, Andrey E.

2013-01-01

The corticotropin-releasing factor (CRF) system plays a key role in a diversity of behaviors accompanying stress, anxiety and depression. There is also substantial research on relationships between social behaviors and the CRF system in a variety of taxa including fish, birds, rodents, and primates. Some of these relationships are due to the broad role of CRF and urocortins in stress and anxiety, but these peptides also modulate social behavior specifically. For example, the social interaction (SI) test is often used to measure anxiety-like behavior. Many components of the CRF system including CRF, urocortin1, and the R1 receptor have been implicated in SI, via general effects on anxiety as well as specific effects depending on the brain region. The CRF system is also highly responsive to chronic social stressors such as social defeat and isolation. Animals exposed to these stressors display a number of anxiety- and stress-related behaviors, accompanied by changes in specific components the CRF system. Although the primary focus of CRF research on social behavior has been on the deleterious effects of social stress, there are also insights on a role for CRF and urocortins in prosocial and affiliative behaviors. The CRF system has been implicated in parental care, maternal defense, sexual behavior, and pair bonding. Species differences in the ligands and CRF receptors have been observed in vole and bird species differing in social behavior. Exogenous administration of CRF facilitates partner preference formation in monogamous male prairie voles, and these effects are dependent on both the CRF R1 and R2 receptors. These findings are particularly interesting as studies have also implicated the CRF and urocortins in social memory. With the rapid progress of social neuroscience and in understanding the complex structure of the CRF system, the next challenge is in parsing the exact contribution of individual components of this system to specific social behaviors. PMID:23754975

The CRF system and social behavior: a review.

PubMed

Hostetler, Caroline M; Ryabinin, Andrey E

2013-01-01

The corticotropin-releasing factor (CRF) system plays a key role in a diversity of behaviors accompanying stress, anxiety and depression. There is also substantial research on relationships between social behaviors and the CRF system in a variety of taxa including fish, birds, rodents, and primates. Some of these relationships are due to the broad role of CRF and urocortins in stress and anxiety, but these peptides also modulate social behavior specifically. For example, the social interaction (SI) test is often used to measure anxiety-like behavior. Many components of the CRF system including CRF, urocortin1, and the R1 receptor have been implicated in SI, via general effects on anxiety as well as specific effects depending on the brain region. The CRF system is also highly responsive to chronic social stressors such as social defeat and isolation. Animals exposed to these stressors display a number of anxiety- and stress-related behaviors, accompanied by changes in specific components the CRF system. Although the primary focus of CRF research on social behavior has been on the deleterious effects of social stress, there are also insights on a role for CRF and urocortins in prosocial and affiliative behaviors. The CRF system has been implicated in parental care, maternal defense, sexual behavior, and pair bonding. Species differences in the ligands and CRF receptors have been observed in vole and bird species differing in social behavior. Exogenous administration of CRF facilitates partner preference formation in monogamous male prairie voles, and these effects are dependent on both the CRF R1 and R2 receptors. These findings are particularly interesting as studies have also implicated the CRF and urocortins in social memory. With the rapid progress of social neuroscience and in understanding the complex structure of the CRF system, the next challenge is in parsing the exact contribution of individual components of this system to specific social behaviors.

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate

PubMed Central

Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

2017-01-01

The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning. PMID:28220796

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

PubMed

Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

2017-07-01

The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

Addiction is a Reward Deficit and Stress Surfeit Disorder

PubMed Central

Koob, George F.

2013-01-01

Drug addiction can be defined by a three-stage cycle – binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation – that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain reward and stress systems. Specific neurochemical elements in these structures include not only decreases in reward system function (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF) and dynorphin-κ opioid systems in the ventral striatum, extended amygdala, and frontal cortex (both between-system opponent processes). CRF antagonists block anxiety-like responses associated with withdrawal, block increases in reward thresholds produced by withdrawal from drugs of abuse, and block compulsive-like drug taking during extended access. Excessive drug taking also engages the activation of CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding. Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for ethanol similar to a CRF1 antagonist. Blockade of the κ opioid system can also block dysphoric-like effects associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress system that contributes to compulsive drug seeking. The loss of reward function and recruitment of brain systems provide a powerful neurochemical basis that drives the compulsivity of addiction. PMID:23914176

Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling.

PubMed

Bangasser, D A; Dong, H; Carroll, J; Plona, Z; Ding, H; Rodriguez, L; McKennan, C; Csernansky, J G; Seeholzer, S H; Valentino, R J

2017-08-01

Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF 1 receptor (CRF 1 ) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF 1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles. Cortical phosphopeptides that distinguished female and male CRF-OE mice were overrepresented in unique pathways that were consistent with Gs-dependent signaling in females and β-arrestin-2 signaling in males. Notably, phosphopeptides that were more abundant in female CRF-OE mice were overrepresented in an Alzheimer's disease (AD) pathway. Phosphoproteomic results were validated by demonstrating that CRF overexpression in females was associated with increased tau phosphorylation and, in a mouse model of AD pathology, phosphorylation of β-secretase, the enzyme involved in the formation of amyloid β. These females exhibited increased formation of amyloid β plaques and cognitive impairments relative to males. Collectively, the findings are consistent with a mechanism whereby the excess CRF that characterizes stress-related diseases initiates distinct cellular processes in male and female brains, as a result of sex-biased CRF 1 signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.

Association between Cardiorespiratory Fitness and Health-Related Quality of Life among Patients at Risk for Cardiovascular Disease in Uruguay.

PubMed

Clennin, Morgan N; Payne, Jonathan P W; Rienzi, Edgardo G; Lavie, Carl J; Blair, Steven N; Pate, Russell R; Sui, Xuemei

2015-01-01

To examine the association between objectively measured CRF and physical and mental components of HRQoL in a Uruguayan cohort at risk for developing CVD. Patient data records from 2002-2012 at the Calidad de Vida Center were examined. To assess CRF, participants performed a submaximal exercise test. During the evaluation, participants also completed the SF-36, a HRQoL measure comprised of eight dimensions that are summarized by physical and mental component scores (PCS and MCS, respectively). ANCOVA was used to examine the relationship between HRQoL dimensions and CRF. Logistic regression was then used to compare the odds of having a HRQoL component score above the norm across CRF. All analyses were performed separately for males and females with additional stratified analyses across age and BMI conducted among significant trends. A total of 2,302 subjects were included in the analysis. Among females, a significant relationship was observed between CRF and vitality, physical functioning, physical role, bodily pain, and general health dimensions. However, for males the only dimension found to be significantly associated with CRF was physical health. After adjusting for potential confounders, a significant linear trend (p<0.001) for PCS scores above the norm across CRF levels was observed for females only. Among females with one or more risk factors for developing CVD, higher levels of CRF were positively associated with the vitality and physical dimensions of HRQoL, as well as the overall PCS. However, among males the only dimension associated with CRF was physical functioning. Future studies should examine this relationship among populations at risk for developing CVD in more detail and over time.

Serum Lipoprotein (a) Levels in Chronic Renal Failure and Liver Cirrhosis Patients. Relationship with Atherosclerosis

PubMed Central

Mady, Essam; Wissa, Gehane; Khalifa, Ali; El-Sabbagh, Mahmoud

1999-01-01

This study was carried out to investigate the relationship between lipoprotein (a) levels and the development of atherosclerosis in chronic renal failure (CRF) patients with the possible role of the liver. Serum Lp (a) levels were measured in samples from 20 CRF patients on hemodialysis (HD), 20 liver cirrhosis (LC) patients, 20 patients having both CRF and LC and undergoing HD, and 20 normal control subjects. Renal function (blood urea nitrogen (BUN) and creatinine), hepatic function (transaminases (ALT and AST), alkaline phosphatase (ALP) and total bilirubin) investigations and serum cholesterol were carried out for all the subjects enrolled in this study. Serum Lp (a) concentration in CRF patients without LC was 87.25 ± 6.17 mg/dl, which was significantly higher than all the investigated groups (P < 0.001). Lp(a) concentration in patients with both CRF and LC was 24.65 ± 1.98 mg/dl, which was not significantly different from the controls, but was significantly higher than that in the subjects with LC only (P < 0.001) where the latter group had significantly low Lp (a) values (11.1 ± 0.99) relative to all the other groups (P < 0.001). Lp (a) correlated positively with cholesterol in all groups except the LC subjects, but did not correlate with age, or renal function in both CRF groups. PMID:10689547

Corticotropin-releasing factor peptide antagonists: design, characterization and potential clinical relevance.

PubMed

Rivier, Jean E; Rivier, Catherine L

2014-04-01

Elusive for more than half a century, corticotropin-releasing factor (CRF) was finally isolated and characterized in 1981 from ovine hypothalami and shortly thereafter, from rat brains. Thirty years later, much has been learned about the function and localization of CRF and related family members (Urocortins 1, 2 and 3) and their 2 receptors, CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2). Here, we report the stepwise development of peptide CRF agonists and antagonists, which led to the CRFR1 agonist Stressin1; the long-acting antagonists Astressin2-B which is specific for CRFR2; and Astressin B, which binds to both CRFR1 and CRFR2.This analog has potential for the treatment of CRF-dependent diseases in the periphery, such as irritable bowel syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.

Increased CRF mRNA expression in the sexually dimorphic BNST of male but not female GAD67 mice and TMT predator odor stress effects upon spatial memory retrieval.

PubMed

Janitzky, K; Peine, A; Kröber, A; Yanagawa, Y; Schwegler, H; Roskoden, T

2014-10-01

The bed nucleus of the stria terminalis (BNST) is an important region for 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) predator odor-induced stress responses in mice. It is sexually dimorphic and a region for corticotropin-releasing factor (CRF)-enhanced stress responses. Dense GABAergic and CRF input from the amygdala to the BNST gives point to relevant interactions between CRF and GABA activity in these brain regions. Hence, to investigate sexual dimorphism of stress-induced neuronal changes, we studied effects of acute TMT exposure on CRF mRNA expression in stress-related brain regions in male and female GAD67 mice and their wild-type littermates. In GAD67 mice, heterozygous knock-in of GFP in GABAergic neurons caused a 50% decrease of GAD67 protein level in the brain [91,99]. Results show higher CRF mRNA levels in the BNST of male but not female GAD67 mice after TMT and control odor exposure. While CRF neurons in the BNST are predominantly GABAergic and CRF enhances GABAergic transmission in the BNST [20,51], the deficit in GABAergic transmission in GAD67 mice could induce a compensatory CRF increase. Sexual dimorphism of the BNST with greater density of GABA-ir neurons in females could explain the differences in CRF mRNA levels between male and female GAD67 mice. Effects of odor exposure were studied in a radial arm maze (RAM) task. Results show impaired retrieval of spatial memory after acute TMT exposure in both sexes and genotypes. However, only GAD67 mice show increased working memory errors after control odor exposure. Our work elicits GAD67 mice as a model to further study interactions of GABA and CRF in the BNST for a better understanding of how sex-specific characteristics of the brain may contribute to differences in anxiety- and stress-related psychological disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists.

PubMed

Rivier, J; Gulyas, J; Kirby, D; Low, W; Perrin, M H; Kunitake, K; DiGruccio, M; Vaughan, J; Reubi, J C; Waser, B; Koerber, S C; Martinez, V; Wang, L; Taché, Y; Vale, W

2002-10-10

We present evidence that members of the corticotropin releasing factor (CRF) family assume distinct structures when interacting with the CRF(1) and CRF(2) receptors. Predictive methods, physicochemical measurements, and structure-activity relationship studies have suggested that CRF, its family members, and competitive antagonists such as astressin [cyclo(30-33)[DPhe(12),Nle(21),Glu(30),Lys(33),Nle(38)]hCRF((12-41))] assume an alpha-helical conformation when interacting with their receptors. We had shown that alpha-helical CRF((9-41)) and sauvagine showed some selectivity for CRF receptors other than that responsible for ACTH secretion(1) and later for CRF2.(2) More recently, we suggested the possibility of a helix-turn-helix motif around a turn encompassing residues 30-33(3) that would confer high affinity for both CRF(1) and CRF(2)(2,4) in agonists and antagonists of all members of the CRF family.(3) On the other hand, the substitutions that conferred ca. 100-fold CRF(2) selectivity to the antagonist antisauvagine-30 [[DPhe(11),His(12)]sauvagine((11-40))] did not confer such property to the corresponding N-terminally extended agonists. We find here that a Glu(32)-Lys(35) side chain to side chain covalent lactam constraint in hCRF and the corresponding Glu(31)-Lys(34) side chain to side chain covalent lactam constraint in sauvagine yield potent ligands that are selective for CRF(2). Additionally, we introduced deletions and substitutions known to increase duration of action to yield antagonists such as cyclo(31-34)[DPhe(11),His(12),C(alpha)MeLeu(13,39),Nle(17),Glu(31),Lys(34)]Ac-sauvagine((8-40)) (astressin(2)-B) with CRF(2) selectivities greater than 100-fold. CRF receptor autoradiography was performed in rat tissue known to express CRF(2) and CRF(1) in order to confirm that astressin(2)-B could indeed bind to established CRF(2) but not CRF(1) receptor-expressing tissues. Extended duration of action of astressin(2)-B vs that of antisauvagine-30 is demonstrated in the CRF(2)-mediated animal model whereby the inhibition of gastric emptying of a solid meal in mice by urocortin administered intraperitoneally at time zero is antagonized by the administration of astressin(2)-B but not by antisauvagine-30 at times -3 and -6 h while both peptides are effective when given 10 min before urocortin.

Association between Cardiorespiratory Fitness and Health-Related Quality of Life among Patients at Risk for Cardiovascular Disease in Uruguay

PubMed Central

Payne, Jonathan P. W.; Rienzi, Edgardo G.; Lavie, Carl J.; Blair, Steven N.; Pate, Russell R.

2015-01-01

To date, few studies have examined the relationship between cardiorespiratory fitness (CRF) and health-related quality of life (HRQoL) in populations at high risk for developing cardiovascular disease (CVD). Purpose To examine the association between objectively measured CRF and physical and mental components of HRQoL in a Uruguayan cohort at risk for developing CVD. Methods Patient data records from 2002–2012 at the Calidad de Vida Center were examined. To assess CRF, participants performed a submaximal exercise test. During the evaluation, participants also completed the SF-36, a HRQoL measure comprised of eight dimensions that are summarized by physical and mental component scores (PCS and MCS, respectively). ANCOVA was used to examine the relationship between HRQoL dimensions and CRF. Logistic regression was then used to compare the odds of having a HRQoL component score above the norm across CRF. All analyses were performed separately for males and females with additional stratified analyses across age and BMI conducted among significant trends. Results A total of 2,302 subjects were included in the analysis. Among females, a significant relationship was observed between CRF and vitality, physical functioning, physical role, bodily pain, and general health dimensions. However, for males the only dimension found to be significantly associated with CRF was physical health. After adjusting for potential confounders, a significant linear trend (p<0.001) for PCS scores above the norm across CRF levels was observed for females only. Conclusion Among females with one or more risk factors for developing CVD, higher levels of CRF were positively associated with the vitality and physical dimensions of HRQoL, as well as the overall PCS. However, among males the only dimension associated with CRF was physical functioning. Future studies should examine this relationship among populations at risk for developing CVD in more detail and over time. PMID:25901358

Is It Really a Matter of Simple Dualism? Corticotropin-Releasing Factor Receptors in Body and Mental Health

PubMed Central

Janssen, Donny; Kozicz, Tamás

2013-01-01

Physiological responses to stress coordinated by the hypothalamo-pituitary-adrenal axis are concerned with maintaining homeostasis in the presence of real or perceived challenges. Regulators of this axis are corticotrophin releasing factor (CRF) and CRF related neuropeptides, including urocortins 1, 2, and 3. They mediate their actions by binding to CRF receptors (CRFR) 1 and 2, which are located in several stress-related brain regions. The prevailing theory has been that the initiation of and the recovery from an elicited stress response is coordinated by two elements, viz. the (mainly) opposing, but well balanced actions of CRFR1 and CRFR2. Such a dualistic view suggests that CRF/CRFR1 controls the initiation of, and urocortins/CRFR2 mediate the recovery from stress to maintain body and mental health. Consequently, failed adaptation to stress can lead to neuropathology, including anxiety and depression. Recent literature, however, challenges such dualistic and complementary actions of CRFR1 and CRFR2, and suggests that stress recruits CRF system components in a brain area and neuron specific manner to promote adaptation as conditions dictate. PMID:23487366

Skeletal muscle metaboreflex in patients with chronic renal failure.

PubMed

Vieira, Paulo J C; Silva, Leonardo R; Maldamer, Vinicius Z; Cipriano, Gerson; Chiappa, Adriana M G; Schuster, Rodrigo; Boni, Victor H F; Grandi, Tatiani; Wolpat, Andiara; Roseguini, Bruno T; Chiappa, Gaspar R

2017-03-01

The sympathetic nervous system is affected in patients with chronic renal failure (CRF). This study tested the hypothesis that patients with CRF have an altered skeletal muscle metaboreflex. Twenty patients with CRF and 18 healthy subjects of similar age participated in the study. The muscle metaboreflex was determined based on heart rate (HR), mean arterial pressure, calf blood flow and calf vascular resistance (CVR) in response to handgrip exercise. The control of vascular resistance in the calf muscle mediated by the metaboreflex was estimated by subtracting the area under the curve with circulatory occlusion from that without occlusion. Arterial pressure and HR responses during exercise and recovery were similar in two groups of subjects. In the control group, CVR increased during exercise and remained elevated during circulatory occlusion, whereas no significant change was seen in the patients. Thus, the index of the metaboreflex was 7·82 ± 9·57 in the patients versus16·52 ± 14 units in the controls. The findings demonstrate that patients with CRF have a decreased vascular resistance response in the calf during the handgrip exercise, which suggests that CRF condition attenuates this reflex. © 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress.

PubMed

Authement, Michael E; Langlois, Ludovic D; Shepard, Ryan D; Browne, Caroline A; Lucki, Irwin; Kassis, Haifa; Nugent, Fereshteh S

2018-03-06

Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders. We found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb. Through its receptor CRFR1 and subsequently protein kinase A (PKA), CRF application increased the intrinsic excitability of LHb neurons by affecting changes in small-conductance SK-type and large-conductance BK-type K + channels. CRF also reduced inhibitory γ-aminobutyric acid-containing (GABAergic) synaptic transmission onto LHb neurons through endocannabinoid-mediated retrograde signaling. Maternal deprivation is a severe early-life stress that alters CRF neural circuitry and is likewise associated with abnormal mental health later in life. LHb neurons from pups deprived of maternal care exhibited increased intrinsic excitability, reduced GABAergic transmission, decreased abundance of SK2 channel protein, and increased activity of PKA, without any substantial changes in Crh or Crhr1 expression. Furthermore, maternal deprivation blunted the response of LHb neurons to subsequent, acute CRF exposure. Activating SK channels or inhibiting postsynaptic PKA activity prevented the effects of both CRF and maternal deprivation on LHb intrinsic excitability, thus identifying potential pharmacological targets to reverse central CRF circuit dysregulation in patients with associated disorders. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Cancer-Related Fatigue in Cancer Survivorship.

PubMed

Ebede, Chidinma C; Jang, Yongchang; Escalante, Carmen P

2017-11-01

Cancer-related fatigue (CRF) significantly interferes with usual functioning because of the distressing sense of physical, emotional, and cognitive exhaustion. Assessment of CRF is important and should be performed during the initial cancer diagnosis, throughout cancer treatment, and after treatment using a fatigue scoring scale (mild-severe). The general approach to CRF management applies to cancer survivors at all fatigue levels and includes education, counseling, and other strategies. Nonpharmacologic interventions include psychosocial interventions, exercise, yoga, physically based therapy, dietary management, and sleep therapy. Pharmacologic interventions include psychostimulants. Antidepressants may also benefit when CRF is accompanied by depression. Copyright © 2017 Elsevier Inc. All rights reserved.

Improvement of gastric motility by hemodialysis in patients with chronic renal failure.

PubMed

Adachi, Hiroshi; Kamiya, Takeshi; Hirako, Makoto; Misu, Naoko; Kobayashi, Yuka; Shikano, Michiko; Matsuhisa, Eriko; Kataoka, Hiromi; Sasaki, Makoto; Ohara, Hirotaka; Nakao, Haruhisa; Orito, Etsuro; Joh, Takashi

2007-10-01

Gastrointestinal (GI) symptoms are common in patients with chronic renal failure (CRF). We have previously demonstrated that patients with predialysis end-stage renal disease showed a high prevalence of GI symptoms and gastric hypomotility, and that gastric hypomotility appears to be an important factor in generating GI symptoms. However, it is not clear whether impaired gastric motor function would improve after hemodialytic treatment. To examine the relationship between gastric motor function and GI symptoms in CRF patients on hemodialysis. The study was performed in 19 patients with CRF treated with hemodialysis for more than six months and in 12 matched healthy controls. GI symptom severity was quantified in all patients. Gastric motility was evaluated with cutaneously recorded electrogastrography (EGG) and gastric emptying of semi-solid meals using the (13)C-acetic acid breath test. Six patients had no symptoms, and 11 had slight GI symptoms with a total symptom score of less than 5. Compared with controls, CRF patients revealed no differences in gastric motility parameters, with the exception of a lower percentage of normogastria in EGG at fasting state. Eleven patients had normal gastric motor function (Group A), and eight showed abnormalities of either gastric myoelectrical activity or gastric emptying (Group B). There was no difference in symptom score between Group A and Group B. More than half of the patients with CRF on hemodialysis demonstrated normal gastric motility, and no or slight GI symptoms. Hemodialytic treatment may improve impaired gastric motility and reduce GI symptoms in patients with CRF.

The Effect of Short Moderate Stress on the Midbrain CRF System in a Macaque Model of Functional Hypothalamic Amenorrhea

PubMed Central

Bethea, Cynthia L; Phu, Kenny; Reddy, Arubala P; Cameron, Judy L

2014-01-01

Objective To study the effect of moderate stress on CRF components in the serotonergic midbrain region in a monkey model of FHA. Design After characterization of stress sensitivity, monkeys were moved to a novel room and given 20% less chow for 5 days prior to euthanasia. Setting University of Pittsburgh nonhuman primate facility. Animals Female cynomolgus macaques (Macaca fascicularis) characterized as highly stress resilient (HSR, n=5), medium stress resilient (MSR, N=4) or stress sensitive (SS, n=4). Intervention 5 days of diet in a novel room with unfamiliar conspecifics. Main Outcome Measures Density of CRF axons in the serotonergic dorsal raphe nucleus; the number of UCN1 cells; the density of UCN1 axons; the expression of CRF-R1 and CRF-R2 in the dorsal raphe nucleus. Results CRF innervation was higher in HSR than SS animals; UCN1 cell number was higher in HSR than SS animals and UCN1 axon bouton density was not different, all opposite of non-stressed animals. CRF-R1 was not different between the sensitivity groups, but CRF-R2 was higher in HSR than SS animals. The relative expression of CRF-R1 and R2 was similar to non-stressed animals. Conclusions HSR animals respond to stress with an increase in CRF delivery to serotonin neurons. With stress, UCN1 transport decreases in HSR animals. CRF receptor expression was similar with or without stress. These changes may contribute to resilience in HSR animals. PMID:23849846

Ghrelin-induced stimulation of colonic propulsion is dependent on hypothalamic neuropeptide Y1- and corticotrophin-releasing factor 1 receptor activation.

PubMed

Tebbe, J J; Mronga, S; Tebbe, C G; Ortmann, E; Arnold, R; Schäfer, M K-H

2005-09-01

Peptides participating in the hypothalamic control of feeding behaviour are also involved in the central autonomic control of gastrointestinal functions, such as secretion and motility. An anatomical interaction and functional relationship in the central nervous system between the feeding-related peptides neuropeptide Y and ghrelin is well documented. Furthermore, it has been shown that feeding-related peptides can influence digestive function via central corticotrophin-releasing factor (CRF) pathways. In the present study, we investigated the role of ghrelin in the central autonomic control of colonic motility. Furthermore, we addressed the hypothesis that ghrelin is involved in the hypothalamic control of colonic motor function, utilizing central neuropeptide Y receptors and hypothalamic CRF pathways. Ghrelin (0.03, 0.06 and 0.12 nmol) bilaterally microinjected into the paraventricular nucleus (PVN) induced a significant stimulation of colonic propulsion. In particular, the colonic transit time decreased from 312+/-7 min to 198+/-12 min. Microinjection of the neuropeptide Y1 receptor antagonist, BIBP-3226 (200 pmol), or the nonselective CRF receptor antagonist, astressin (30 pmol), into the PVN abolished the stimulatory effect of ghrelin injected into the PVN on colonic transit time, whereas pretreatment with the selective CRF2 receptor, antisauvagine-30 (28 pmol), failed to affect the effect of PVN-ghrelin injection on colonic propulsion. These results suggest that ghrelin can act as central modulator of gastrointestinal motor functions at the level of the PVN via neuropeptide Y1- and CRF1 receptor-dependent mechanisms.

Testing a Theoretical Model of Perceived Self-Efficacy for Cancer-Related Fatigue Self-Management and Optimal Physical Functional Status

PubMed Central

Hoffman, Amy J.; von Eye, Alexander; Gift, Audrey G.; Given, Barbara A.; Given, Charles W.; Rothert, Marilyn

2009-01-01

Background Critical gaps exist in the understanding of cancer symptoms, particularly for cancer-related fatigue (CRF). Existing theories and models do not examine the key role perceived self-efficacy (PSE) plays in a person's ability to manage symptoms. Objectives To test the hypothesis that physical functional status (PFS) is predicted through patient characteristics, CRF, other symptoms, and PSE for fatigue self-management in persons with cancer. Methods This study is a secondary data analysis from the baseline observation of two randomized control trials. The combined data set includes 298 subjects who were undergoing a course of chemotherapy. Key variables included physiological and contextual patient characteristics, the severity from CRF and other symptoms, PSE, and PFS. Path analysis examined the relationships among the variables in the proposed theoretical model. Results Persons with cancer reported CRF as the most prevalent symptom among a mean of 7.4 other concurrent symptoms. The severity from CRF had a direct and indirect effect on PFS, with CRF having a direct adverse impact on PFS (t = -7.02) and an indirect adverse effect as part of the severity from the other symptoms (t = 9.69) which also adversely impacted PFS (t = -2.71). Consistent with the proposed theoretical model, PSE had a positive effect on the PFS (t = 2.87) of persons with cancer while serving as a mediator between CRF severity and PFS. Discussion Cancer-related fatigure is prevalent and related to the presence of other symptoms, and PSE for fatigue self-management is an important factor influencing CRF and PFS. A foundation is provided for future intervention studies to increase PSE to achieve optimal PFS in persons with cancer. PMID:19092553

Change of Peripheral Blood Treg/Thl7 in Cognitive Impairment with Chronic Renal Failure Patients.

PubMed

Wang, Jie; Li, Xue-Bin; Huang, Peng; Huang, Mei-Ying; Gu, Xian-Jun

2018-01-01

To investigate the changes in peripheral blood Treg/Th17 cell balance and its significance in patients with chronic renal failure (CRF) and cognitive impairment. A total of 71 patients with CRF were enrolled as a study group. The patients were divided into a cognitive impairment group and a normal cognitive function group according to the Mini-Mental State Examination (MMSE). Peripheral blood Treg and Th17 cells were analyzed by flow cytometry and their relevant cytokines (IL-17, IL-10 and TGF-β) and other biochemical indicators, including C-reactive protein (CRP) and IL-6, were determined by ELISA. Thepatients with both CRF and cognitive impairment were older than the cognitive normal groups. Peripheral blood Treg cells by Flow cytometry (the CRF cognitive impairment group 5.57±1.3%, CRF group with normal cognitive function 7.5 ± 0.9% and normal control group 9.7 ± 1.7%,P<0.05) and its related cytokines (IL-10 and TGF-β) by ELISA detection were lower in the group with cognitive impairment than in the group without cognitive impairment ( IL-10, 7.4±4.2 pg/mL, 13.8±3.9 pg/mL, 18.3±3.2 pg/mL; TGF-β 335.6±175.3 pg/mL, 512.7 ± 114.6 pg/mL, 953.8±373.4 pg/mL P < 0.05, respectively).However, Th17 cell numbers (the CRF cognitive impairment group 3.3 ± 0.7%, CRF group with normal cognitive function2.2 ± 0.5% and normal control group 1.5 ± 0.3%),and cytokine levels (IL-17, IL-6 and CRP) were higher in the group with cognitive impairment IL-6 (21.3 ± 5.1 pg/mL), IL-17 (18.5 ± 4.2 pg/mL) and CRP (20.3 ± 5.9 mg/L) in the CRF group with cognitive impairment when compared with the CRF group and normal cognitive function (12.2 ± 4.5 pg/mL, 12.1 ± 3.7 pg/mL and 13.5 ± 4.6 mg/L, respectively) or the normal control group (9.2 ± 5.8 pg/mL, 7.4 ± 2.6 pg/mL and 3.2 ± 1.3 mg/L, respectively, P<0.05). The frequencies of Treg in patients with CRF were positively correlated with the MMSE scores ((r = 0.518, P < 0.05), but the Th17 numbers were negatively correlated (r = -0.435, P < 0.05). An imbalance of peripheral blood Treg/Th17 cells is associated with cognitive impairment in patients with CRF. © 2018 The Author(s). Published by S. Karger AG, Basel.

Presence of acute and chronic renal failure in patients with paroxysmal nocturnal hemoglobinuria: results of a retrospective analysis from the Spanish PNH Registry.

PubMed

Villegas, Ana; Núñez, Ramiro; Gaya, Anna; Cuevas-Ruiz, María Victoria; Bosch, José Miguel; Carral, Anna; Arrizabalaga, Beatriz; Gómez-Roncero, María Isabel; Mora, Asunción; Bravo, Pilar; Lavilla, Esperanza; Monteserín, Carmen; Hernández, Belén; Martínez-Barranco, Pilar; Jarque, Isidro; Urquía, María Anunciación; García-Donas, Gloria; Brunet, Salut; González, Fernando Ataulfo; Urbano, Álvaro

2017-10-01

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disease. With the advent of eculizumab treatment, renal function has substantially improved, although no data from real-world clinical practice are available. An observational, retrospective, multicenter study was conducted in Spain on clinical data obtained from outpatient visits of patients with PNH (Spanish PNH Registry) who had experienced acute (ARF) or chronic (CRF) renal failure. Of the 128 patients registered (April 2014), 60 were diagnosed with classic PNH. Twenty-seven (45.0%) patients with a mean age of 48.5 (±16.2) years had renal failure, ARF or CRF, and were included in this study. Near half of the patients (n = 13; 48.1%) presented with ARF alone, 33.3% (n = 9) had CRF with episodes of ARF, while 18.5% (n = 5) were diagnosed with CRF alone. For patients with diagnosis of PNH and renal failure (n = 27), the median time to the first ARF episode was 6.5 (CI 95%; 2.2, 14.9) years, whereas the median to the diagnosis of CRF was 14.5 (CI 95%; 3.8, 19.2) years after the diagnosis of PNH. Patients with ARF (n = 22) were treated with eculizumab and did not experience new episodes of ARF, except for one patient with sepsis. Of the patients with CRF, two received treatment without experiencing further episodes of ARF. Sixteen patients who completed treatment (11 with ARF and 5 with ARF + CRF) recovered from the episode of ARF or from CRF. Of the remaining patients treated with eculizumab, one patient improved from stages III to II, three patients stabilized without showing disease progression, and one patient progressed from stages III to IV. Treatment with eculizumab in PNH patients has beneficial effects on renal function, preventing ARF and progression to CRF.

The psyche and gastric functions.

PubMed

Nardone, Gerardo; Compare, Debora

2014-01-01

Although the idea that gastric problems are in some way related to mental activity dates back to the beginning of the last century, until now it has received scant attention by physiologists, general practitioners and gastroenterologists. The major breakthrough in understanding the interactions between the central nervous system and the gut was the discovery of the enteric nervous system (ENS) in the 19th century. ENS (also called 'little brain') plays a crucial role in the regulation of the physiological gut functions. Furthermore, the identification of corticotropin-releasing factor (CRF) and the development of specific CRF receptor antagonists have permitted to characterize the neurochemical basis of the stress response. The neurobiological response to stress in mammals involves three key mechanisms: (1) stress is perceived and processed by higher brain centers; (2) the brain mounts a neuroendocrine response by way of the hypothalamic-pituitary-adrenal axis (HPA) and the autonomic nervous system (ANS), and (3) the brain triggers feedback mechanisms by HPA and ANS stimulation to restore homeostasis. Various stressors such as anger, fear, painful stimuli, as well as life or social learning experiences affect both the individual's physiologic and gastric function, revealing a two-way interaction between brain and stomach. There is overwhelming experimental and clinical evidence that stress influences gastric function, thereby outlining the pathogenesis of gastric diseases such as functional dyspepsia, gastroesophageal reflux disease and peptic ulcer disease. A better understanding of the role of pathological stressors in the modulation of disease activity may have important pathogenetic and therapeutic implications. © 2014 S. Karger AG, Basel.

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

PubMed Central

Zorrilla, Eric P.; Heilig, Markus; de Wit, Harriet; Shaham, Yavin

2013-01-01

Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence. PMID:23294766

Differential effects of stress and amphetamine administration on Fos-like protein expression in corticotropin releasing factor-neurons of the rat brain.

PubMed

Rotllant, David; Nadal, Roser; Armario, Antonio

2007-05-01

Corticotropin releasing factor (CRF) appears to be critical for the control of important aspects of the behavioral and physiological response to stressors and drugs of abuse. However, the extent to which the different brain CRF neuronal populations are similarly activated after stress and drug administration is not known. We then studied, using double immunohistochemistry for CRF and Fos protein, stress and amphetamine-induced activation of CRF neurons in cortex, central amygdala (CeA), medial parvocellular dorsal, and submagnocellular parvocellular regions of the paraventricular nucleus of the hypothalamus (PVNmpd and PVNsm, respectively) and Barrington nucleus (Bar). Neither exposure to a novel environment (hole-board, HB) nor immobilization (IMO) increased Fos-like immunoreactivity (FLI) in the CeA, but they did to the same extent in cortical regions. In other regions only IMO increased FLI. HB and IMO both failed to activate CRF+ neurons in cortical areas, but after IMO, some neurons expressing FLI in the PVNsm and most of them in the PVNmpd and Bar were CRF+. Amphetamine administration increased FLI in cortical areas and CeA (with some CRF+ neurons expressing FLI), whereas the number of CRF+ neurons increased only in the PVNsm, in contrast to the effects of IMO. The present results indicate that stress and amphetamine elicited a distinct pattern of brain Fos-like protein expression and differentially activated some of the brain CRF neuronal populations, despite similar levels of overall FLI in the case of IMO and amphetamine.

Sex differences in activated CRF neurons within stress-related neurocircuitry and HPA axis hormones following restraint in rats

PubMed Central

Babb, Jessica A; Masini, Cher V; Day, Heidi E W; Campeau, Serge

2013-01-01

Women may be more vulnerable to certain stress-related psychiatric illnesses than men due to differences in hypothalamic-pituitary-adrenocortical (HPA) axis function. To investigate potential sex differences in forebrain regions associated with HPA axis activation in rats, these experiments utilized acute exposure to a psychological stressor. Male and female rats in various stages of the estrous cycle were exposed to 30 min of restraint, producing a robust HPA axis hormonal response in all animals, the magnitude of which was significantly higher in female rats. Although both male and female animals displayed equivalent c-fos expression in many brain regions known to be involved in the detection of threatening stimuli, three regions had significantly higher expression in females: the paraventricular nucleus of the hypothalamus (PVN), the anteroventral division of the bed nucleus of the stria terminalis (BSTav), and the medial preoptic area (MPOA). Dual fluorescence in-situ hybridization analysis of neurons containing c-fos and corticotropin-releasing factor (CRF) mRNA in these regions revealed significantly more c-fos and CRF single-labeled neurons, as well as significantly more double-labeled neurons in females. Surprisingly, there was no effect of the estrous cycle on any measure analyzed, and an additional experiment revealed no demonstrable effect of estradiol replacement following ovariectomy on HPA axis hormone induction following stress. Taken together, these data suggest sex differences in HPA axis activation in response to perceived threat may be influenced by specific populations of CRF neurons in key stress-related brain regions, the BSTav, MPOA, and PVN, which may be independent of circulating sex steroids. PMID:23305762

mRNA expression of corticotropin-releasing factor and urocortin 1 after restraint and foot shock together with alprazolam administration.

PubMed

Cespedes, Isabel C; de Oliveira, Amanda R; da Silva, Joelcimar M; da Silva, André V; Sita, Luciane V; Bittencourt, Jackson C

2010-12-01

Corticotropin-releasing factor (CRF) is expressed in the paraventricular nucleus of the hypothalamus (PVN), and act centrally to provoke stress-like autonomic and behavioral responses. Urocortins 1-3 are additional ligands to the CRF receptors 1 and 2. Ucn 1 neurons are primarily concentrated in the Edinger-Westphal (EW) nucleus and also have been associated with stress responses. It is also known that UCN 1 respond in different ways depending on the stressor presented. Benzodiazepines can act via the CRF peptidergic system and chronic administration of alprazolam does not interfere with CRF mRNA expression in the PVN, but significantly increase Ucn 1 mRNA expression in the EW. The aim of our study was to investigate the relationship between different stressor stimuli, foot shock (FS) and restraint (R), and the mRNA expression of CRF and Ucn 1 in the PVN and EW using alprazolam (A). We employed fos activation and in situ hybridization. Restraint group presented increased fos-ir and CRF mRNA expression in the PVN compared to FS group. The stress responses of R group were prevented by A. In the EW, fos-ir was higher in the FS group than in the R group, whereas Ucn 1 mRNA expression was higher in the R group than in the FS group. Alprazolam significantly increased fos-ir and Ucn 1 mRNA expression in both groups. Our results show that PVN and EW respond in different ways to the same stressors. Furthermore, EW of stressed animals replies in a complementary way comparing to PVN with the use of Alprazolam. Copyright © 2010 Elsevier Inc. All rights reserved.

Visceral sensation and irritable bowel syndrome; with special reference to comparison with functional abdominal pain syndrome.

PubMed

Nozu, Tsukasa; Okumura, Toshikatsu

2011-04-01

Stress-induced visceral hypersensitivity may play an important role in the pathogenesis of irritable bowel syndrome (IBS) but not in functional abdominal pain syndrome (FAPS). We examined rectal sensation in those patients. Experiment 1: Rectal thresholds of pain (PT) and maximum tolerance were assessed by barostat with ramp distention before and after repetitive rectal painful distention (RRD). Experiment 2, PT was measured in basal state and after intravenous CRF (100 µg) or vehicle, together with or without RRD. Experiment 3: Three phasic distentions at physiological range were randomly loaded. The subjects were asked to mark the visual analogue scale (VAS) in reference to subjective intensity of sensation. Experiment 1: Majority of IBS patients showed rectal hypersensitivity before RRD in contrast to FAPS. All IBS patients developed hypersensitivity after RRD, however, none of the FAPS patients did. RRD significantly reduced both thresholds in IBS (n=7) but did not change in controls (n=14) and FAPS (n=6). Experiment 2: PT was not modified by RRD in placebo group (n=6), while it was significantly reduced in CRF-treated group (n=5). On the other hand, CRF (n=5) or vehicle (n=5) without RRD did not alter PT. Experiment 3: The VAS ratings were increased in IBS (n=7) but significantly decreased in FAPS (n=6) as compared to controls (n=14). RRD-induced rectal hypersensitivity seems to be reliable marker for IBS, and CRF may contribute to this response. FAPS patients may have hyposensitivity to non-noxious physiological distention, suggesting FAPS has different pathogenesis from IBS. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Midazolam treatment before re-exposure to contextual fear reduces freezing behavior and amygdala activity differentially in high- and low-anxiety rats.

PubMed

Skórzewska, Anna; Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Turzyńska, Danuta; Sobolewska, Alicja; Krząścik, Paweł; Płaźnik, Adam

2015-02-01

The aim of this study was to examine the effects of benzodiazepine (midazolam) administration on rat conditioned fear responses and on local brain activity (c-Fos and CRF expressions) of low- (LR) and high- (HR)anxiety rats after the first and second contextual fear test sessions. The animals were divided into LR and HR groups based on the duration of their conditioned freezing response in the first contextual fear test. The fear-re-conditioned LR and HR animals (28 days later) had increased freezing durations compared with those durations during the first conditioned fear test. These behavioral effects were accompanied by increased c-Fos expression in the medial amygdala (MeA), the basolateral amygdala (BLA), and the paraventricular hypothalamic nuclei and elevated CRF expression in the MeA. All these behavioral and immunochemical effects of fear re-conditioning were stronger in the LR group compared with the effects in the HR group. Moreover, in the LR rats, the re-conditioning led to decreased CRF expression in the primary motor cortex (M1) and to increased CRF expression in the BLA. The pretreatment of rats with midazolam before the second exposure to the aversive context significantly attenuated the conditioned fear response, lowered the serum corticosterone concentration, decreased c-Fos and CRF expressions in the MeA and in the BLA, and increased CRF complex density in M1 area only in the LR group. These studies have demonstrated that LR rats are more sensitive to re-exposure to fear stimuli and that midazolam pretreatment was associated with modified brain activity in the amygdala and in the prefrontal cortex in this group of animals. The current data may facilitate a better understanding of the neurobiological mechanisms responsible for individual differences in the psychopathological processes accompanying some anxiety disorders characterized by stronger reactivity to re-exposure to stressful challenges, e.g., posttraumatic stress disorder. Copyright © 2013 Elsevier Inc. All rights reserved.

Broad Antibody Mediated Cross-Neutralization and Preclinical Immunogenicity of New Codon-Optimized HIV-1 Clade CRF02_AG and G Primary Isolates

PubMed Central

Agwale, Simon M.; Forbi, Joseph C.; Notka, Frank; Wrin, Terri; Wild, Jens; Wagner, Ralf; Wolf, Hans

2011-01-01

Creation of an effective vaccine for HIV has been an elusive goal of the scientific community for almost 30 years. Neutralizing antibodies are assumed to be pivotal to the success of a prophylactic vaccine but previous attempts to make an immunogen capable of generating neutralizing antibodies to primary “street strain” isolates have resulted in responses of very limited breadth and potency. The objective of the study was to determine the breadth and strength of neutralizing antibodies against autologous and heterologous primary isolates in a cohort of HIV-1 infected Nigerians and to characterize envelopes from subjects with particularly broad or strong immune responses for possible use as vaccine candidates in regions predominated by HIV-1 CRF02_AG and G subtypes. Envelope vectors from a panel of primary Nigerian isolates were constructed and tested with plasma/sera from the same cohort using the PhenoSense HIV neutralizing antibody assay (Monogram Biosciences Inc, USA) to assess the breadth and potency of neutralizing antibodies. The immediate goal of this study was realized by the recognition of three broadly cross-neutralizing sera: (NG2-clade CRF02_AG, NG3-clade CRF02_AG and NG9- clade G). Based on these findings, envelope gp140 sequences from NG2 and NG9, complemented with a gag sequence (Clade G) and consensus tat (CRF02_AG and G) antigens have been codon-optimized, synthesized, cloned and evaluated in BALB/c mice. The intramuscular administration of these plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial specific humoral response against all constructs and strong cellular responses against the gag and tat constructs. These preclinical findings provide a framework for the design of candidate vaccine for use in regions where the HIV-1 epidemic is driven by clades CRF02_AG and G. PMID:21829720

Broad antibody mediated cross-neutralization and preclinical immunogenicity of new codon-optimized HIV-1 clade CRF02_AG and G primary isolates.

PubMed

Agwale, Simon M; Forbi, Joseph C; Notka, Frank; Wrin, Terri; Wild, Jens; Wagner, Ralf; Wolf, Hans

2011-01-01

Creation of an effective vaccine for HIV has been an elusive goal of the scientific community for almost 30 years. Neutralizing antibodies are assumed to be pivotal to the success of a prophylactic vaccine but previous attempts to make an immunogen capable of generating neutralizing antibodies to primary "street strain" isolates have resulted in responses of very limited breadth and potency. The objective of the study was to determine the breadth and strength of neutralizing antibodies against autologous and heterologous primary isolates in a cohort of HIV-1 infected Nigerians and to characterize envelopes from subjects with particularly broad or strong immune responses for possible use as vaccine candidates in regions predominated by HIV-1 CRF02_AG and G subtypes. Envelope vectors from a panel of primary Nigerian isolates were constructed and tested with plasma/sera from the same cohort using the PhenoSense HIV neutralizing antibody assay (Monogram Biosciences Inc, USA) to assess the breadth and potency of neutralizing antibodies. The immediate goal of this study was realized by the recognition of three broadly cross-neutralizing sera: (NG2-clade CRF02_AG, NG3-clade CRF02_AG and NG9- clade G). Based on these findings, envelope gp140 sequences from NG2 and NG9, complemented with a gag sequence (Clade G) and consensus tat (CRF02_AG and G) antigens have been codon-optimized, synthesized, cloned and evaluated in BALB/c mice. The intramuscular administration of these plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial specific humoral response against all constructs and strong cellular responses against the gag and tat constructs. These preclinical findings provide a framework for the design of candidate vaccine for use in regions where the HIV-1 epidemic is driven by clades CRF02_AG and G.

Exercise improves cardiorespiratory fitness in people with depression: A meta-analysis of randomized control trials.

PubMed

Stubbs, Brendon; Rosenbaum, Simon; Vancampfort, Davy; Ward, Philip B; Schuch, Felipe B

2016-01-15

Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular disease and all-cause mortality. CRF improves in response to exercise interventions, yet the effectiveness of such interventions to improve CRF among people with depression is unclear. We conducted a systematic review and meta-analysis to evaluate whether CRF improves in people with depression in exercise randomized control trials (RCTs). Three authors identified RCTs from a recent Cochrane review and conducted updated searches of major electronic databases. We included RCTs of exercise interventions in people with depression (including major depressive disorder (MDD) and above-threshold depressive symptoms) that reported CRF (defined as predicted maximal oxygen uptake (VO2max predicted) or peak oxygen uptake (VO2peak)) versus a control condition. A random effects meta-analysis was conducted. Seven unique RCTs including 8 aerobic exercise interventions for depression were eligible, including 293 people allocated to exercise (mean age=40.3 years, range=27.2-64.7 years and 35-100% female) and 205 allocated to control conditions. Across all studies exercise results in a significant increase in CRF (g=0.64, 95%CI=0.32-0.96, p<0.001) equating to a mean increase of 3.05 ml/kg/min. Results remained significant when restricted to MDD only (N=5, g=0.41, 95%CI=0.18-0.64, p<0.001) and in high quality studies (N=5, g=0.60, 95%CI=0.19-1.00, p=0.004). People with depression can achieve clinically relevant improvements in CRF in response to exercise interventions. Targeting 'fitness' rather than 'fatness' may be another feasible intervention strategy in this population. Copyright © 2015 Elsevier B.V. All rights reserved.

Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area.

PubMed

Sotomayor-Zárate, Ramón; Abarca, Jorge; Araya, Katherine A; Renard, Georgina M; Andrés, María E; Gysling, Katia

2015-11-01

A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20μM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10μM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100μM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structural Basis for Hormone Recognition by the Human CRFR2[alpha] G Protein-coupled Receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pal, Kuntal; Swaminathan, Kunchithapadam; Xu, H. Eric

2012-05-09

The mammalian corticotropin releasing factor (CRF)/urocortin (Ucn) peptide hormones include four structurally similar peptides, CRF, Ucn1, Ucn2, and Ucn3, that regulate stress responses, metabolism, and cardiovascular function by activating either of two related class B G protein-coupled receptors, CRFR1 and CRFR2. CRF and Ucn1 activate both receptors, whereas Ucn2 and Ucn3 are CRFR2-selective. The molecular basis for selectivity is unclear. Here, we show that the purified N-terminal extracellular domains (ECDs) of human CRFR1 and the CRFR2{alpha} isoform are sufficient to discriminate the peptides, and we present three crystal structures of the CRFR2{alpha} ECD bound to each of the Ucn peptides.more » The CRFR2{alpha} ECD forms the same fold observed for the CRFR1 and mouse CRFR2{beta} ECDs but contains a unique N-terminal {alpha}-helix formed by its pseudo signal peptide. The CRFR2{alpha} ECD peptide-binding site architecture is similar to that of CRFR1, and binding of the {alpha}-helical Ucn peptides closely resembles CRF binding to CRFR1. Comparing the electrostatic surface potentials of the ECDs suggests a charge compatibility mechanism for ligand discrimination involving a single amino acid difference in the receptors (CRFR1 Glu104/CRFR2{alpha} Pro-100) at a site proximate to peptide residue 35 (Arg in CRF/Ucn1, Ala in Ucn2/3). CRFR1 Glu-104 acts as a selectivity filter preventing Ucn2/3 binding because the nonpolar Ala-35 is incompatible with the negatively charged Glu-104. The structures explain the mechanisms of ligand recognition and discrimination and provide a molecular template for the rational design of therapeutic agents selectively targeting these receptors.« less

Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects

PubMed Central

Herman, Melissa; Kallupi, Marsida; Luu, George; Oleata, Christopher; Heilig, Markus; Koob, George F.; Ciccocioppo, Roberto; Roberto, Marisa

2012-01-01

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF1) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically-selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF1 antagonist in msP, Sprague-Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABAA-inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague-Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF1 antagonist (R121919, 1 μM) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF1 antagonist in msP rats, suggesting increased GABA release and decreased CRF1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naïve mSP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence. PMID:23220399

EMG biofeedback: the effects of CRF, FR, VR, FI, and VI schedules of reinforcement on the acquisition and extinction of increases in forearm muscle tension.

PubMed

Cohen, S L; Richardson, J; Klebez, J; Febbo, S; Tucker, D

2001-09-01

Biofeedback was used to increase forearm-muscle tension. Feedback was delivered under continuous reinforcement (CRF), variable interval (VI), fixed interval (FI), variable ratio (VR), and fixed ratio (FR) schedules of reinforcement when college students increased their muscle tension (electromyograph, EMG) above a high threshold. There were three daily sessions of feedback, and Session 3 was immediately followed by a session without feedback (extinction). The CRF schedule resulted in the highest EMG, closely followed by the FR and VR schedules, and the lowest EMG scores were produced by the FI and VI schedules. Similarly, the CRF schedule resulted in the greatest amount of time-above-threshold and the VI and FI schedules produced the lowest time-above-threshold. The highest response rates were generated by the FR schedule, followed by the VR schedule. The CRF schedule produced relatively low response rates, comparable to the rates under the VI and FI schedules. Some of the data are consistent with the partial-reinforcement-extinction effect. The present data suggest that different schedules of feedback should be considered in muscle-strengthening-contexts such as during the rehabilitation of muscles following brain damage or peripheral nervous-system injury.

Association between glycemic load and cognitive function in community-dwelling older adults: Results from the Brain in Motion study.

PubMed

Garber, Anna; Csizmadi, Ilona; Friedenreich, Christine M; Sajobi, Tolulope T; Longman, Richard S; Tyndall, Amanda V; Drogos, Lauren L; Davenport, Margie H; Poulin, Marc J

2017-07-17

Impaired glucose tolerance is a risk factor for non-age-related cognitive decline and is also associated with measures of physical activity (PA) and cardiorespiratory fitness (CRF). A low glycemic load (GL) diet can aid in the management of blood glucose levels, but little is known about its effect on cognition with poor glucoregulation. We assessed the relation between GL and cognitive function by glucoregulation and possible mediatory effects by CRF and PA in older adults from the Brain in Motion Study. A cross-sectional analysis of 194 cognitively healthy adults aged ≥55 years (mean = 65.7, SD = 6.1) was conducted. GL was assessed using a quantitative food frequency questionnaire, and glucoregulation was characterized on the HOMA-IR index. Subjects also completed a cognitive assessment, CRF testing, a validated self-reported PA questionnaire, and a blood draw. Multiple linear regression models adjusted for significant covariates were used to evaluate the relation between GL and cognition, and mediation by CRF and PA was also assessed. GL was inversely associated with global cognition (β = -0.014; 95% CI -0.024, -0.004) and figural memory (β = -0.035; 95% CI -0.052, -0.018) in subjects with poor glucoregulation. Neither CRF nor PA mediated these relations. In subjects with good glucoregulation, no association was found between GL and cognitive function (p > 0.05). A low GL diet is associated with better cognitive function in older adults with poor glucoregulation. This study provides supportive evidence for the role of GL in maintaining better cognitive function during the aging process. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Comparative Effects of Urocortins and Stresscopin on Cardiac Myocyte Contractility

PubMed Central

Makarewich, Catherine A.; Troupes, Constantine D.; Schumacher, Sarah M.; Gross, Polina; Koch, Walter J.; Crandall, David L.; Houser, Steven R.

2015-01-01

Rationale There is a current need for development of new therapies for patients with heart failure. Objective To test the effects of members of the Corticotropin-Releasing Factor (CRF) family of peptides on myocyte contractility to validate them as potential heart failure therapeutics. Methods and Results Adult feline left ventricular myocytes (AFMs) were isolated and contractility was assessed in the presence and absence of CRF peptides Urocortin 2 (UCN2), Urocortin 3 (UCN3), Stresscopin (SCP), and the β-adrenergic agonist isoproterenol (Iso). An increase in fractional shortening and peak Ca2+ transient amplitude was seen in the presence of all CRF peptides. A decrease in Ca2+ decay rate (Tau) was also observed at all concentrations tested. cAMP generation was measured by ELISA in isolated AFMs in response to the CRF peptides and Iso and significant production was seen at all concentrations and time points tested. Conclusions The CRF family of peptides effectively increases cardiac contractility and should be evaluated as potential novel therapeutics for heart failure patients. PMID:26231084

The CRF system, stress, depression and anxiety – insights from human genetic studies

PubMed Central

Binder, Elisabeth B.; Nemeroff, Charles B.

2011-01-01

A concatenation of findings from preclinical and clinical studies support a preeminent role for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically variants in the gene encoding the CRF1 receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In depth characterization of these variants will likely be important in furthering our understanding of the long term consequences of adverse experience. PMID:20010888

Corticotropin-releasing factor (CRF) and α 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats.

PubMed

Park, Paula E; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Schulteis, Gery; Koob, George F

2013-09-01

Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2 mg/kg s.c.) displayed an increased ASR when tested 4 h after heroin treatment. A similar increase in ASR was found in rats 10-20 h into withdrawal from extended access (12 h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the α 2 adrenergic receptor agonist clonidine (10 μg/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20 mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and α 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25 mg/kg s.c.)-potentiated startle and clonidine on CRF (2 μg i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and α 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions.

CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD.

PubMed

Adamec, Robert; Fougere, Dennis; Risbrough, Victoria

2010-07-01

Post traumatic stress disorder (PTSD) is a chronic anxiety disorder initiated by an intensely threatening, traumatic event. There is a great need for more efficacious pharmacotherapy and preventive treatments for PTSD. In animals, corticotropin-releasing factor (CRF) and the CRF1 receptor play a critical role in behavioural and neuroendocrine responses to stress. We tested the hypothesis that CRF1 activation is required for initiation and consolidation of long-term effects of trauma on anxiety-like behaviour in the predator exposure (predator stress) model of PTSD. Male C57BL6 mice were treated with the selective CRF1 antagonist CRA0450 (2, 20 mg/kg) 30 min before or just after predator stress. Long-term effects of stress on rodent anxiety were measured 7 d later using acoustic startle, elevated plus maze (EPM), light/dark box, and hole-board tests. Predator stress increased startle amplitude and delayed startle habituation, increased time in and decreased exits from the dark chamber in the light/dark box test, and decreased risk assessment in the EPM. CRF1 antagonism had limited effects on these behaviours in non-stressed controls, with the high dose decreasing risk assessment in the EPM. However, in stressed animals CRF1 antagonism blocked initiation and consolidation of stressor effects on startle, and returned risk assessment to baseline levels in predator-stressed mice. These findings implicate CRF1 activation in initiation and post-trauma consolidation of predator stress effects on anxiety-like behaviour, specifically on increased arousal as measured by exaggerated startle behaviours. These data support further research of CRF1 antagonists as potential prophylactic treatments for PTSD.

Corticotropin Releasing Factor (CRF) Modulates Fear-Induced Alterations in Sleep in Mice

PubMed Central

Yang, Linghui; Tang, Xiangdong; Wellman, Laurie L.; Liu, Xianling; Sanford, Larry D.

2009-01-01

Contextual fear significantly reduces rapid eye movement sleep (REM) during post-exposure sleep in mice and rats. Corticotropin releasing factor (CRF) plays a major role in CNS responses to stressors. We examined the influence of CRF and astressin (AST), a non-specific CRF antagonist, on sleep after contextual fear in BALB/c mice. Male mice were implanted with transmitters for recording sleep via telemetry and with a guide cannula aimed into the lateral ventricle. Recordings for vehicle and handling control were obtained after ICV microinjection of saline (SAL) followed by exposure to a novel chamber. Afterwards, the mice were subjected to shock training (20 trials, 0.5 mA, 0.5 s duration) for 2 sessions. After training, separate groups of mice received ICV microinjections of SAL (0.2 microl, n=9), CRF (0.4 microg, n=8), or AST (1.0 microg, n=8) prior to exposure to the shock context alone. Sleep was then recorded for 20 hours (8-hour light and 12-hour dark period). Compared to handling control, contextual fear significantly decreased REM during the 8-h light period in mice receiving SAL and in mice receiving CRF, but not in the mice receiving AST. Mice receiving CRF exhibited reductions in REM during the 12-h dark period after contextual fear, whereas mice receiving SAL or AST did not. CRF also reduced non-REM (NREM) delta (slow wave) amplitude in the EEG. Only mice receiving SAL prior to contextual fear exhibited significant reductions in NREM and total sleep. These findings demonstrate a role for the central CRF system in regulating alterations in sleep induced by contextual fear. PMID:19376095

Elevated CSF Corticotropin-Releasing Factor Concentrations in Posttraumatic Stress Disorder

PubMed Central

Bremner, J. Douglas; Licinio, Julio; Darnell, Adam; Krystal, John H.; Owens, Michael J.; Southwick, Steven M.; Nemeroff, Charles B.; Charney, Dennis S.

2011-01-01

Objective Corticotropin-releasing factor (CRF) and somatostatin both play important roles in mediating responses to acute and chronic stress. The purpose of this study was to measure CSF concentrations of CRF and somatostatin in patients with chronic combat-related post-traumatic stress disorder (PTSD) and comparison subjects. Method Lumbar punctures for collection of CSF were performed in Vietnam combat veterans with PTSD (N=11) and comparison subjects (N=17). CSF concentrations of CRF and somatostatin were compared between the two groups. Results CSF concentrations of CRF were higher in the PTSD patients than in the comparison subjects (mean=29.0 pg/ml, SD=7.8, versus mean=21.9 pg/ml, SD=6.0). This group difference remained significant after covariance for age. CSF somatostatin concentrations in PTSD patients were higher than those of the comparison subjects (mean=19.9 pg/ml, SD=5.4, versus mean=13.7 pg/ml, SD=8.0). However, covarying for age reduced the level of significance. Conclusions Higher CSF CRF concentrations in patients with PTSD may reflect alterations in stress-related neurotransmitter systems. The higher CSF CRF concentrations may play a role in disturbances of arousal in patients with PTSD. PMID:9137116

Salivary markers in patients with chronic renal failure.

PubMed

Pallos, Debora; Leão, Mariella V P; Togeiro, Fernanda C F B; Alegre, Larissa; Ricardo, Lucilene Hernandes; Perozini, Caroline; Ruivo, Gilson Fernandes

2015-12-01

Chronic renal failure (CRF) is a progressive loss of renal function over a period of months or years. The major function of the kidneys is the removal of metabolic waste products, electrolytes and water. When this function is impaired, systemic changes, oral complications and alterations in salivary composition may occur. This study aimed to compare the levels of immunological and inflammatory components in the saliva samples from patients that undergo to hemodialysis treatment (HD), without HD and control. This study evaluated IgA, IgG, C reactive protein (CRP) and nitric oxide (NO) in saliva samples from 119 patients, who were divided into the control group (C), chronic renal failure (CRF) patient group and CRF patients on hemodialysis treatment (HD) group. IgA and IgG levels were analyzed by ELISA. Nitric oxide levels were determined indirectly by the nitrite concentration using Griess reagent; CRP by agglutination tests; and total proteins, by Bradford assay. The HD group showed significantly higher levels of IgG, IgA and CRP compared with the control and CRF groups. The CRF group presented the same amounts of IgG, IgA and CRP as the C group but significantly higher levels of NO similar to the HD group. Renal disease, particularly hemodialysis treatment during renal disease, seems to alter salivary immunological and inflammatory components. Thus, analyzing the levels of IgA, IgG, NO and CRP in saliva may be beneficial for monitoring renal disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

PubMed

Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

2016-09-01

Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Association between left ventricular dysfunction, anemia, and chronic renal failure. Analysis of the Heart Failure Prevalence and Predictors in Turkey (HAPPY) cohort.

PubMed

Kepez, A; Mutlu, B; Degertekin, M; Erol, C

2015-06-01

Anemia and chronic renal failure (CRF) are frequent comorbidities in patients with heart failure (HF), and they have been reported to be associated with increased mortality and hospitalization rates. HF, anemia, and CRF have been reported to interact with each other forming a vicious cycle termed cardio-renal-anemia syndrome. The aim of the present study was to evaluate the association of HF, anemia, and CRF using data from the large-scale"Heart Failure Prevalence and Predictors in Turkey (HAPPY)" study. Among the HAPPY cohort, 3,369 subjects who had either left ventricular dysfunction (LVD) or normal left ventricular function on echocardiography or normal serum NT-proBNP levels were included in this analysis. The prevalence of anemia and CRF was significantly higher in patients with LVD compared with subjects with normal ventricular function (20.7 % vs. 4.0 % and 19.0 % vs. 3.7 %, respectively; p < 0.001 for each). Binary logistic regression analyses for the presence of LVD, anemia, and CRF demonstrated that each one was an independent predictor for the presence of the others. These findings point to the presence of cardio-renal-anemia syndrome and the necessity of treating these comorbidities in patients with HF.

Innately activated TLR4 signal in the nucleus accumbens is sustained by CRF amplification loop and regulates impulsivity.

PubMed

Balan, Irina; Warnock, Kaitlin T; Puche, Adam; Gondre-Lewis, Marjorie C; Aurelian, Laure

2018-03-01

Cognitive impulsivity is a heritable trait believed to represent the behavior that defines the volition to initiate alcohol drinking. We have previously shown that a neuronal Toll-like receptor 4 (TLR4) signal located in the central amygdala (CeA) and ventral tegmental area (VTA) controls the initiation of binge drinking in alcohol-preferring P rats, and TLR4 expression is upregulated by alcohol-induced corticotropin-releasing factor (CRF) at these sites. However, the function of the TLR4 signal in the nucleus accumbens shell (NAc-shell), a site implicated in the control of reward, drug-seeking behavior and impulsivity and the contribution of other signal-associated genes, are still poorly understood. Here we report that P rats have an innately activated TLR4 signal in NAc-shell neurons that co-express the α2 GABA A receptor subunit and CRF prior to alcohol exposure. This signal is not present in non-alcohol drinking NP rats. The TLR4 signal is sustained by a CRF amplification loop, which includes TLR4-mediated CRF upregulation through PKA/CREB activation and CRF-mediated TLR4 upregulation through the CRF type 1 receptor (CRFR1) and the MAPK/ERK pathway. NAc-shell Infusion of a neurotropic, non-replicating herpes simplex virus vector for TLR4-specific small interfering RNA (pHSVsiTLR4) inhibits TLR4 expression and cognitive impulsivity, implicating the CRF-amplified TLR4 signal in impulsivity regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of an HIV-1 BG Intersubtype Recombinant Form (CRF73_BG), Partially Related to CRF14_BG, Which Is Circulating in Portugal and Spain

PubMed Central

Fernández-García, Aurora; Delgado, Elena; Cuevas, María Teresa; Vega, Yolanda; Montero, Vanessa; Sánchez, Mónica; Carrera, Cristina; López-Álvarez, María José; Miralles, Celia; Pérez-Castro, Sonia; Cilla, Gustavo; Hinojosa, Carmen; Pérez-Álvarez, Lucía; Thomson, Michael M.

2016-01-01

HIV-1 exhibits a characteristically high genetic diversity, with the M group, responsible for the pandemic, being classified into nine subtypes, 72 circulating recombinant forms (CRFs) and numerous unique recombinant forms (URFs). Here we characterize the near full-length genome sequence of an HIV-1 BG intersubtype recombinant virus (X3208) collected in Galicia (Northwest Spain) which exhibits a mosaic structure coincident with that of a previously characterized BG recombinant virus (9601_01), collected in Germany and epidemiologically linked to Portugal, and different from currently defined CRFs. Similar recombination patterns were found in partial genome sequences from three other BG recombinant viruses, one newly derived, from a virus collected in Spain, and two retrieved from databases, collected in France and Portugal, respectively. Breakpoint coincidence and clustering in phylogenetic trees of these epidemiologically-unlinked viruses allow to define a new HIV-1 CRF (CRF73_BG). CRF73_BG shares one breakpoint in the envelope with CRF14_BG, which circulates in Portugal and Spain, and groups with it in a subtype B envelope fragment, but the greatest part of its genome does not appear to derive from CRF14_BG, although both CRFs share as parental strain the subtype G variant circulating in the Iberian Peninsula. Phylogenetic clustering of partial pol and env segments from viruses collected in Portugal and Spain with X3208 and 9691_01 indicates that CRF73_BG is circulating in both countries, with proportions of around 2–3% Portuguese database HIV-1 isolates clustering with CRF73_BG. The fact that an HIV-1 recombinant virus characterized ten years ago as a URF has been shown to represent a CRF suggests that the number of HIV-1 CRFs may be much greater than currently known. PMID:26900693

Prefrontal Cortex Corticotropin-Releasing Factor Receptor 1 Conveys Acute Stress-Induced Executive Dysfunction.

PubMed

Uribe-Mariño, Andrés; Gassen, Nils C; Wiesbeck, Maximilian F; Balsevich, Georgia; Santarelli, Sara; Solfrank, Beate; Dournes, Carine; Fries, Gabriel R; Masana, Merce; Labermeier, Christiana; Wang, Xiao-Dong; Hafner, Kathrin; Schmid, Bianca; Rein, Theo; Chen, Alon; Deussing, Jan M; Schmidt, Mathias V

2016-11-15

The medial prefrontal cortex (mPFC) subserves complex cognition and is impaired by stress. Corticotropin-releasing factor (CRF), through CRF receptor 1 (CRFR1), constitutes a key element of the stress response. However, its contribution to the effects of stress in the mPFC remains unclear. Mice were exposed to acute social defeat stress and subsequently to either the temporal order memory (n = 11-12) or reversal learning (n = 9-11) behavioral test. Changes in mPFC Crhr1 messenger RNA levels were measured in acutely stressed mice (n = 12). Crhr1 loxP/loxP mice received either intra-mPFC adeno-associated virus-Cre or empty microinjections (n = 17-20) and then were submitted to acute stress and later to the behavioral tests. Co-immunoprecipitation was used to detect activation of the protein kinase A (PKA) signaling pathway in the mPFC of acutely stressed mice (n = 8) or intra-mPFC CRF injected mice (n = 7). Finally, mice received intra-mPFC CRF (n = 11) and/or Rp-isomer cyclic adenosine 3',5' monophosphorothioate (Rp-cAMPS) (n = 12) microinjections and underwent behavioral testing. We report acute stress-induced effects on mPFC-mediated cognition, identify CRF-CRFR1-containing microcircuits within the mPFC, and demonstrate stress-induced changes in Crhr1 messenger RNA expression. Importantly, intra-mPFC CRFR1 deletion abolishes acute stress-induced executive dysfunction, whereas intra-mPFC CRF mimics acute stress-induced mPFC dysfunction. Acute stress and intra-mPFC CRF activate the PKA signaling pathway in the mPFC, leading to cyclic AMP response element binding protein phosphorylation in intra-mPFC CRFR1-expressing neurons. Finally, PKA blockade reverses the intra-mPFC CRF-induced executive dysfunction. Taken together, these results unravel a molecular mechanism linking acute stress to executive dysfunction via CRFR1. This will aid in the development of novel therapeutic targets for stress-induced cognitive dysfunction. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Mice overexpressing corticotropin-releasing factor show brain atrophy and motor dysfunctions.

PubMed

Goebel, Miriam; Fleming, Sheila M; Million, Mulugeta; Stengel, Andreas; Taché, Yvette; Wang, Lixin

2010-03-31

Chronic stress and persistently high glucocorticoid levels can induce brain atrophy. Corticotropin-releasing factor (CRF)-overexpressing (OE) mice are a genetic model of chronic stress with elevated brain CRF and plasma corticosterone levels and Cushing's syndrome. The brain structural alterations in the CRF-OE mice, however, are not well known. We found that adult male and female CRF-OE mice had significantly lower whole brain and cerebellum weights than their wild type (WT) littermates (347.7+/-3.6mg vs. 460.1+/-4.3mg and 36.3+/-0.8mg vs. 50.0+/-1.3mg, respectively) without sex-related difference. The epididymal/parametrial fat mass was significantly higher in CRF-OE mice. The brain weight was inversely correlated to epididymal/parametrial fat weight, but not to body weight. Computerized image analysis system in Nissl-stained brain sections of female mice showed that the anterior cingulate and sensorimotor cortexes of CRF-OE mice were significantly thinner, and the volumes of the hippocampus, hypothalamic paraventricular nucleus and amygdala were significantly reduced compared to WT, while the locus coeruleus showed a non-significant increase. Motor functions determined by beam crossing and gait analysis showed that CRF-OE mice took longer time and more steps to traverse a beam with more errors, and displayed reduced stride length compared to their WT littermates. These data show that CRF-OE mice display brain size reduction associated with alterations of motor coordination and an increase in visceral fat mass providing a novel animal model to study mechanisms involved in brain atrophy under conditions of sustained elevation of brain CRF and circulating glucocorticoid levels. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Angiotensin II and CRF receptors in the central nucleus of the amygdala mediate hemodynamic response variability to cocaine in conscious rats.

PubMed

Watanabe, Mari A; Kucenas, Sarah; Bowman, Tamara A; Ruhlman, Melissa; Knuepfer, Mark M

2010-01-14

Stress or cocaine evokes either a large increase in systemic vascular resistance (SVR) or a smaller increase in SVR accompanied by an increase in cardiac output (designated vascular and mixed responders, respectively) in Sprague-Dawley rats. We hypothesized that the central nucleus of the amygdala (CeA) mediates this variability. Conscious, freely-moving rats, instrumented for measurement of arterial pressure and cardiac output and for drug delivery into the CeA, were given cocaine (5 mg/kg, iv, 4-6 times) and characterized as vascular (n=15) or mixed responders (n=10). Subsequently, we administered cocaine after bilateral microinjections (100 nl) of saline or selective agents in the CeA. Muscimol (80 pmol), a GABA(A) agonist, or losartan (43.4 pmol), an AT(1) receptor antagonist, attenuated the cocaine-induced increase in SVR in vascular responders, selectively, such that vascular responders were no longer different from mixed responders. The corticotropin releasing factor (CRF) antagonist, alpha-helical CRF(9-41) (15.7 pmol), abolished the difference between cardiac output and SVR in mixed and vascular responders. We conclude that greater increases in SVR observed in vascular responders are dependent on AT(1) receptor activation and, to a lesser extent on CRF receptors. Therefore, AT(1) and CRF receptors in the CeA contribute to hemodynamic response variability to intravenous cocaine.

Angiotensin II and CRF Receptors in the Central Nucleus of the Amygdala Mediate Hemodynamic Response Variability to Cocaine in Conscious Rats

PubMed Central

Watanabe, Mari A.; Kucenas, Sarah; Bowman, Tamara A.; Ruhlman, Melissa; Knuepfer, Mark M.

2009-01-01

Stress or cocaine evokes either a large increase in systemic vascular resistance (SVR) or a smaller increase in SVR accompanied by an increase in cardiac output (designated vascular and mixed responders, respectively) in Sprague-Dawley rats. We hypothesized that the central nucleus of the amygdala (CeA) mediates this variability. Conscious, freely-moving rats, instrumented for measurement of arterial pressure and cardiac output and for drug delivery into the CeA, were given cocaine (5 mg/kg, iv, 4-6 times) and characterized as vascular (n=15) or mixed responders (n=10). Subsequently, we administered cocaine after bilateral microinjections (100 nl) of saline or selective agents in the CeA. Muscimol (80 pmol), a GABAA agonist, or losartan (43.4 pmol), an AT1 receptor antagonist, attenuated the cocaine-induced increase in SVR in vascular responders, selectively, such that vascular responders were no longer different from mixed responders. The corticotropin releasing factor (CRF) antagonist, α-helical CRF9-41 (15.7 pmol), abolished the difference between cardiac output and SVR in mixed and vascular responders. We conclude that greater increases in SVR observed in vascular responders are dependent on AT1 receptor activation and, to a lesser extent on CRF receptors. Therefore, AT1 and CRF receptors in the CeA contribute to hemodynamic response variability to intravenous cocaine. PMID:19879859

Effects of milling on functional properties of rice flour.

PubMed

Kadan, R S; Bryant, R J; Miller, J A

2008-05-01

A commercial long-grain rice flour (CRF) and the flours made by using a pin mill and the Udy mill from the same batch of broken second-head white long-grain rice were evaluated for their particle size and functional properties. The purpose of this study was to compare the commercial rice flour milling method to the pin and Udy milling methods used in our laboratory and pilot plant. The results showed that pin milled flour had more uniform particle size than the other 2 milled flours. The chalky kernels found in broken white milled rice were pulverized more into fines in both Udy milled flour and CRF than in the pin milled flour. The excessive amount of fines in flours affected their functional properties, for example, WSI and their potential usage in the novel foods such as rice breads (RB). The RB made from CRF collapsed more than loaves made from pin milled Cypress long-grain flours.

The impact of a 3-year after-school obesity prevention program in elementary school children.

PubMed

Yin, Zenong; Moore, Justin B; Johnson, Maribeth H; Vernon, Marlo M; Gutin, Bernard

2012-02-01

Children tend to be sedentary during the after-school hours, and this has deleterious effects on their health. The objective of the present study was to determine the effects of a 3-year after-school physical activity (PA) program, without restriction of dietary energy intake, on percent body fat (%BF), cardiorespiratory fitness (CRF), and cardiometabolic markers in children. A cluster randomization design was employed. A total of 574 3rd grade children from 18 elementary schools in the southeastern United States participated. The intervention consisted of 80 minutes of age-appropriate moderate-to-vigorous PA each school day. The main outcomes of interest were %BF measured by dual-energy X-ray absorptiometry; CRF measured by heart rate in response to a submaximal step test; nonfasting total and high-density lipoprotein cholesterol (HDL-C); and resting blood pressure (BP). Intent-to-treat analyses showed significant treatment by time interactions for %BF (p = 0.009) and CRF (p = 0.0003). The change pattern of the means suggested that %BF and CRF in intervention children improved relative to control children during the school months, rebounding to the levels of control children over the summers following years 1 and 2. Year-by-year analyses of what occurred during the months when the program was offered revealed dose–response relations for %BF and CRF, such that the clearest beneficial effects were seen for those youth who attended at least 60% of the after-school sessions. No significant intervention effects were seen for cholesterol or BP. An after-school PA program was effective in reducing adiposity and improving CRF, especially in the children who attended the sessions at least 3 days/week. However, the favorable effects on %BF and CRF were lost over the summer. Thus, it is critical to incorporate strategies that attract and retain the children to receive an adequate dose of PA year-round.

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

PubMed

Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

2015-10-01

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Characterization of central and peripheral components of the hypothalamus-pituitary-adrenal axis in the inbred Roman rat strains.

PubMed

Carrasco, Javier; Márquez, Cristina; Nadal, Roser; Tobeña, Adolfo; Fernández-Teruel, Albert; Armario, Antonio

2008-05-01

Several studies performed in outbred Roman high- and low-avoidance lines (RHA and RLA, respectively) have demonstrated that the more anxious line (RLA) is characterized by a higher hypothalamic-pituitary-adrenal (HPA) response to certain stressors than the less anxious one (RHA). However, inconsistent results have also been reported. Taking advantage of the generation of an inbred colony of RLA and RHA rats (RHA-I and RLA-I, respectively), we have characterized in the two strains not only resting and stress levels of peripheral HPA hormones but also central components of the HPA axis, including CRF gene expression in extra-hypothalamic areas. Whereas resting levels of ACTH and corticosterone did not differ between the strains, a greater response to a novel environment was found in RLA-I as compared to RHA-I rats. RLA-I rats showed enhanced CRF gene expression in the paraventricular nucleus (PVN) of the hypothalamus, with normal arginin-vasopressin gene expression in both parvocellular and magnocellular regions of the PVN. This enhanced CRF gene expression is not apparently related to altered negative corticosteroid feedback as similar levels of expression of brain glucorticoid and mineralocorticoid receptors were found in the two rat strains. CRF gene expression tended to be higher in the central amygdala and it was significantly higher in the dorsal region of the bed nucleus of stria terminalis (BNST) of RLA-I rats, while no differences appeared in the ventral region of BNST. Considering the involvement of CRF and the BNST in anxiety and stress-related behavioral alterations, the present data suggest that the CRF system may be a critical neurobiological substrate underlying differences between the two rat strains.

Controlled-rate freezer cryopreservation of highly concentrated peripheral blood mononuclear cells results in higher cell yields and superior autologous T-cell stimulation for dendritic cell-based immunotherapy.

PubMed

Buhl, Timo; Legler, Tobias J; Rosenberger, Albert; Schardt, Anke; Schön, Michael P; Haenssle, Holger A

2012-11-01

Availability of large quantities of functionally effective dendritic cells (DC) represents one of the major challenges for immunotherapeutic trials against infectious or malignant diseases. Low numbers or insufficient T-cell activation of DC may result in premature termination of treatment and unsatisfying immune responses in clinical trials. Based on the notion that cryopreservation of monocytes is superior to cryopreservation of immature or mature DC in terms of resulting DC quantity and immuno-stimulatory capacity, we aimed to establish an optimized protocol for the cryopreservation of highly concentrated peripheral blood mononuclear cells (PBMC) for DC-based immunotherapy. Cryopreserved cell preparations were analyzed regarding quantitative recovery, viability, phenotype, and functional properties. In contrast to standard isopropyl alcohol (IPA) freezing, PBMC cryopreservation in an automated controlled-rate freezer (CRF) with subsequent thawing and differentiation resulted in significantly higher cell yields of immature and mature DC. Immature DC yields and total protein content after using CRF were comparable with results obtained with freshly prepared PBMC and exceeded results of standard IPA freezing by approximately 50 %. While differentiation markers, allogeneic T-cell stimulation, viability, and cytokine profiles were similar to DC from standard freezing procedures, DC generated from CRF-cryopreserved PBMC induced a significantly higher antigen-specific IFN-γ release from autologous effector T cells. In summary, automated controlled-rate freezing of highly concentrated PBMC represents an improved method for increasing DC yields and autologous T-cell stimulation.

Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis.

PubMed

Togashi, Yosuke; Masago, Katsuhiro; Fukudo, Masahide; Terada, Tomohiro; Ikemi, Yasuaki; Kim, Young Hak; Fujita, Shiro; Irisa, Kaoru; Sakamori, Yuichi; Mio, Tadashi; Inui, Ken-Ichi; Mishima, Michiaki

2010-05-01

Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Cardiorespiratory Fitness and Cardiac Autonomic Function in Diabetes.

PubMed

Röhling, Martin; Strom, Alexander; Bönhof, Gidon J; Roden, Michael; Ziegler, Dan

2017-10-23

This review summarizes the current knowledge on the relationship of physical activity, exercise, and cardiorespiratory fitness (CRF) with cardiovascular autonomic neuropathy (CAN) based on epidemiological, clinical, and interventional studies. The prevalence of CAN increases with age and duration of diabetes. Further risk factors for CAN comprise poor glycemic control, dyslipidemia, abdominal obesity, hypertension, and the presence of diabetic complications. CAN has been also linked to reduced CRF. We recently showed that CRF parameters (e.g., maximal oxidative capacity or oxidative capacity at the anaerobic threshold) are associated with cardiac autonomic function in patients recently diagnosed with type 1 or type 2 diabetes. Exercise interventions have shown that physical activity can increase cardiovagal activity and reduce sympathetic overactivity. In particular, long-term and regularly, but also supervised, performed endurance and high-intense and high-volume exercise improves cardiac autonomic function in patients with type 2 diabetes. By contrast, the evidence in those with type 1 diabetes and also in individuals with prediabetes or metabolic syndrome is weaker. Overall, the studies reviewed herein addressing the question whether favorably modulating the autonomic nervous system may improve CRF during exercise programs support the therapeutic concept to promote physical activity and to achieve physical fitness. However, high-quality exercise interventions, especially in type 1 diabetes and metabolic syndrome including prediabetes, are further required to better understand the relationship between physical activity, fitness, and cardiac autonomic function.

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response.

PubMed

Stengel, Andreas; Taché, Yvette F

2017-01-01

Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates-in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis-other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

Disinhibition outside receptive fields in the visual cortex.

PubMed

Walker, Gary A; Ohzawa, Izumi; Freeman, Ralph D

2002-07-01

By definition, the region outside the classical receptive field (CRF) of a neuron in the visual cortex does not directly activate the cell. However, the response of a neuron can be influenced by stimulation of the surrounding area. In previous work, we showed that this influence is mainly suppressive and that it is generally limited to a local region outside the CRF. In the experiments reported here, we investigate the mechanisms of the suppressive effect. Our approach is to find the position of a grating patch that is most effective in suppressing the response of a cell. We then use a masking stimulus at different contrasts over the grating patch in an attempt to disinhibit the response. We find that suppressive effects may be partially or completely reversed by use of the masking stimulus. This disinhibition suggests that effects from outside the CRF may be local. Although they do not necessarily underlie the perceptual analysis of a figure-ground visual scene, they may provide a substrate for this process.

Muscle mass as a target to reduce fatigue in patients with advanced cancer.

PubMed

Neefjes, Elisabeth C W; van den Hurk, Renske M; Blauwhoff-Buskermolen, Susanne; van der Vorst, Maurice J D L; Becker-Commissaris, Annemarie; de van der Schueren, Marian A E; Buffart, Laurien M; Verheul, Henk M W

2017-08-01

Cancer-related fatigue (CRF) reduces quality of life and the activity level of patients with cancer. Cancer related fatigue can be reduced by exercise interventions that may concurrently increase muscle mass. We hypothesized that low muscle mass is directly related to higher CRF. A total of 233 patients with advanced cancer starting palliative chemotherapy for lung, colorectal, breast, or prostate cancer were studied. The skeletal muscle index (SMI) was calculated as the patient's muscle mass on level L3 or T4 of a computed tomography scan, adjusted for height. Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-fatigue questionnaire (cut-off for fatigue <34). Multiple linear regression analyses were conducted to study the association between SMI and CRF adjusting for relevant confounders. In this group of patients with advanced cancer, the median fatigue score was 36 (interquartile range 26-44). A higher SMI on level L3 was significantly associated with less CRF for men (B 0.447, P 0.004) but not for women (B - 0.401, P 0.090). No association between SMI on level T4 and the Functional Assessment of Chronic Illness Therapy-fatigue score was found (n = 82). The association between SMI and CRF may lead to the suggestion that male patients may be able to reduce fatigue by exercise interventions aiming at an increased muscle mass. In women with advanced cancer, CRF is more influenced by other causes, because it is not significantly related to muscle mass. To further reduce CRF in both men and women with cancer, multifactorial assessments need to be performed in order to develop effective treatment strategies. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Molecular Recognition of Corticotropin releasing Factor by Its G protein-coupled Receptor CRFR1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pioszak, Augen A.; Parker, Naomi R.; Suino-Powell, Kelly

2009-01-15

The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observedmore » for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.« less

Addiction research centres and the nurturing of creativity. The Centre for Alcohol and Drug Research: social science alcohol and drug research in Denmark.

PubMed

Pedersen, Mads U; Elmeland, Karen; Frank, Vibeke A

2011-12-01

The purpose of this paper is to introduce the social science alcohol and drug research undertaken by the Centre for Alcohol and Drug Research (CRF) and at the same time offer an insight into the development in Danish alcohol and drug research throughout the past 15-20 years. A review of articles, books and reports published by researcher from CRF from the mid-1990s until today and an analysis of the policy-making in the Danish substance use and misuse area. CRF is a result of the discussions surrounding social, health and allocation policy questions since the mid-1980s. Among other things, these discussions led to the formal establishment of the Centre in 1991 under the Aarhus University, the Faculty of Social Science. Since 2001 the Centre has received a permanent basic allocation, which has made it possible to appoint tenured senior researchers; to work under a more long-term research strategy; to function as a milieu for educating PhD students; and to diversify from commissioned research tasks to initiating projects involving more fundamental research. Research at the Centre is today pivoted around four core areas: consumption, policy, prevention and treatment. The emergence, continuation, financing and character of the research taking place at CRF can be linked closely to the specific Danish drug and alcohol discourse and to the division of the responsibility for alcohol and drug research into separate Ministries. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Preserved autonomic heart rate modulation in chronic renal failure patients in response to hemodialysis and orthostatism.

PubMed

Lerma, Claudia; González, Hortensia; Pérez-Grovas, Hector; José, Marco V; Infante, Oscar

2015-04-01

The aim of this work was to measure the impact of active orthostatism and hemodialysis (HD) upon heart rate variability (HRV) in chronic renal failure (CRF) patients before and after HD. Nineteen healthy subjects (age 27 ± 8 years old, 13 were female) and 19 unmedicated CRF patients with HD thrice per week (average HD vintage = 12 months, age 32 ± 9 years old, 11 were female) were included. Five-minute length HRV time series were obtained during supine position and orthostatism. Recordings from CRF patients were obtained before and after HD. Time domain and frequency domain HRV indexes were compared by analysis of variance. The correlation between each HRV index and change in sympathetic weighting induced by different maneuvers was tested by Kendall's Tau correlation. A p value <0.05 was considered statistically significant. HRV indexes which are associated with sympathetic activity increased in response to orthostatism in the healthy group, e.g., low-frequency to high-frequency (LF/HF) ratio, Ln (LF/HF) = -0.3 ± 0.9 versus 0.9 ± 0.9. CRF patients before HD had higher sympathetic weighting than healthy participants, even in supine position, Ln (LF/HF) = 0.6 ± 1.0, but such a difference was accentuated during orthostatism, Ln (LF/HF) = 1.5 ± 1.0, and after HD: Ln (LF/HF) = 0.8 ± 1.3 (supine position) and 2.5 ± 2.1 (orthostatism). All HRV indexes were associated with increments in sympathetic weighting between maneuvers (Kendall's correlations absolute values ≥ 0.24). Unmedicated young CRF patients treated with hemodynamically stable maintenance HD showed preserved capacity of autonomic response (with gradual sympathetic increases) induced by cardiovascular challenges such as orthostatism and HD.

Identification of biomechanical properties of the cornea: the ocular response analyzer.

PubMed

Terai, Naim; Raiskup, Frederik; Haustein, Michael; Pillunat, Lutz E; Spoerl, Eberhard

2012-07-01

Several methods have been devised for measuring geometric parameters of the cornea but, until now, the biomechanics of the cornea have been largely ignored. The relatively new Ocular Response Analyzer (ORA) provides such biomechanical information. In order to correctly interpret the underlying biomechanics of ORA data, we review reported ORA measurements and provide a compendium of factors influencing these measurements, with discussion of possible explanations for ORA measurement results. This review comprised a literature search using "ocular response analyzer" and "ocular response analyser" as keywords. We reviewed and compared reported results from recent ORA studies so obtained, with an eye to understanding corneal biomechanics. Several ORA biomechanical parameters of the cornea - corneal hysteresis (CH) and corneal resistant factor (CRF) - characterize the viscoelastic properties of the cornea, especially those of the ground substance. The impact on CH and CRF values of various independent factors, e.g. intraocular pressure (IOP), age, central corneal thickness (CCT), and corneal swelling, are discussed. The impact on CH and CRF of treatment-related structural changes of the cornea, i.e. those occurring after refractive surgical procedures, placement of intracorneal rings, and collagen crosslinking (CXL), as well as pathological changes of the cornea, e.g. those resulting from keratoconus, edema, and glaucoma, are discussed. Changes in CRF and CH may be reflective of structural changes in the ground substance of the cornea. Thus, ORA provides invaluable information for delineating biomechanical conditions pertaining to the cornea, with special regard to ocular diseases, e.g. keratoconus and glaucoma.

Nicotine modulation of adolescent dopamine receptor signaling and hypothalamic peptide response

PubMed Central

Mojica, Celina Y.; Dao, Jasmin M.; Yuan, Menglu; Loughlin, Sandra E.; Leslie, Frances M.

2013-01-01

Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown that a 4-day, low-dose nicotine (0.06 mg/kg) pretreatment enhances locomotor and penile response to the D2-like agonist, quinpirole (0.4 mg/kg), in adolescent but not adult rats. The present study is designed to determine mechanisms underlying this effect. Nicotine enhancement of adolescent quinpirole-induced locomotion was mediated by D2 receptors (D2Rs) since it was blocked by the D2R antagonist, L-741,626, but not by the D3R and D4R antagonists, NGB 2904 and L-745,870. Enhancement of quinpirole-induced erectile response was blocked by both L-741,626 and NGB 2904, indicating involvement of D3Rs. Whereas D2R binding was unaffected by adolescent nicotine pretreatment, effector coupling in the striatum was increased, as determined by GTPγS binding. Nicotine pretreatment enhanced quinpirole-induced c-fos mRNA expression in the hypothalamic paraventricular and supraoptic nuclei in adolescents only. Adolescent nicotine pretreatment enhanced c-fos mRNA expression in corticotropin releasing factor (CRF) cells of the paraventricular nucleus, and enhancement of penile erection was blocked by the CRF-1 receptor antagonist, CP 376,396. These findings suggest that adolescent dopamine and CRF systems are vulnerable to alteration by nicotine. This is the first evidence for a role of CRF in adolescent erectile response. PMID:24157491

Molecular and Cell Signaling Targets for PTSD Pathophysiology and Pharmacotherapy

PubMed Central

Hauger, Richard L.; Olivares-Reyes, J. Alberto; Dautzenberg, Frank M.; Lohr, James B.; Braun, Sandra; Oakley, Robert H.

2012-01-01

The reasons for differences in vulnerability or resilience to the development of posttraumatic stress disorder (PTSD) are unclear. Here we review key genetic diatheses and molecular targets especially signaling pathways that mediate responses to trauma and severe stress and their potential contribution to the etiology of PTSD. Sensitization of glucocorticoid receptor (GR) signaling and dysregulation of GR modulators FKBP5, STAT5B, Bcl-2, and Bax have been implicated in PTSD pathophysiology. Furthermore, Akt, NFκB, MKP-1, and p11, which are G protein-coupled receptor (GPCR) pathway molecules, can promote or prevent sustained high anxiety and depressive-like behavior following severe stress. Agonist-induced activation of the corticotropin-releasing factor CRF1 receptor is crucial for survival in the context of serious danger or trauma, but persistent CRF1 receptor hypersignaling when a threatening or traumatic situation is no longer present is maladaptive. CRF1 receptor single nucleotide polymorphisms (SNPs) can confer susceptibility or resilience to childhood trauma while a SNP for the PAC1 receptor, another class B1 GPCR, has been linked genetically to PTSD. GRK3 phosphorylation of the CRF1 receptor protein and subsequent binding of βarrestin2 rapidly terminate Gs-coupled CRF1 receptor signaling by homologous desensitization. A deficient GRK-βarrestin2 mechanism would result in excessive CRF1 receptor signaling thereby contributing to PTSD and co-morbid posttraumatic depression. Clinical trials are needed to assess if small molecule CRF1 receptor antagonists are effective prophylactic agents when administered immediately after trauma. βarrestin2-biased agonists for CRF receptors and possibly other GPCRs implicated in PTSD, however, may prove to be novel pharmacotherapy with greater selectivity and therapeutic efficacy. PMID:22122881

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

PubMed Central

Morisot, Nadège; Rouibi, Khalil; Contarino, Angelo

2015-01-01

Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF2−/−) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of up-shifted motivational states long after opiate withdrawal. Nevertheless, neither CRF2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and long-lasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence. PMID:25672976

Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia.

PubMed

Tenk, Judit; Rostás, Ildikó; Füredi, Nóra; Mikó, Alexandra; Solymár, Margit; Soós, Szilvia; Gaszner, Balázs; Feller, Diana; Székely, Miklós; Pétervári, Erika; Balaskó, Márta

2017-02-01

Hypothalamic corticotropin-releasing factor (CRF) lays downstream to catabolic melanocortins and at least partly mediates their catabolic effects. Age-related changes in the melanocortin system (weak responsiveness in middle-aged and a strong one in old rats) have been shown to contribute to middle-aged obesity and later to aging anorexia and cachexia of old age groups. We hypothesized that catabolic (anorexigenic and hypermetabolic) CRF effects vary with aging similarly to those of melanocortins. Thus, we aimed to test whether age-related variations of CRF effects may also contribute to middle-aged obesity and aging anorexia leading to weight loss of old age groups. Food intake, body weight, core temperature, heart rate, and activity were recorded in male Wistar rats of young, middle-aged, aging, and old age groups (from 3 to 24 months) during a 7-day intracerebroventricular CRF infusion (0.2 μg/μl/h) in a biotelemetric system. In addition, CRF gene expression was also assessed by quantitative RT-PCR in the paraventricular nucleus (PVN) of intact animals of the same age groups. The infusion suppressed body weight in the young, aging, and old rats, but not in middle-aged animals. Weak anorexigenic and hypermetabolic effects were detected in the young, whereas strong anorexia (without hypermetabolism) developed in the oldest age groups in which post mortem analysis showed also a reduction of retroperitoneal fat mass. CRF gene expression in the PVN increased with aging. Our results support the potential contribution of age-related changes in CRF effects to aging anorexia and cachexia. The role of the peptide in middle-aged obesity cannot be confirmed.

Cardiorespiratory fitness and muscle strength in late adolescence and long-term risk of early heart failure in Swedish men.

PubMed

Lindgren, Martin; Åberg, Maria; Schaufelberger, Maria; Åberg, David; Schiöler, Linus; Torén, Kjell; Rosengren, Annika

2017-05-01

Aims To investigate the association between cardiorespiratory fitness (CRF) and muscle strength in late adolescence and the long-term risk of heart failure (HF). Methods A cohort was created of Swedish men enrolled in compulsory military service between 1968 and 2005 with measurements for CRF and muscle strength ( n = 1,226,623; mean age 18.3 years). They were followed until 31 December 2014 for HF hospitalization as recorded in the Swedish national inpatient registry. Results During the follow-up period (median (interquartile range) 28.4 (22.0-37.0) years), 7656 cases of first HF hospitalization were observed (mean ± SD age at diagnosis 50.1 ± 7.9 years). CRF and muscle strength were estimated by maximum capacity cycle ergometer testing and strength exercises (knee extension, elbow flexion and hand grip). Inverse dose-response relationships were found between CRF and muscle strength with HF as a primary or contributory diagnosis with an adjusted hazards ratio (95% confidence interval) of 1.60 (1.44-1.77) for low CRF and 1.45 (1.32-1.58) for low muscle strength categories. The associations of incident HF with CRF and muscle strength persisted, regardless of adjustments for the other potential confounders. The highest risk was observed for HF associated with coronary heart disease, diabetes or hypertension. Conclusions In this longitudinal study of young men, we found inverse and mutually independent associations between CRF and muscle strength with risk of hospitalization for HF. If causal, these results may emphasize the importance of the promotion of CRF and muscle strength in younger populations.

PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment.

PubMed

Dunn, Henry A; Chahal, Harpreet S; Caetano, Fabiana A; Holmes, Kevin D; Yuan, George Y; Parikh, Ruchi; Heit, Bryan; Ferguson, Stephen S G

2016-05-01

Corticotropin-releasing factor (CRF) is a neuropeptide commonly associated with the hypothalamic-pituitary adrenal axis stress response. Upon release, CRF activates two G protein-coupled receptors (GPCRs): CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2). Although both receptors contribute to mood regulation, CRFR1 antagonists have demonstrated anxiolytic and antidepressant-like properties that may be exploited in the generation of new pharmacological interventions for mental illnesses. Previous studies have demonstrated CRFR1 capable of heterologously sensitizing serotonin 2A receptor (5-HT2AR) signaling: another GPCR implicated in psychiatric disease. Interestingly, this phenomenon was dependent on Postsynaptic density 95 (PSD-95)/Disc Large/Zona Occludens (PDZ) interactions on the distal carboxyl termini of both receptors. In the current study, we demonstrate that endogenous PSD-95 can be co-immunoprecipitated with CRFR1 from cortical brain homogenate, and this interaction appears to be primarily via the PDZ-binding motif. Additionally, PSD-95 colocalizes with CRFR1 within the dendritic projections of cultured mouse neurons in a PDZ-binding motif-dependent manner. In HEK 293 cells, PSD-95 overexpression inhibited CRFR1 endocytosis, whereas PSD-95 shRNA knockdown enhanced CRFR1 endocytosis. Although PSD-95 does not appear to play a significant role in CRF-mediated cAMP or ERK1/2 signaling, PSD-95 was demonstrated to suppress β-arrestin2 recruitment: providing a potential mechanism for PSD-95's inhibition of endocytosis. In revisiting previously documented heterologous sensitization, PSD-95 shRNA knockdown did not prevent CRFR1-mediated enhancement of 5-HT2AR signaling. In conclusion, we have identified and characterized a novel functional relationship between CRFR1 and PSD-95 that may have implications in the design of new treatment strategies for mental illness. Copyright © 2016 Elsevier Inc. All rights reserved.

High Dynamic Range Imaging Using Multiple Exposures

NASA Astrophysics Data System (ADS)

Hou, Xinglin; Luo, Haibo; Zhou, Peipei; Zhou, Wei

2017-06-01

It is challenging to capture a high-dynamic range (HDR) scene using a low-dynamic range (LDR) camera. This paper presents an approach for improving the dynamic range of cameras by using multiple exposure images of same scene taken under different exposure times. First, the camera response function (CRF) is recovered by solving a high-order polynomial in which only the ratios of the exposures are used. Then, the HDR radiance image is reconstructed by weighted summation of the each radiance maps. After that, a novel local tone mapping (TM) operator is proposed for the display of the HDR radiance image. By solving the high-order polynomial, the CRF can be recovered quickly and easily. Taken the local image feature and characteristic of histogram statics into consideration, the proposed TM operator could preserve the local details efficiently. Experimental result demonstrates the effectiveness of our method. By comparison, the method outperforms other methods in terms of imaging quality.

Stress, gender, and addiction: potential roles of CRF, oxytocin and argininevasopressin

PubMed Central

Bisagno, Verónica; Lud Cadet, Jean

2014-01-01

Stress sensitivity and gender are predictive factors for the development of neuropsychiatric disorders. Life stresses are not only risk factors for the development of addiction but they are also triggers for relapse to drug use. Therefore, it is imperative to elucidate the molecular mechanisms underlying the interactions between stress and drug abuse, because this understanding may help in the development of novel and more effective therapeutic approaches to block the clinical manifestations of drug addiction. The development and clinical course of addiction-related disorders do appear to involve neuroadaptations within neurocircuitries that modulate stress responses and are influenced by several neuropeptides. These include corticotropin releasing factor (CRF), the prototypic member of this class, as well as oxytocin (OXY) and arginine-vasopressin (AVP) that play important roles in affiliative behaviors. Interestingly, these peptides function to balance emotional behaviors in a sexual dimorphism of OXY/AVP systems, a fact that might play an important role in the differential responses of women and men to stressful stimuli and the specific gender-based prevalence of certain addictive disorders. Thus, this review aims to summarize (1) the contribution of sex differences to the function of dopamine systems, and (2) the behavioral, neurochemical, and anatomical changes in brain stress systems. PMID:24949572

Central apelin mediates stress-induced gastrointestinal motor dysfunction in rats.

PubMed

Bülbül, Mehmet; İzgüt-Uysal, V Nimet; Sinen, Osman; Birsen, İlknur; Tanrıöver, Gamze

2016-02-15

Apelin, an endogenous ligand for APJ receptor, has been reported to be upregulated in paraventricular nucleus (PVN) following stress. Central apelin is known to stimulate release of corticotropin-releasing factor (CRF) via APJ receptor. We tested the hypothesis that stress-induced gastrointestinal (GI) dysfunction is mediated by central apelin. We also assessed the effect of exogenous apelin on GI motility under nonstressed (NS) conditions in conscious rats. Prior to solid gastric emptying (GE) and colon transit (CT) measurements, APJ receptor antagonist F13A was centrally administered under NS conditions and following acute stress (AS), chronic homotypic stress (CHS), and chronic heterotypic stress (CHeS). Plasma corticosterone was assayed. Strain gage transducers were implanted on serosal surfaces of antrum and distal colon to record postprandial motility. Stress exposure induced coexpression of c-Fos and apelin in hypothalamic PVN. Enhanced hypothalamic apelin and CRF levels in microdialysates were detected following AS and CHeS, which were negatively and positively correlated with GE and CT, respectively. Central F13A administration abolished delayed GE and accelerated CT induced by AS and CHeS. Central apelin-13 administration increased the plasma corticosterone and inhibited GE and CT by attenuating antral and colonic contractions. The inhibitory effect elicited by apelin-13 was abolished by central pretreatment of CRF antagonist CRF9-41 in antrum, but not in distal colon. Central endogenous apelin mediates stress-induced changes in gastric and colonic motor functions through APJ receptor. The inhibitory effects of central exogenous apelin-13 on GI motility appear to be partly CRF dependent. Apelin-13 inhibits colon motor functions through a CRF-independent pathway. Copyright © 2016 the American Physiological Society.

Region-Specific Onset of Handling-Induced Changes in Corticotropin-Releasing Factor and Glucocorticoid Receptor Expression

PubMed Central

Fenoglio, Kristina A.; Brunson, Kristen L.; Avishai-Eliner, Sarit; Chen, Yuncai; Baram, Tallie Z.

2011-01-01

Early-life experience including maternal care profoundly influences hormonal stress responses during adulthood. Daily handling on postnatal day (P) 2–9, eliciting augmented maternal care upon returning pups to their cage, permanently modifies the expression of the stress neuromodulators corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR). We have previously demonstrated reduced hypothalamic CRF expression already at the end of the handling period, followed by enhanced hippocampal GR mRNA levels (by P45). However, the initial site(s) and time of onset of these enduring changes have remained unclear. Therefore, we used semiquantitative in situ hybridization to delineate the spatiotemporal evolution of CRF and GR expression throughout stress-regulatory brain regions in handled (compared with undisturbed) pups. Enhanced CRF mRNA expression was apparent in the amygdaloid central nucleus (ACe) of handled pups already by P6. By P9, the augmented CRF mRNA levels persisted in ACe, accompanied by increased peptide expression in the bed nucleus of the stria terminalis and reduced expression in the paraventricular nucleus. The earliest change in GR consisted of reduced expression in the ACe of handled pups on P9, a time point when hippocampal GR expression was not yet affected. Thus, altered gene expression in ACe, bed nucleus of the stria terminalis as well as paraventricular nucleus may contribute to the molecular cascade by which handling (and increased maternal care) influences the stress response long term. PMID:15044366

Chronic Anabolic Androgenic Steroid Exposure Alters Corticotropin Releasing Factor Expression and Anxiety-Like Behaviors in the Female Mouse

PubMed Central

Costine, Beth A; Oberlander, Joseph G; Davis, Matthew C; Penatti, Carlos A A; Porter, Donna M; Leaton, Robert N; Henderson, Leslie P

2010-01-01

Summary In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BNST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST. PMID:20537804

Identification of members of the gonadotropin-releasing hormone (GnRH), corticotropin-releasing factor (CRF) families in the genome of the holocephalan, Callorhinchus milii (elephant shark).

PubMed

Nock, Tanya G; Chand, Dhan; Lovejoy, David A

2011-04-01

The gonadotropin-releasing hormone (GnRH) and corticotropin-releasing family (CRF) are two neuropeptides families that are strongly conserved throughout evolution. Recently, the genome of the holocephalan, Callorhinchus milii (elephant shark) has been sequenced. The phylogenetic position of C. milii, along with the relatively slow evolution of the cartilaginous fish suggests that neuropeptides in this species may resemble the earliest gnathostome forms. The genome of the elephant shark was screened, in silico, using the various conserved motifs of both the vertebrate CRF paralogs and the insect diuretic hormone sequences to identify the structure of the C. milii CRF/DH-like peptides. A similar approach was taken to identify the GnRH peptides using conserved motifs in both vertebrate and invertebrate forms. Two CRF peptides, a urotensin-1 peptide and a urocortin 3 peptide were found in the genome. There was only about 50% sequence identity between the two CRF peptides suggesting an early divergence. In addition, the urocortin 2 peptide seems to have been lost and was identified as a pseudogene in C. milii. In contrast to the number of CRF family peptides, only a GnRH-II preprohormone with the conserved mature decapeptide was found. This confirms early studies about the identity of GnRH in the Holocephali, and suggests that the Holocephali and Elasmobranchii differ with respect to GnRH structure and function. Copyright © 2011 Elsevier Inc. All rights reserved.

Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin

PubMed Central

Martin-Fardon, Rémi; Zorrilla, Eric P.; Ciccocioppo, Roberto; Weiss, Friedbert

2010-01-01

Stress-like symptoms are an integral part of acute and protracted drug withdrawal, and several lines of evidence have shown that dysregulation of brain stress systems, including the extrahypothalamic corticotropin-releasing factor (CRF) system, following long-term drug use is of major importance in maintaining drug and alcohol addiction. Recently, two other neuropeptide systems have attracted interest, the nociceptin/orphanin FQ (N/OFQ) and orexin/hypocretin (Orx/Hcrt) systems. N/OFQ participates in a wide range of physiological responses, and the hypothalamic Orx/Hcrt system helps regulate several physiological processes, including feeding, energy metabolism, and arousal. Moreover, these two systems have been suggested to participate in psychiatric disorders, including anxiety and drug addiction. Dysregulation of these systems by chronic drug exposure has been hypothesized to play a role in the maintenance of addiction and dependence. Recent evidence demonstrated that interactions between CRF-N/OFQ and CRF-Orx/Hcrt systems may be functionally relevant for the control of stress-related addictive behavior. The present review discusses recent findings that support the hypotheses of the participation and dysregulation of these systems in drug addiction and evaluates the current understanding of interactions among these stress-regulatory peptides. PMID:20026088

Effects of Orthostatism and Hemodialysis on Mean Heart Period and Fractal Heart Rate Properties of Chronic Renal Failure Patients.

PubMed

Echeverría, Juan C; Infante, Oscar; Pérez-Grovas, Héctor; González, Hortensia; José, Marco V; Lerma, Claudia

2017-11-01

The aim of this work was to evaluate the short-term fractal index (α 1 ) of heart rate variability (HRV) in chronic renal failure (CRF) patients by identifying the effects of orthostatism and hemodialysis (HD), and by evaluating the correlation between α 1 and the mean RR interval from sinus beats (meanNN). HRV time series were derived from ECG data of 19 CRF patients and 20 age-matched healthy subjects obtained at supine and orthostatic positions (lasting 5 min each). Data from CRF patients were collected before and after HD. α 1 was calculated from each time series and compared by analysis of variance. Pearson's correlations between meanNN and α 1 were calculated using the data from both positions by considering three groups: healthy subjects, CRF before HD and CRF after HD. At supine position, α 1 of CRF patients after HD (1.17 ± 0.30) was larger (P < 0.05) than in healthy subjects (0.89 ± 0.28) but not before HD (1.10 ± 0.34). α 1 increased (P < 0.05) in response to orthostatism in healthy subjects (1.29 ± 0.26) and CRF patients after HD (1.34 ± 0.31), but not before HD (1.25 ± 0.37). Whereas α 1 was correlated (P < 0.05) with the meanNN of healthy subjects (r = -0.562) and CRF patients after HD (r = -0.388), no significance in CRF patients before HD was identified (r = 0.003). Multiple regression analysis confirmed that α 1 was mainly predicted by the orthostatic position (in all groups) and meanNN (healthy subjects and patients after HD), showing no association with the renal disease condition in itself. In conclusion, as in healthy subjects, α 1 of CRF patients correlates with meanNN after HD (indicating a more irregular-like HRV behavior at slower heart rates). This suggests that CRF patients with stable blood pressure preserve a regulatory adaptability despite a shifted setting point of the heart period (i.e., higher heart rate) in comparison with healthy subjects. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Integrative nonpharmacologic behavioral interventions for the management of cancer-related fatigue.

PubMed

Mustian, Karen M; Morrow, Gary R; Carroll, Jennifer K; Figueroa-Moseley, Colmar D; Jean-Pierre, Pascal; Williams, Geoffrey C

2007-01-01

Cancer-related fatigue (CRF) is a debilitating, multi-faceted biopsychosocial symptom experienced by the majority of cancer survivors during and after treatment. CRF begins after diagnosis and frequently persists long after treatments end, even when the cancer is in remission. The etiological pathopsychophysiology underlying CRF is multifactorial and not well delineated. Mechanisms may include abnormal accumulation of muscle metabolites, dysregulation of the homeostatic status of cytokines, irregularities in neuromuscular function, abnormal gene expression, inadequate ATP synthesis, serotonin dysregulation, abnormal vagal afferent nerve activation, as well as an array of psychosocial mechanisms, including self-efficacy, causal attributions, expectancy, coping, and social support. An important first step in the management of CRF is the identification and treatment of associated comorbidities, such as anemia, hypothyroidism, pain, emotional distress, insomnia, malnutrition, and other comorbid conditions. However, even effective clinical management of these conditions will not necessarily alleviate CRF for a significant proportion of cancer survivors. For these individuals, intervention with additional therapeutic modalities may be required. The National Comprehensive Cancer Network guidelines recommend that integrative nonpharmacologic behavioral interventions be implemented for the effective management of CRF. These types of interventions may include exercise, psychosocial support, stress management, energy conservation, nutritional therapy, sleep therapy, and restorative therapy. A growing body of scientific evidence supports the use of exercise and psychosocial interventions for the management of CRF. Research on these interventions has yielded positive outcomes in cancer survivors with different diagnoses undergoing a variety of cancer treatments. The data from trials investigating the efficacy of other types of integrative nonpharmacologic behavioral therapies for the management of CRF, though limited, are also encouraging. This article provides an overview of current research on the relative merits of integrative nonpharmacologic behavioral interventions for the effective clinical management of CRF and makes recommendations for future research. Disclosure of potential conflicts of interest is found at the end of this article.

Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism.

PubMed

Han, Xiao; DeBold, Joseph F; Miczek, Klaus A

2017-09-01

A history of brief intermittent social defeat stress can escalate cocaine self-administration and induce long-term adaptations in the mesolimbic dopamine system. Extra-hypothalamic corticotrophin releasing factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use. How repeated stress modulates CRF release in the ventral tegmental area (VTA) and the roles of CRF receptors during different phases of stress-induced cocaine self-administration remain to be defined. The current study examines the roles of CRF and CRF receptor 1 (CRFR1) in escalated intravenous cocaine self-administration after exposure to social defeat stress in mice. First, CRFR1 antagonist (CP 376,395, 15 mg/kg, i.p.) given 30 min prior to each social defeat episode prevented later escalated cocaine self-administration. When CP 376,395 (5 and 15 mg/kg, i.p.) was administered 10 days after the last episode of social stress, the escalation of cocaine intake was dose-dependently reversed. Moreover, socially defeated mice showed increased CRF release in the VTA compared to controls. To further explore the role of CRFR1, CP 376,395 (0.5 and 1 μg/0.2 μl) was infused directly into the VTA before the cocaine self-administration session. Intra-VTA antagonism of CRFR1 was sufficient to reverse social defeat stress-escalated cocaine self-administration. These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration.

Responding for a conditioned reinforcer or unconditioned sensory reinforcer in mice: interactions with environmental enrichment, social isolation, and monoamine reuptake inhibitors.

PubMed

Browne, Caleb J; Fletcher, Paul J; Zeeb, Fiona D

2016-03-01

Environmental factors influence the etiology of many psychiatric disorders. Likewise, environmental factors can alter processes central to motivation. Therefore, motivational deficits present in many disorders may be influenced by early life environmental conditions. We examined whether housing animals in different environmental conditions influenced the ability of sensory stimuli to acquire incentive value and whether elevated monoamine activity altered responsing for these stimuli. Isolation-housed (IH), pair-housed (PH), and environmentally enriched (EE) male C57BL/6N mice were examined in tests of responding for a conditioned reinforcer (CRf) or an unconditioned sensory reinforcer (USRf). The CRf was previously paired with saccharin delivery through Pavlovian conditioning, while the USRf was not conditioned with a reward. Following baseline tests of responding for the CRf or USRf, the effects of elevated monoamine activity were examined. At baseline, PH and EE mice responded similarly for the CRf or USRf. IH mice responded more for the CRf but exhibited slower acquisition of responding for the USRf. Administration of citalopram, a serotonin transporter blocker, or atomoxetine, a norepinephrine transporter blocker, decreased responding for the CRf and USRf in all groups. The dopamine transporter blocker GBR 12909 generally increased responding for the CRf and USRf, but further analysis revealed enhanced responding for both reinforcers only in EE mice. Baseline incentive motivation is strongly influenced by the social component of housing conditions. Furthermore, environmental enrichment increased the sensitivity to elevated dopamine activity, while acute elevations in serotonin and norepinephrine inhibit incentive motivation irrespective of housing condition.

The relationship between corneal biomechanical properties and confocal microscopy findings in normal and keratoconic eyes.

PubMed

Hurmeric, Volkan; Sahin, Afsun; Ozge, Gokhan; Bayer, Atilla

2010-06-01

To investigate the relationship between corneal biomechanical properties and confocal microscopy (CM) findings in normal and keratoconic eyes. The study consisted of 28 eyes of 28 healthy volunteers and 23 eyes of 15 patients with keratoconus. The diagnosis of keratoconus was made with corneal topography and clinical findings. The corneal hysteresis (CH) and corneal resistance factor (CRF) were measured by the ocular response analyzer. In vivo CM was performed with NIDEK Confoscan 3. CH and CRF were compared with corneal morphological findings (detailed cell counts of endothelial, stromal, and epithelial cells) in vivo. CH was 10.1 +/- 1.3 mm Hg in normal eyes and 7.4 +/- 1.5 mm Hg in keratoconic eyes (P < 0.0001). CRF was 10.1 +/- 1.8 mm Hg in normal eyes and 6.2 +/- 1.4 mm Hg in keratoconic eyes (P < 0.0001). CH and CRF were negatively correlated with full-thickness stromal keratocyte density (P < 0.01; r = -0.52 and P < 0.001; r = -0.67, respectively) in healthy eyes. Keratocyte density of the posterior half of the stroma was found to be significantly related with CRF in healthy eyes (beta = -0.404; P = 0.01). There was no significant relationship among CH, CRF, and CM findings in eyes with keratoconus. There is a significant relationship between CRF and keratocyte density of the posterior half of the stroma in healthy eyes. Our results suggest that corneal elasticity is related to not only stromal matrix but also cellular structure of the cornea.

Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

PubMed

Peciña, Susana; Schulkin, Jay; Berridge, Kent C

2006-04-13

Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 microl) or amphetamine (20 microg/0.2 microl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 microg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent attempts to ameliorate aversive states. We conclude that CRF in nucleus accumbens shell amplifies positive motivation for cued rewards, in particular by magnifying incentive salience that is attributed to Pavlovian cues previously associated with those rewards. CRF-induced magnification of incentive salience provides a novel explanation as to why stress may produce cue-triggered bursts of binge eating, drug addiction relapse, or other excessive pursuits of rewards.

Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

PubMed Central

Peciña, Susana; Schulkin, Jay; Berridge, Kent C

2006-01-01

Background Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl) or amphetamine (20 μg/0.2 μl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Results Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 μg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent attempts to ameliorate aversive states. Conclusion We conclude that CRF in nucleus accumbens shell amplifies positive motivation for cued rewards, in particular by magnifying incentive salience that is attributed to Pavlovian cues previously associated with those rewards. CRF-induced magnification of incentive salience provides a novel explanation as to why stress may produce cue-triggered bursts of binge eating, drug addiction relapse, or other excessive pursuits of rewards. PMID:16613600

Dose-adjusted arsenic trioxide for acute promyelocytic leukaemia in chronic renal failure.

PubMed

Firkin, Frank; Roncolato, Fernando; Ho, Wai Khoon

2015-10-01

To determine the potential for arsenic trioxide (ATO) to be safely and effectively incorporated into induction therapy of newly diagnosed acute promyelocytic leukaemia (APL) in patients with severe chronic renal failure (CRF) by reduction of the ATO dosage to compensate for reduced renal elimination of arsenic in CRF. Two of the four CRF patients with APL in the study were dialysis-dependent, and two had eGFRs of 18 and 19 mL/min/1.73 m(2) . ATO dosage schedules were adjusted to obtain comparable whole-blood arsenic levels to those in APL patients with normal renal function who achieved molecular remission (MR) while receiving 10 mg ATO daily for 28 d. Average ATO administered per day in CRF patients ranged from 36 to 50% of the ATO administered to APL patients with normal renal function. No clinically significant cardiac, hepatic or other toxicities were detected. RT-PCR-negative MR was achieved after one treatment course in two patients and after two courses in the others. Relapse-free survival is 155, 60, 43 and 5 months. The observations in this pilot study have demonstrated whole-blood arsenic levels can provide a guide to adjustments of ATO dosage schedules that permit safe and effective therapeutic outcomes in APL patients with severely compromised renal function. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of Citalopram on Serotonin and CRF Systems in the Midbrain of Primates with Differences in Stress Sensitivity

PubMed Central

Bethea, Cynthia L.; Lima, Fernanda B.; Centeno, Maria L.; Weissheimer, Karin V.; Senashova, Olga; Reddy, Arubala P.; Cameron, Judy L.

2011-01-01

This chapter reviews the neurobiological effects of stress sensitivity and CIT treatment observed in our nonhuman primate model of Functional Hypothalamic Amenorrhea (FHA). This type of infertility, also known as stress-induced amenorrhea, is exhibited by cynomolgus macaques. In small populations, some individuals are stress sensitive (SS) and others are highly stress resilient (HSR). The SS macaques have suboptimal secretion of estrogen and progesterone during normal menstrual cycles. SS monkeys also have decreased serotonin gene expression and increased CRF expression compared to HSR monkeys. Recently, we found that s-citalopram (CIT) treatment improved ovarian steroid secretion in SS monkeys, but had no effect in HSR monkeys. Examination of the serotonin system revealed that SS monkeys had significantly lower Fev (fifth Ewing variant, rodent Pet1), TPH2 (tryptophan hydroxylase 2), 5HT1A autoreceptor and SERT (serotonin reuptake transporter) expression in the dorsal raphe than SR monkeys. However, CIT did not alter the expression of either Fev, TPH2, SERT or 5HT1A mRNAs. In contrast, SS monkeys tended to a higher density of CRF fiber innervation of the dorsal raphe than HSR monkeys, and CIT significantly decreased the CRF fiber density in SS animals. In addition, CIT increased CRF-R2 gene expression in the dorsal raphe. We speculate that in a 15-week time frame, the therapeutic effect of S-citalopram may be achieved through a mechanism involving extracellular serotonin inhibition of CRF and stimulation of CRF-R2, rather than alteration of serotonin-related gene expression. PMID:21683135

Cerebellar learning properties are modulated by the CRF receptor in granular cells.

PubMed

Ezra-Nevo, Gili; Prestori, Francesca; Locatelli, Francesca; Soda, Teresa; Ten Brinke, Michiel M; Engel, Mareen; Boele, Henk-Jan; Botta, Laura; Leshkowitz, Dena; Ramot, Assaf; Tsoory, Michael; Biton, Inbal E; Deussing, Jan; D'Angelo, Egidio; De Zeeuw, Chris I; Chen, Alon

2018-06-22

Corticotropin-releasing factor (CRF) and its type 1 receptor (CRFR 1 ) play an important role in the responses to stressful challenges. Despite the well-established expression of CRFR 1 in granular cells (GrCs), its role in procedural motor performance and memory formation remains elusive. To investigate the role of CRFR 1 expression in cerebellar GrCs, we used a mouse model depleted of CRFR 1 in these cells. We detected changes in the cellular learning mechanisms in GrCs depleted of CRFR 1 in that they showed changes in intrinsic excitability and long-term synaptic plasticity. Moreover, male mice depleted of CRFR 1 specifically in GrCs showed accelerated Pavlovian associative eye-blink conditioning, but no differences in baseline motor performance, locomotion or fear and anxiety-related behaviors. Last, we analyzed cerebella transcriptome of KO and control mice and detected prominent alterations in the expression of calcium signaling pathways components. Our findings shed light on the interplay between stress-related central mechanisms and cerebellar motor conditioning, highlighting the role of the CRF system in regulating particular forms of cerebellar learning. SIGNIFICANCE STATEMENT Although it is known that CRFR 1 is highly expressed in the cerebellum, little attention has been given to its role in cerebellar functions in the behaving animal. Moreover, most of the attention was directed to the effect of CRF on Purkinje cells at the cellular level, and to this date, almost no data exist on the role of this stress-related receptor in other cerebellar structures. Here, we explored the behavioral and cellular effect of GrCs specific ablation of CRFR 1 We found a profound effect on learning, both at the cellular and behavioral levels, without affecting baseline motor skills. Copyright © 2018 the authors.

Induction of A. fumigatus-specific CD4-positive T cells in patients recovering from invasive aspergillosis

PubMed Central

Jolink, Hetty; Hagedoorn, Renate S.; Lagendijk, Ellen L.; Drijfhout, Jan W.; van Dissel, Jaap T.; Falkenburg, J.H. Frederik; Heemskerk, Mirjam H.M.

2014-01-01

After allogeneic stem cell transplantation patients are at risk of invasive aspergillosis, especially during the period of neutropenia. Recent data suggest that impaired T-cell immune reconstitution after transplantation plays an important role in this increased risk. In this study we investigated whether Aspergillus-specific T cells are involved in the recovery from invasive aspergillosis by analyzing the Aspergillus-specific T-cell response in patients with invasive aspergillosis. In nine patients whose Aspergillus infection improved, we identified Crf1- or Catalase1-specific T cells on the basis of CD154 expression and interferon-γ production following stimulation with overlapping peptides of the A. fumigatus proteins Crf1 and Catalase1. These Aspergillus-specific T cells were induced at the moment of regression of the aspergillus lesions. Crf1- and Catalase1-specific T cells, sorted on the basis of CD154 expression at the peak of the immune response, had a T helper-1 phenotype and recognized a variety of T-cell epitopes. In contrast, in two patients with progressive invasive aspergillosis, no Crf1- or Catalase1-specific T cells were identified. These data indicate that the presence of Aspergillus-specific T cells with a T helper-1 phenotype correlates with the clearance of aspergillus infection. PMID:24747947

Cardiorespiratory fitness moderates the effect of an affect-guided physical activity prescription: a pilot randomized controlled trial.

PubMed

Baldwin, Austin S; Kangas, Julie L; Denman, Deanna C; Smits, Jasper A J; Yamada, Tetsuhiro; Otto, Michael W

2016-11-01

Physical activity (PA) interventions have a clear role in promoting mental health. Current PA guidelines directed toward specific PA intensities may have negative effects on affective response to exercise, and affective response is an important determinant of PA adherence. In this randomized trial of 67 previously inactive adults, we compared the effects of a PA prescription emphasizing the maintenance of positive affect to one emphasizing a target heart rate, and tested the extent to which the effect of the affect-guided prescription on PA is moderated by cardiorespiratory fitness (CRF). We found the effect of an affect-guided prescription was significantly moderated by CRF. At one week, for participants with lower CRF (i.e. poor conditioning), the affect-guided prescription resulted in significantly greater change in PA minutes (M = 240.8) than the heart rate-guided prescription (M = 165.7), reflecting a moderate-sized effect (d = .55). For those with higher CRF (i.e. good conditioning), the means were in the opposite direction but not significantly different. At one month, the same pattern emerged but the interaction was not significant. We discuss the implications of these findings for the type of PA prescriptions offered to individuals in need.

Adding high-intensity interval training to conventional training modalities: optimizing health-related outcomes during chemotherapy for breast cancer: the OptiTrain randomized controlled trial.

PubMed

Mijwel, Sara; Backman, Malin; Bolam, Kate A; Jervaeus, Anna; Sundberg, Carl Johan; Margolin, Sara; Browall, Maria; Rundqvist, Helene; Wengström, Yvonne

2018-02-01

Exercise training is an effective and safe way to counteract cancer-related fatigue (CRF) and to improve health-related quality of life (HRQoL). High-intensity interval training has proven beneficial for the health of clinical populations. The aim of this randomized controlled trial was to compare the effects of resistance and high-intensity interval training (RT-HIIT), and moderate-intensity aerobic and high-intensity interval training (AT-HIIT) to usual care (UC) in women with breast cancer undergoing chemotherapy. The primary endpoint was CRF and the secondary endpoints were HRQoL and cancer treatment-related symptoms. Two hundred and forty women planned to undergo chemotherapy were randomized to supervised RT-HIIT, AT-HIIT, or UC. Measurements were performed at baseline and at 16 weeks. Questionnaires included Piper Fatigue Scale, EORTC-QLQ-C30, and Memorial Symptom Assessment Scale. The RT-HIIT group was superior to UC for CRF: total CRF (p = 0.02), behavior/daily life (p = 0.01), and sensory/physical (p = 0.03) CRF. Role functioning significantly improved while cognitive functioning was unchanged for RT-HIIT compared to declines shown in the UC group (p = 0.04). AT-HIIT significantly improved emotional functioning versus UC (p = 0.01) and was superior to UC for pain symptoms (p = 0.03). RT-HIIT reported a reduced symptom burden, while AT-HIIT remained stable compared to deteriorations shown by UC (p < 0.01). Only RT-HIIT was superior to UC for total symptoms (p < 0.01). 16 weeks of resistance and HIIT was effective in preventing increases in CRF and in reducing symptom burden for patients during chemotherapy for breast cancer. These findings add to a growing body of evidence supporting the inclusion of structured exercise prescriptions, including HIIT, as a vital component of cancer rehabilitation. Clinicaltrials.gov Registration Number: NCT02522260.

The CRF-1 receptor antagonist, CP-154,526, attenuates stress-induced increases in ethanol consumption by BALB/cJ mice.

PubMed

Lowery, Emily G; Sparrow, Angela M; Breese, George R; Knapp, Darin J; Thiele, Todd E

2008-02-01

Corticotropin-releasing factor (CRF) signaling modulates neurobiological responses to stress and ethanol, and may modulate observed increases in ethanol consumption following exposure to stressful events. The current experiment was conducted to further characterize the role of CRF1 receptor (CRF1R) signaling in stress-induced increases in ethanol consumption in BALB/cJ and C57BL/6N mice. Male BALB/cJ and C57BL/6N mice were given continuous access to 8% (v/v) ethanol and water for the duration of the experiment. When a baseline of ethanol consumption was established, animals were exposed to 5 minutes of forced swim stress on each of 5 consecutive days. Thirty minutes before each forced swim session, animals were given an intraperitoneal injection of a 10 mg/kg dose of CP-154,526, a selective CRF1R antagonist, or an equal volume of vehicle. The effect of forced swim stress exposure on consumption of a 1% (w/v) sucrose solution was also investigated in an ethanol-naïve group of BALB/cJ mice. Exposure to forced swim stress significantly increased ethanol consumption by the BALB/cJ, but not of the C57BL/6N, mice. Stress-induced increases in ethanol consumption were delayed and became evident approximately 3 weeks after the first stressor. Additionally, forced swim stress did not cause increases of food or water intake and did not promote delayed increases of sucrose consumption. Importantly, BALB/cJ mice pretreated with the CRF1R antagonist showed blunted stress-induced increases in ethanol intake, and the CRF1R antagonist did not influence the ethanol drinking of non-stressed mice. The present results provide evidence that CRF1R signaling modulates the delayed increase of ethanol consumption stemming from repeated exposure to a stressful event in BALB/cJ mice.

Emergence as an outbreak of the HIV-1 CRF19_cpx variant in treatment-naïve patients in southern Spain.

PubMed

González-Domenech, Carmen M; Viciana, Isabel; Delaye, Luis; Mayorga, María Luisa; Palacios, Rosario; de la Torre, Javier; Jarilla, Francisco; Castaño, Manuel; Del Arco, Alfonso; Clavijo, Encarnación; Santos, Jesús

2018-01-01

CRF19_cpx is a complex circulating recombination form (CRF) of HIV-1. We describe the characteristics of an outbreak of the CRF19_cpx variant among treatment-naïve patients in southern Spain. The study was undertaken at the Virgen de la Victoria Hospital, a reference centre for the analysis of HIV-1 genotype in Malaga (Spain). Subtyping was performed through REGA v3.0 and the relationship of our CRF19_cpx sequences, among themselves and regarding other reference sequences from the same variant, was defined by phylogenetic analysis. We used PhyML program to perform a reconstruction of the phylogeny by Maximum Likelihood method as well as further confirmation of the transmission clusters by Bayesian inference. Additionally, we collected demographic, clinical and immunovirological data. Between 2011 and 2016, we detected 57 treatment-naïve patients with the CRF19_cpx variant. Of these, 55 conformed a very well-defined transmission cluster, phylogenetically close to CRF19_cpx sequences from the United Kingdom. The origin of this subtype in Malaga was dated between 2007 and 2010. Over 50% of the patients presented the non-nucleoside reverse transcriptase inhibitor G190A resistance mutation. This variant was mostly represented by young adult Spanish men who had sex with men. Almost half of them were recent seroconverters, though a similar percentage was diagnosed at a late state of HIV infection. Five cases of AIDS and one non-AIDS defined death occurred during follow-up. The majority of patients treated with first-line combination antiretroviral therapy (ART) responded. We report the largest HIV-1 CRF19_cpx cohort of treatment-naïve patients outside Cuba, almost all emerging as an outbreak in the South of Spain. Half the cases had the G190A resistance mutation. Unlike previous studies, the variant from Malaga seems less pathogenic, with few AIDS events and an excellent response to ART.

Therapeutic Utility of Non-Peptidic CRF1 Receptor Antagonists in Anxiety, Depression, and Stress-Related Disorders: Evidence from Animal Models

PubMed Central

Kehne, John H.; Cain, Christopher K.

2012-01-01

Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF1) receptors in stress response system pathways is linked to stress-related psychopathology and CRF1 receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders. CRAs have a distinct phenotype in animals that has similarities to, and differences from, those of classic antidepressants and anxiolytics. CRAs are generally behaviorally silent, indicating that CRF1 receptors are normally in a state of low basal activation. CRAs reduce stressor-induced HPA axis activation by blocking pituitary and possibly brain CRF1 receptors which may ameliorate chronic stress-induced pathology. In animal models sensitive to anxiolytics and/or antidepressants, CRAs are generally more active in those with high stress levels, conditions which may maximize CRF1 receptor hyperactivation. Clinically, CRAs have demonstrated good tolerability and safety, but have thus far lacked compelling efficacy in major depressive disorder, generalized anxiety disorder, or irritable bowel syndrome. CRAs may be best suited for disorders in which stressors clearly contribute to the underlying pathology (e.g. posttraumatic stress disorder, early life trauma, withdrawal/abstinence from addictive substances), though much work is needed to explore these possibilities. An evolving literature exploring the genetic, developmental and environmental factors linking CRF1 receptor dysfunction to stress-related psychopathology is discussed in the context of improving the translational value of current animal models. PMID:20826181

Involvement of CRF2 signaling in enterocyte differentiation

PubMed Central

Ducarouge, Benjamin; Pelissier-Rota, Marjolaine; Powell, Rebecca; Buisson, Alain; Bonaz, Bruno; Jacquier-Sarlin, Muriel

2017-01-01

AIM To determine the role of corticotropin releasing factor receptor (CRF2) in epithelial permeability and enterocyte cell differentiation. METHODS For this purpose, we used rat Sprague Dawley and various colon carcinoma cell lines (SW620, HCT8R, HT-29 and Caco-2 cell lines). Expression of CRF2 protein was analyzed by fluorescent immunolabeling in normal rat colon and then by western blot in dissociated colonic epithelial cells and in the lysates of colon carcinoma cell lines or during the early differentiation of HT-29 cells (ten first days). To assess the impact of CRF2 signaling on colonic cell differentiation, HT-29 and Caco-2 cells were exposed to Urocortin 3 recombinant proteins (Ucn3, 100 nmol/L). In some experiments, cells were pre-exposed to the astressin 2b (A2b) a CRF2 antagonist in order to inhibit the action of Ucn3. Intestinal cell differentiation was first analyzed by functional assays: the trans-cellular permeability and the para-cellular permeability were determined by Dextran-FITC intake and measure of the transepithelial electrical resistance respectively. Morphological modifications associated to epithelial dysfunction were analyzed by confocal microscopy after fluorescent labeling of actin (phaloidin-TRITC) and intercellular adhesion proteins such as E-cadherin, p120ctn, occludin and ZO-1. The establishment of mature adherens junctions (AJ) was monitored by following the distribution of AJ proteins in lipid raft fractions, after separation of cell lysates on sucrose gradients. Finally, the mRNA and the protein expression levels of characteristic markers of intestinal epithelial cell (IEC) differentiation such as the transcriptional factor krüppel-like factor 4 (KLF4) or the dipeptidyl peptidase IV (DPPIV) were performed by RT-PCR and western blot respectively. The specific activities of DPPIV and alkaline phosphatase (AP) enzymes were determined by a colorimetric method. RESULTS CRF2 protein is preferentially expressed in undifferentiated epithelial cells from the crypts of colon and in human colon carcinoma cell lines. Furthermore, CRF2 expression is down regulated according to the kinetic of HT-29 cell differentiation. By performing functional assays, we found that Ucn3-induced CRF2 signaling alters both para- and trans-cellular permeability of differentiated HT-29 and Caco-2 cells. These effects are partly mediated by Ucn3-induced morphological changes associated with the disruption of mature AJ in HT-29 cells and tight junctions (TJ) in Caco-2 cells. Ucn3-mediated activation of CRF2 decreases mRNA and protein expression levels of KLF4 a transcription factor involved in IEC differentiation. This signaling is correlated to a down-regulation of key IEC markers such as DPPIV and AP, at both transcriptional and post-transcriptional levels. CONCLUSION Our findings suggest that CRF2 signaling could modulate IEC differentiation. These mechanisms could be relevant to the stress induced epithelial alterations found in inflammatory bowel diseases. PMID:28811708

Involvement of CRF2 signaling in enterocyte differentiation.

PubMed

Ducarouge, Benjamin; Pelissier-Rota, Marjolaine; Powell, Rebecca; Buisson, Alain; Bonaz, Bruno; Jacquier-Sarlin, Muriel

2017-07-28

To determine the role of corticotropin releasing factor receptor (CRF2) in epithelial permeability and enterocyte cell differentiation. For this purpose, we used rat Sprague Dawley and various colon carcinoma cell lines (SW620, HCT8R, HT-29 and Caco-2 cell lines). Expression of CRF2 protein was analyzed by fluorescent immunolabeling in normal rat colon and then by western blot in dissociated colonic epithelial cells and in the lysates of colon carcinoma cell lines or during the early differentiation of HT-29 cells (ten first days). To assess the impact of CRF2 signaling on colonic cell differentiation, HT-29 and Caco-2 cells were exposed to Urocortin 3 recombinant proteins (Ucn3, 100 nmol/L). In some experiments, cells were pre-exposed to the astressin 2b (A2b) a CRF2 antagonist in order to inhibit the action of Ucn3. Intestinal cell differentiation was first analyzed by functional assays: the trans-cellular permeability and the para-cellular permeability were determined by Dextran-FITC intake and measure of the transepithelial electrical resistance respectively. Morphological modifications associated to epithelial dysfunction were analyzed by confocal microscopy after fluorescent labeling of actin (phaloidin-TRITC) and intercellular adhesion proteins such as E-cadherin, p120ctn, occludin and ZO-1. The establishment of mature adherens junctions (AJ) was monitored by following the distribution of AJ proteins in lipid raft fractions, after separation of cell lysates on sucrose gradients. Finally, the mRNA and the protein expression levels of characteristic markers of intestinal epithelial cell (IEC) differentiation such as the transcriptional factor krüppel-like factor 4 (KLF4) or the dipeptidyl peptidase IV (DPPIV) were performed by RT-PCR and western blot respectively. The specific activities of DPPIV and alkaline phosphatase (AP) enzymes were determined by a colorimetric method. CRF2 protein is preferentially expressed in undifferentiated epithelial cells from the crypts of colon and in human colon carcinoma cell lines. Furthermore, CRF2 expression is down regulated according to the kinetic of HT-29 cell differentiation. By performing functional assays, we found that Ucn3-induced CRF2 signaling alters both para- and trans-cellular permeability of differentiated HT-29 and Caco-2 cells. These effects are partly mediated by Ucn3-induced morphological changes associated with the disruption of mature AJ in HT-29 cells and tight junctions (TJ) in Caco-2 cells. Ucn3-mediated activation of CRF2 decreases mRNA and protein expression levels of KLF4 a transcription factor involved in IEC differentiation. This signaling is correlated to a down-regulation of key IEC markers such as DPPIV and AP, at both transcriptional and post-transcriptional levels. Our findings suggest that CRF2 signaling could modulate IEC differentiation. These mechanisms could be relevant to the stress induced epithelial alterations found in inflammatory bowel diseases.

Predicted contextual modulation varies with distance from pinwheel centers in the orientation preference map

PubMed Central

Okamoto, Tsuyoshi; Ikezoe, Koji; Tamura, Hiroshi; Watanabe, Masataka; Aihara, Kazuyuki; Fujita, Ichiro

2011-01-01

In the primary visual cortex (V1) of some mammals, columns of neurons with the full range of orientation preferences converge at the center of a pinwheel-like arrangement, the ‘pinwheel center' (PWC). Because a neuron receives abundant inputs from nearby neurons, the neuron's position on the cortical map likely has a significant impact on its responses to the layout of orientations inside and outside its classical receptive field (CRF). To understand the positional specificity of responses, we constructed a computational model based on orientation preference maps in monkey V1 and hypothetical neuronal connections. The model simulations showed that neurons near PWCs displayed weaker but detectable orientation selectivity within their CRFs, and strongly reduced contextual modulation from extra-CRF stimuli, than neurons distant from PWCs. We suggest that neurons near PWCs robustly extract local orientation within their CRF embedded in visual scenes, and that contextual information is processed in regions distant from PWCs. PMID:22355631

CRF-CRF1 receptor system in the central and basolateral nuclei of the amygdala differentially mediates excessive eating of palatable food.

PubMed

Iemolo, Attilio; Blasio, Angelo; St Cyr, Stephen A; Jiang, Fanny; Rice, Kenner C; Sabino, Valentina; Cottone, Pietro

2013-11-01

Highly palatable foods and dieting are major contributing factors for the development of compulsive eating in obesity and eating disorders. We previously demonstrated that intermittent access to palatable food results in corticotropin-releasing factor-1 (CRF1) receptor antagonist-reversible behaviors, which include excessive palatable food intake, hypophagia of regular chow, and anxiety-like behavior. However, the brain areas mediating these effects are still unknown. Male Wistar rats were either fed chow continuously for 7 days/week (Chow/Chow group), or fed chow intermittently 5 days/week, followed by a sucrose, palatable diet 2 days/week (Chow/Palatable group). Following chronic diet alternation, the effects of microinfusing the CRF1 receptor antagonist R121919 (0, 0.5, 1.5 μg/side) in the central nucleus of the amygdala (CeA), the basolateral nucleus of the amygdala (BlA), or the bed nucleus of the stria terminalis (BNST) were evaluated on excessive intake of the palatable diet, chow hypophagia, and anxiety-like behavior. Furthermore, CRF immunostaining was evaluated in the brain of diet cycled rats. Intra-CeA R121919 blocked both excessive palatable food intake and anxiety-like behavior in Chow/Palatable rats, without affecting chow hypophagia. Conversely, intra-BlA R121919 reduced the chow hypophagia in Chow/Palatable rats, without affecting excessive palatable food intake or anxiety-like behavior. Intra-BNST treatment had no effect. The treatments did not modify the behavior of Chow/Chow rats. Immunohistochemistry revealed an increased number of CRF-positive cells in CeA--but not in BlA or BNST--of Chow/Palatable rats, during both withdrawal and renewed access to the palatable diet, compared with controls. These results provide functional evidence that the CRF-CRF1 receptor system in CeA and BlA has a differential role in mediating maladaptive behaviors resulting from palatable diet cycling.

Predictive value of ADAMTS-13 on concealed chronic renal failure in COPD patients

PubMed Central

Zeng, Mian; Chen, Qingui; Liang, Wenjie; He, Wanmei; Zheng, Haichong; Huang, Chunrong

2017-01-01

Background Impaired renal function is often neglected in COPD patients. Considering that COPD patients usually have an ongoing prothrombotic state and systemic inflammation status, we investigated the association among them and explored the predictive value of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), on concealed chronic renal failure (CRF) in COPD patients. Methods COPD patients were recruited from the First Affiliated Hospital of Sun Yat-Sen University between January 2015 and December 2016. Control was selected from contemporaneous hospitalized patients without COPD and matched by age and gender at a ratio of 1:1. Estimated glomerular filtration rate (eGFR) was calculated by using the Chronic Kidney Disease Epidemiology Collaboration formula, and all subjects were categorized as having normal renal function (eGFR ≥60 mL min−1 1.73 m−2) and having concealed CRF (normal serum creatinine while eGFR <60 mL min−1 1.73 m−2). Independent correlates of concealed CRF were investigated by logistic regression analysis, and receiver operating characteristic (ROC) curves were used to determine the predictive value of ADAMTS-13. Results In total, 106 COPD and 106 non-COPD patients were finally recruited, and the incidences of concealed CRF were 19.81% and 7.55%, respectively. ADAMTS-13 (odds ratio [OR] =0.858, 95% CI =0.795–0.926), D-dimer (OR =1.095, 95% CI =1.027–1.169), and C-reactive protein (OR =1.252, 95% CI =1.058–1.480) were significantly associated with concealed CRF. Sensitivity and specificity at an ADAMTS-13 cutoff of 318.72 ng/mL were 100% and 81.2%, respectively. The area under the ROC curve was 0.959. Conclusion Prothrombotic state and systemic inflammation status might contribute to explaining the high incidence of concealed CRF in COPD, and plasma ADAMTS-13 levels may serve as a strong predictor. PMID:29255356

Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y.

PubMed

Inui, A; Okita, M; Nakajima, M; Momose, K; Ueno, N; Teranishi, A; Miura, M; Hirosue, Y; Sano, K; Sato, M; Watanabe, M; Sakai, T; Watanabe, T; Ishida, K; Silver, J; Baba, S; Kasuga, M

1998-01-01

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in behavior and its disorders. To understand the long-term modulation of neuronal functions by NPY, we raised transgenic mice created with a novel central nervous system (CNS) neuron-specific expression vector of human Thy- gene fragment linked to mouse NPY cDNA. In situ hybridization analysis demonstrated transgene-derived NPY expression in neurons (e.g., in the hippocampus, cerebral cortex, and the arcuate nucleus of the hypothalamus) in the transgenic mice. The modest increase of NPY protein in the brain was demonstrated by semiquantitative immunohistochemical analysis and by radioreceptor assay (115% in transgenic mice compared to control littermates). Double-staining experiments indicated colocalization of the transgene-derived NPY message and NPY protein in the same neurons, such as in the arcuate nucleus. The transgenic mice displayed behavioral signs of anxiety and hypertrophy of adrenal zona fasciculata cells, but no change in food intake was observed. The anxiety-like behavior of transgenic mice was reversed, at least in part, by administration of corticotropin-releasing factor (CRF) antagonists, alpha-helical CRF9-41, into the third cerebral ventricle. These results suggest that NPY has a role in anxiety and behavioral responses to stress partly via the CRF neuronal system. This genetic model may provide a unique opportunity to study human anxiety and emotional disorders.

[Does a short-term hemodialysis treatment influence function of the pituitary-testicular axis in patients with chronic renal failure?].

PubMed

Starzyk, J; Grzeszczak, W

1993-01-01

Abnormal function of the pituitary-gonadal axis is a well documented endocrine abnormality in chronic renal failure (CRF). The purpose of the work was to assess the influence of the short-term haemodialysis treatment on LH, FSH and testosterone secretion. In 17 men dialyzed up to 50 months and 10 non-dialyzed male patients with advanced CRF the test of stimulation with LHRH was done. Results obtained in patients were compared with those assessed in healthy subjects. Significantly higher concentration of LH and FSH and lower concentration of testosterone in serum under basal conditions were found in patients as compared to controls. Basal concentrations of LH, FSH and testosterone in dialyzed patients and in non dialyzed men were similar. The area under the curve of LH, FSH and testosterone in both groups of patients was similar. These results suggest that in men dialyzed shorter than 50 months haemodialysis treatment does not change significantly the function of the pituitary-testicular axis as compared to men with advanced CRF.

Tracking cardiorespiratory fitness and physical activity in children with and without motor coordination problems.

PubMed

Cairney, John; Veldhuizen, Scott; King-Dowling, Sara; Faught, Brent E; Hay, John

2017-04-01

Previous research has shown children with Developmental Coordination Disorder (DCD) have lower cardiorespiratory fitness (CRF) than typically developing (TD) children. This has been hypothesized to be due to an activity deficit, whereby poor motor functioning discourages children from participating in physical activities, but this hypothesis has not been directly tested. In this study, we use longitudinal data to measure the extent to which physical activity explains differences in CRF between children with and without motor coordination deficits. Longitudinal observational study. The study sample is an open cohort of children, numbering 2278 at baseline (age 9-10), that was followed for up to 5 years (to age 13-14). Motor skills were assessed once over the study period. Children scoring at or below the 5th percentile (n=103) on the Bruininks-Oseretsky Test of Motor Proficiency-Short Form were considered to have possible DCD (pDCD). CRF (estimated peak VO 2 ) was estimated from performance on the Léger 20m shuttle run test, and physical activity was measured with the Participation Questionnaire. Both fitness and physical activity were measured up to 7 times over the study period. Children with pDCD had significantly lower CRF than their TD peers at each time point. CRF declined for both groups, but this decline was steeper for children with pDCD. Physical activity explained only a small part of the difference in CRF. The activity deficit did not contribute to the persistent and gradually widening gap in CRF between children with and without possible DCD. Possible reasons for this and future directions are discussed. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo

PubMed Central

Ramsey, Simeon J; Attkins, Neil J; Fish, Rebecca; van der Graaf, Piet H

2011-01-01

BACKGROUND AND PURPOSE A series of novel non-peptide corticotropin releasing factor type-1 receptor (CRF1) antagonists were found to display varying degrees of insurmountable and non-competitive behaviour in functional in vitro assays. We describe how we attempted to relate this behaviour to ligand receptor-binding kinetics in a quantitative manner and how this resulted in the development and implementation of an efficient pharmacological screening method based on principles described by Motulsky and Mahan. EXPERIMENTAL APPROACH A non-equilibrium binding kinetic assay was developed to determine the receptor binding kinetics of non-peptide CRF1 antagonists. Nonlinear, mixed-effects modelling was used to obtain estimates of the compounds association and dissociation rates. We present an integrated pharmacokinetic–pharmacodynamic (PKPD) approach, whereby the time course of in vivo CRF1 receptor binding of novel compounds can be predicted on the basis of in vitro assays. KEY RESULTS The non-competitive antagonist behaviour appeared to be correlated to the CRF1 receptor off-rate kinetics. The integrated PKPD model suggested that, at least in a qualitative manner, the in vitro assay can be used to triage and select compounds for further in vivo investigations. CONCLUSIONS AND IMPLICATIONS This study provides evidence for a link between ligand offset kinetics and insurmountable/non-competitive antagonism at the CRF1 receptor. The exact molecular pharmacological nature of this association remains to be determined. In addition, we have developed a quantitative framework to study and integrate in vitro and in vivo receptor binding kinetic behaviour of CRF1 receptor antagonists in an efficient manner in a drug discovery setting. PMID:21449919

Is cardiac autonomic function associated with cardiorespiratory fitness and physical activity in children and adolescents? A systematic review of cross-sectional studies.

PubMed

Oliveira, Ricardo Santos; Barker, Alan Robert; Wilkinson, Kelly Michelle; Abbott, Rebecca Anne; Williams, Craig Anthony

2017-06-01

Heart rate variability (HRV) is considered to explain improvements in cardiovascular health accrued by physical activity (PA) and cardiorespiratory fitness (CRF) over and above traditional cardiovascular risk factors. To systematically address associations between HRV, PA and CRF in children and adolescents. Medline, EMBASE, SportDISCUS and CINAHL Plus were searched on 5th September 2015 and updated on 4th August 2016. Observational studies comparing HRV in different groups of PA and CRF, and/or studies investigating associations between PA, CRF and HRV. Sports practices and PA intensities were also included. The square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD), the spectral density in the high (HF) and low (LF) frequency, and the LF/HF ratio were included. Risk of bias was assessed using the adapted Newcastle-Ottawa Scale (NOS). Heterogeneity exists in the assessment of the exposures and outcomes, and sample characteristics. Risk of bias (NOS) was observed in most of the studies. Studies with low risk of bias showed positive associations between moderate-to-vigorous PA and RMSSD. The evidence for the associations between PA and frequency indices is weak. Similarly, the evidence for the association between CRF and HRV is weak. Despite the heterogeneity in the studies, moderate-to-vigorous PA is positively associated with RMSSD, but less clear are the associations between CRF and HRV, as well as other PA intensities. Further research is needed to clarify the role of PA and CRF on HRV in children and adolescents. Copyright © 2017 Elsevier B.V. All rights reserved.

A systematic review of the scales used for the measurement of cancer-related fatigue (CRF).

PubMed

Minton, O; Stone, P

2009-01-01

Fatigue in cancer is very common and can be experienced at all stages of disease and in survivors. There is no accepted definition of cancer-related fatigue (CRF) and no agreement on how it should be measured. A number of scales have been developed to quantify the phenomenon of CRF. These vary in the quality of psychometric properties, ease of administration, dimensions of CRF covered and extent of use in studies of cancer patients. This review seeks to identify the available tools for measuring CRF and to make recommendations for ongoing research into CRF. A systematic review methodology was used to identify scales that have been validated to measure CRF. The inclusion criteria required the scale to have been validated for use in cancer patients and/or widely used in this population. Scales also had to meet a minimum quality score for inclusion. The reviewers identified 14 scales that met the inclusion criteria. The most commonly used scales and best validated were the Functional Assessment of Cancer Therapy Fatigue (FACT F), the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) (fatigue subscale) and the Fatigue Questionnaire (FQ). Unidimensional scales are the easiest to administer and have been most widely used. The authors recommend the use of the EORTC QLQ C30 fatigue subscale or the FACT F. The FQ gives a multidimensional assessment and has also been widely used. A substantial minority of the scales identified have not been used extensively or sufficiently validated in cancer patients and cannot be recommended for routine use without further validation.

Cancer related fatigue: implementing guidelines for optimal management.

PubMed

Pearson, Elizabeth J M; Morris, Meg E; McKinstry, Carol E

2017-07-18

Cancer-related fatigue (CRF) is a key concern for people living with cancer and can impair physical functioning and activities of daily living. Evidence-based guidelines for CRF are available, yet inconsistently implemented globally. This study aimed to identify barriers and enablers to applying a cancer fatigue guideline and to derive implementation strategies. A mixed-method study explored the feasibility of implementing the CRF guideline developed by the Canadian Association for Psychosocial Oncology (CAPO). Health professionals, managers and consumers from different practice settings participated in a modified Delphi study with two survey rounds. A reference group informed the design of the study including the surveys. The first round focused on guideline characteristics, compatibility with current practice and experience, and behaviour change. The second survey built upon and triangulated the first round. Forty-five health practitioners and managers, and 68 cancer survivors completed the surveys. More than 75% of participants endorsed the CAPO cancer related fatigue guidelines. Some respondents perceived a lack of resources for accessible and expert fatigue management services. Further barriers to guideline implementation included complexity, limited practical details for some elements, and lack of clinical tools such as assessment tools or patient education materials. Recommendations to enhance guideline applicability centred around four main themes: (1) balancing the level of detail in the CAPO guideline with ease of use, (2) defining roles of different professional disciplines in CRF management, (3) how best to integrate CRF management into policy and practice, (4) how best to ensure a consumer-focused approach to CRF management. Translating current knowledge on optimal management of CRF into clinical practice can be enhanced by the adoption of valid guidelines. This study indicates that it is feasible to adopt the CAPO guidelines. Clinical application may be further enhanced with guideline adaptation, professional education and integration with existing practices.

Biodegradable Magnesium (Mg) Implantation Does Not Impose Related Metabolic Disorders in Rats with Chronic Renal Failure

PubMed Central

Wang, Jiali; Xu, Jiankun; Liu, Waiching; Li, Yangde; Qin, Ling

2016-01-01

Mg and its alloys have been considered as one of the most promising biodegradable medical devices, but it was still unclear whether hypermagnesemia involved health risks would occur in persons with kidney disease due to their deteriorated kidney function for Mg ions excretion from their body. In this study, we established a chronic renal failure (CRF) model in rats induced by adenine administration prior to Mg implantation, aiming to predict if CRF patients are suitable for the use of Mg implants. The results showed that Mg levels in serum, urine, feces and internal organs had no significant changes after Mg implantation for both normal and CRF rats. Biochemical indices detection and histopathological analysis in kidney, liver and heart tissue confirmed that Mg implants did not induce any extra damage in animals even with renal failure. Our study indicates that Mg based orthopaedic medical device may be considered for use in CRF patients without biosafety concerns. PMID:27210744

Biodegradable Magnesium (Mg) Implantation Does Not Impose Related Metabolic Disorders in Rats with Chronic Renal Failure

NASA Astrophysics Data System (ADS)

Wang, Jiali; Xu, Jiankun; Liu, Waiching; Li, Yangde; Qin, Ling

2016-05-01

Mg and its alloys have been considered as one of the most promising biodegradable medical devices, but it was still unclear whether hypermagnesemia involved health risks would occur in persons with kidney disease due to their deteriorated kidney function for Mg ions excretion from their body. In this study, we established a chronic renal failure (CRF) model in rats induced by adenine administration prior to Mg implantation, aiming to predict if CRF patients are suitable for the use of Mg implants. The results showed that Mg levels in serum, urine, feces and internal organs had no significant changes after Mg implantation for both normal and CRF rats. Biochemical indices detection and histopathological analysis in kidney, liver and heart tissue confirmed that Mg implants did not induce any extra damage in animals even with renal failure. Our study indicates that Mg based orthopaedic medical device may be considered for use in CRF patients without biosafety concerns.

Cardiorespiratory Fitness is Associated with Reduced Risk of Respiratory Diseases in Middle-Aged Caucasian Men: A Long-Term Prospective Cohort Study.

PubMed

Kunutsor, Setor K; Laukkanen, Tanjaniina; Laukkanen, Jari A

2017-10-01

Cardiorespiratory fitness (CRF), an index of cardiac and respiratory functioning, is strongly associated with a reduced risk of adverse health outcomes. We aimed to assess the prospective association of CRF with the risk of respiratory diseases (defined as chronic obstructive pulmonary disease, pneumonia, or asthma). Cardiorespiratory fitness, as measured by maximal oxygen uptake, was assessed in 1974 middle-aged men. During a median follow-up of 25.7 years, 382 hospital diagnosed respiratory diseases were recorded. Cardiorespiratory fitness was linearly associated with risk of respiratory diseases. In analysis adjusted for several established and potential risk factors, the hazard ratio (HR) (95% CI) for respiratory diseases was 0.63 (0.45-0.88), when comparing extreme quartiles of CRF levels. The corresponding multivariate adjusted HR (95% CI) for pneumonia was 0.67 (0.48-0.95). Our findings indicate a graded inverse and independent association between CRF and the future risk of respiratory diseases in a general male Caucasian population.

The effects of corticotrophin-releasing factor and two antagonists on breathing movements in fetal sheep.

PubMed Central

Bennet, L; Johnston, B M; Vale, W W; Gluckman, P D

1990-01-01

1. The respiratory effects of corticotrophin-releasing factor (CRF) and the CRF antagonists alpha-helical CRF 9-41 (alpha hCRF) and [DPhe 12, Nle 21-38] rCRF (12-41) (DPhe CRF) have been studied in unanaesthetized fetal lambs of 125-140 days gestation. 2. CRF when given as a 10 micrograms bolus followed by a 5 micrograms h-1 infusion into a lateral cerebral ventricle caused prolonged continuous fetal breathing movements which were stimulated in both amplitude and frequency but which did not persist during hypoxia. 3. Lower doses of CRF (20 ng bolus followed by 10 ng h-1) increased the amplitude but not the frequency of fetal breathing movements which did not become continuous. 4. At higher doses (20 micrograms bolus followed by 10-15 micrograms h-1) CRF induced cerebral convulsions which were also associated with fetal breathing movements of increased amplitude and frequency. 5. The CRF antagonists alpha hCRF and DPhe CRF both inhibited fetal breathing movements and induced a prolonged apnoea which was resistant to the stimulatory effects of 5-6% hypercapnia. 6. We conclude that CRF stimulates breathing movements in the fetal lamb. The finding that administration of the CRF antagonists alone cause apnoea suggests that CRF may have a tonic role in the regulation of fetal breathing movements. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:2348387

Chronic renal failure induces cell death in rat hippocampal CA1 via upregulation of αCaMKII/NR2A synaptic complex and phosphorylated GluR1-containing AMPA receptor cascades.

PubMed

Kim, Jong Wan; Ha, Gyoung Yim; Jung, Yong Wook

2014-09-01

N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propinoic acid (AMPA) receptors bound to postsynaptic density-95 (PSD-95) and α isoform of calcium/calmodulin-dependent protein kinase II (αCaMKII) is fundamentally involved in the regulation of working memory. The aim of present study was to investigate the alterations of NMDA and AMPA receptors responsible for hippocampal synaptic dysfunction and selective neuronal cell death after chronic renal failure (CRF) which may be associated with impairment of working memory. Altered interactions between NMDA and AMPA receptors and PSD-95 and αCaMKII were analyzed in the cornu ammonis (CA) 1 and CA3/dentate gyrus (DG) subfields of the uremic rat hippocampi using the immunoblotting and immunoprecipitation methods. Uremia induced by CRF produced necrotic cell death and decreased neuronal nucleoli protein levels in the hippocampal CA1 subfield, but not in the CA3/DG subfields. The CA1 subfields of CRF rats exhibited significant decreases and increases, respectively, in the expressions of PSD-95/NR2B and αCaMKII/NR2A synaptic complex. Moreover, increased phosphorylation of glutamate receptor type 1 (GluR1) AMPA receptor at ser831 was observed in the CA1 subfield after CRF. These hippocampal CA1 neuronal vulnerability may be responsible for memory dysfunction after CRF as mediated by an increase in NR2A-containing NMDA receptors bound to αCaMKII and subsequent activation of GluR1-containing AMPA receptors caused by the phosphorylation of GluR1 at ser831.

Autonomic control of adrenal function.

PubMed Central

Edwards, A V; Jones, C T

1993-01-01

Recent studies of adrenal function in conscious calves are reviewed. These have involved collecting the whole of the adrenal effluent blood from the right adrenal gland at intervals and, where necessary, prior functional hypophysectomy by destruction of the pituitary stalk under general halothane anaesthesia 3 d previously. The adrenal medulla was found to release numerous neuropeptides, in addition to catecholamines, in response to stimulation of the peripheral end of the right splanchnic nerve, which was carried out below behavioural threshold. Many of these responses were enhanced by stimulating intermittently at a relatively high frequency. Intra-aortic infusions of a relatively low dose of acetylcholine (4.5 nmol min-1 kg-1) elicited similar responses. In the adrenal cortex, agonists which either potentiated the steroidogenic response to ACTH or exerted a direct steroidogenic action included VIP, CGRP, CRF and ACh acting via muscarinic receptors. Stimulation of the peripheral end of the right splanchnic nerve strongly potentiated the steroidogenic response to ACTH and there is compelling evidence that the innervation normally plays an important part in cortisol secretion. PMID:8300417

The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal.

PubMed

Contarino, Angelo; Papaleo, Francesco

2005-12-20

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF1) and CRF2. Here we report that genetic disruption of CRF1 receptor pathways in mice eliminates the negative affective states of opiate withdrawal. In particular, neither CRF1 receptor heterozygous (CRF1+/-) nor homozygous (CRF1-/-) null mutant mice avoided environmental cues repeatedly paired with the early phase of opiate withdrawal. These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H. We also examined the impact of CRF1 receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal. Consistent with the behavioral indices, we found that, during the early phase of opiate withdrawal, neither CRF1+/- nor CRF1-/- showed increased dynorphin mRNA levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction.

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area.

PubMed

Holly, Elizabeth N; Boyson, Christopher O; Montagud-Romero, Sandra; Stein, Dirson J; Gobrogge, Kyle L; DeBold, Joseph F; Miczek, Klaus A

2016-04-06

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats.In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h "binge." VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction. Copyright © 2016 the authors 0270-6474/16/364094-13$15.00/0.

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area

PubMed Central

Boyson, Christopher O.; Montagud-Romero, Sandra; Stein, Dirson J.; Gobrogge, Kyle L.; DeBold, Joseph F.; Miczek, Klaus A.

2016-01-01

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats. In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h “binge.” VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. SIGNIFICANCE STATEMENT Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction. PMID:27053215

The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis.

PubMed

Ramos, Joyce S; Dalleck, Lance C; Tjonna, Arnt Erik; Beetham, Kassia S; Coombes, Jeff S

2015-05-01

Vascular dysfunction is a precursor to the atherosclerotic cascade, significantly increasing susceptibility to cardiovascular events such as myocardial infarction or stroke. Previous studies have revealed a strong relationship between vascular function and cardiorespiratory fitness (CRF). Thus, since high-intensity interval training (HIIT) is a potent method of improving CRF, several small randomized trials have investigated the impact on vascular function of HIIT relative to moderate-intensity continuous training (MICT). The aim of this study was to systematically review the evidence and quantify the impact on vascular function of HIIT compared with MICT. Three electronic databases (PubMed, Embase, and MEDLINE) were searched (until May 2014) for randomized trials comparing the effect of at least 2 weeks of HIIT and MICT on vascular function. HIIT protocols involved predominantly aerobic exercise at a high intensity, interspersed with active or passive recovery periods. We performed a meta-analysis to compare the mean difference in the change in vascular function assessed via brachial artery flow-mediated dilation (FMD) from baseline to post-intervention between HIIT and MICT. The impact of HIIT versus MICT on CRF, traditional cardiovascular disease (CVD) risk factors, and biomarkers associated with vascular function (oxidative stress, inflammation, and insulin resistance) was also reviewed across included studies. Seven randomized trials, including 182 patients, met the eligibility criteria and were included in the meta-analysis. A commonly used HIIT prescription was four intervals of 4 min (4 × 4 HIIT) at 85-95% of maximum or peak heart rate (HRmax/peak), interspersed with 3 min of active recovery at 60-70% HRmax/peak, three times per week for 12-16 weeks. Brachial artery FMD improved by 4.31 and 2.15% following HIIT and MICT, respectively. This resulted in a significant (p < 0.05) mean difference of 2.26%. HIIT also had a greater tendency than MICT to induce positive effects on secondary outcome measures, including CRF, traditional CVD risk factors, oxidative stress, inflammation, and insulin sensitivity. HIIT is more effective at improving brachial artery vascular function than MICT, perhaps due to its tendency to positively influence CRF, traditional CVD risk factors, oxidative stress, inflammation, and insulin sensitivity. However, the variability in the secondary outcome measures, coupled with the small sample sizes in these studies, limits this finding. Nonetheless, this review suggests that 4 × 4 HIIT, three times per week for at least 12 weeks, is a powerful form of exercise to enhance vascular function.

Enduring Effects Of Traumatic Stress On Brain Neuropeptide Y (NPY) and Corticotropin-Releasing Factor (CRF) Systems: Molecular and Neuropharmacologic Studies

DTIC Science & Technology

2009-12-01

neuropeptide, corticotropin-releasing factor, neuropeptide Y, anxiety, depression, behavior, treatment , gene expression. 16. SECURITY CLASSIFICATION OF...preclinical evidence that neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) systems acutely modulate stress and dysphoria responses and 2...2.5 weeks after the final defeat (data not shown). Treatment with twice daily imipramine (i.p., 2.5 mg/kg) for 2.5 weeks, eliminated the effects of

[Failure of static pulmonary volume measurements in mucoviscidosis].

PubMed

Haluszka, J; Zebrak, J

1984-01-01

With worsening of bronchial obstruction during the course of cystic fibrosis the functional residual capacity (CRF) measured by plethysmography increases progressively. The difference between values of CRF obtained by plethysmography or by Helium dilution increases even more. The difference between the two methods (for CRF) is supposed to show the volume of "trapped"' gas. A similar outcome, although less marked, is observed after physiotherapy. The extent of pulmonary distention and gas trapping is markedly overestimated by plethysmographic measurements, when one considers the anatomical and radiological anomalies. It was recently suggested that the rise in compliance of the walls of the extra-thoracic airways in the presence of bronchial obstruction may lead to an over-estimation of the pulmonary volumes measured by plethysmography. This may be the case during the course of mucoviscidosis, when repeated infections lead to a destruction of the bronchial walls. However, this anomaly does not explain this rise in CRF after mucolytic treatment and postural drainage. The CRF seems to reflect not only the volume of trapper gas in the lung, but equally the failure to equalize the interior pressures of the obstructed airways. In order to appreciate the effects of respiratory physiotherapy, different methods of measuring pulmonary volumes are necessary but the interpretation of the results take account of the complex meterology.

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking.

PubMed

Schreiber, Allyson L; Gilpin, Nicholas W

2018-01-28

Alcohol use is pervasive in the United States. In the transition from nonhazardous drinking to hazardous drinking and alcohol use disorder, neuroadaptations occur within brain reward and brain stress systems. One brain signaling system that has received much attention in animal models of excessive alcohol drinking and alcohol dependence is corticotropin-releasing factor (CRF). The CRF system is composed of CRF, the urocortins, CRF-binding protein, and two receptors - CRF type 1 and CRF type 2. This review summarizes how acute, binge, and chronic alcohol dysregulates CRF signaling in hypothalamic and extra-hypothalamic brain regions and how this dysregulation may contribute to changes in alcohol reinforcement, excessive alcohol consumption, symptoms of negative affect during withdrawal, and alcohol relapse. In addition, it summarizes clinical work examining CRF type 1 receptor antagonists in humans and discusses why the brain CRF system is still relevant in alcohol research.

Decoding Corticotropin-Releasing Factor Receptor Type 1 Crystal 
Structures

PubMed Central

Doré, Andrew S.; Bortolato, Andrea; Hollenstein, Kaspar; Cheng, Robert K.Y.; Read, Randy J.; Marshall, Fiona H.

2017-01-01

The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Cor-ticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the trans-membrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hex-agonal setting with translational non-crystallographic symmetry. Molecular dynamics and metadynamics simulations on this novel structure and the existing TMD structure for CRF1R provides insight as to how the small molecule ligand gains access to the induced-fit allosteric binding site with implications for the observed selectivity against CRF2R. Furthermore, molecular dynamics simulations performed using a full-length receptor model point to key interactions between the ECD and extracellular loop 3 of the TMD providing insight into the full inactive state of multidomain class B GPCRs. PMID:28183242

Glutamine enhances tight junction protein expression and modulates corticotropin-releasing factor signaling in the jejunum of weanling piglets.

PubMed

Wang, Hao; Zhang, Chen; Wu, Guoyao; Sun, Yuli; Wang, Bin; He, Beibei; Dai, Zhaolai; Wu, Zhenlong

2015-01-01

Dysfunction of tight junction integrity is associated with decreased nutrient absorption and numerous gastrointestinal diseases in humans and piglets. Although l-glutamine has been reported to enhance intestinal-mucosal mass and barrier function under stressful conditions, in vivo data to support a functional role for l-glutamine on intestinal tight junction protein (TJP) expression in weanling mammals are limited. This study tested the hypothesis that glutamine regulates expression of TJPs and stress-related corticotropin-releasing factor (CRF) signaling in the jejunum of weanling piglets. Piglets were reared by sows or weaned at 21 d of age to a corn and soybean meal-based diet that was or was not supplemented with 1% l-glutamine for 7 d. Growth performance, intestinal permeability, TJP abundance, and CRF expression were examined. Weaning caused increases (P < 0.05) in intestinal permeability by 40% and in CRF concentrations by 4.7 times in association with villus atrophy (P < 0.05). Western blot analysis showed reductions (P < 0.05) in jejunal expression of occludin, claudin-1, zonula occludens (ZO) 2, and ZO-3, but no changes in the abundance of claudin-3, claudin-4, or ZO-1 in weanling piglets compared with age-matched suckling controls. Glutamine supplementation improved (P < 0.05) intestinal permeability and villus height, while reducing (P < 0.05) jejunal mRNA and protein levels for CRF and attenuating (P < 0.05) weanling-induced decreases in occludin, claudin-1, ZO-2, and ZO-3 protein abundances. Collectively, our results support an important role for l-glutamine in regulating expression of TJPs and CRF in the jejunum of weanling piglets. © 2015 American Society for Nutrition.

Ethanol produces corticotropin releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala

PubMed Central

Silberman, Yuval; Fetterly, Tracy L.; Awad, Elias K.; Milano, Elana J.; Usdin, Ted B.; Winder, Danny G.

2015-01-01

Background Ethanol modulation of Central Amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin releasing factor (CRF) receptor system. Previous work has predominantly focused on ethanol/CRF interactions on the CeA GABA circuitry; however our lab recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine if ethanol modulates CeA glutamate transmission via activation of CRF signaling. Methods The effects of ethanol on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRFCeAhDTR) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post-hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRFDTA mice) ablated CRF neurons throughout the CNS, as assessed by qRT-PCR quantification of CRF mRNA. Results Acute bath application of ethanol significantly increased sEPSC frequency in a concentration dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRF receptor 1 and CRF receptor 2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, ethanol did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of ethanol to enhance CeA sEPSC frequency was not altered in CRFCeAhDTR mice despite a ~78% reduction in CeA CRF cell counts. The ability of ethanol to enhance CeA sEPSC frequency was also not altered in the CRFDTA mice despite a three-fold reduction in CRF mRNA levels. Conclusion These findings demonstrate that ethanol enhances spontaneous glutamatergic transmission in the CeA via a CRF receptor dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF. PMID:26503065

Time-scale of minor HIV-1 complex circulating recombinant forms from Central and West Africa.

PubMed

Delatorre, Edson; Bello, Gonzalo

2016-11-16

Several HIV-1 circulating recombinant forms with a complex mosaic structure (CRFs_cpx) circulate in central and western African regions. Here we reconstruct the evolutionary history of some of these complex CRFs (09_cpx, 11_cpx, 13_cpx and 45_cpx) and further investigate the dissemination dynamic of the CRF11_cpx clade by using a Bayesian coalescent-based method. The analysis of two HIV-1 datasets comprising 181 pol (36 CRF09_cpx, 116 CRF11_cpx, 20 CRF13_cpx and 9 CRF45_cpx) and 125 env (12 CRF09_cpx, 67 CRF11_cpx, 17 CRF13_cpx and 29 CRF45_cpx) sequences pointed to quite consistent onset dates for CRF09_cpx (~1966: 1958-1979), CRF11_cpx (~1957: 1950-1966) and CRF13_cpx (~1965: 1958-1973) clades; while some divergence was found for the estimated date of origin of CRF45_cpx clade [pol = 1970 (1964-1976); env = 1960 (1952-1969)]. Phylogeographic reconstructions indicate that the HIV-1 CRF11_cpx clade most probably emerged in Cameroon and from there it was first disseminated to the Central Africa Republic and Chad in the early 1970s and to other central and western African countries from the early 1980s onwards. Demographic reconstructions suggest that the CRF11_cpx epidemic grew between 1960 and 1990 with a median exponential growth rate of 0.27 year -1 , and stabilized after. These results reveal that HIV-1 CRFs_cpx clades have been circulating in Central Africa for a period comparable to other much more prevalent HIV-1 group M lineages. Cameroon was probably the epicenter of dissemination of the CRF11_cpx clade that seems to have experienced a long epidemic growth phase before stabilization. The epidemic growth of the CRF11_cpx clade was roughly comparable to other HIV-1 group M lineages circulating in Central Africa.

Effect of different tropospheric mapping functions on the TRF, CRF and position time-series estimated from VLBI

NASA Astrophysics Data System (ADS)

Tesmer, Volker; Boehm, Johannes; Heinkelmann, Robert; Schuh, Harald

2007-06-01

This paper compares estimated terrestrial reference frames (TRF) and celestial reference frames (CRF) as well as position time-series in terms of systematic differences, scale, annual signals and station position repeatabilities using four different tropospheric mapping functions (MF): The NMF (Niell Mapping Function) and the recently developed GMF (Global Mapping Function) consist of easy-to-handle stand-alone formulae, whereas the IMF (Isobaric Mapping Function) and the VMF1 (Vienna Mapping Function 1) are determined from numerical weather models. All computations were performed at the Deutsches Geodätisches Forschungsinstitut (DGFI) using the OCCAM 6.1 and DOGS-CS software packages for Very Long Baseline Interferometry (VLBI) data from 1984 until 2005. While it turned out that CRF estimates only slightly depend on the MF used, showing small systematic effects up to 0.025 mas, some station heights of the computed TRF change by up to 13 mm. The best agreement was achieved for the VMF1 and GMF results concerning the TRFs, and for the VMF1 and IMF results concerning scale variations and position time-series. The amplitudes of the annual periodical signals in the time-series of estimated heights differ by up to 5 mm. The best precision in terms of station height repeatability is found for the VMF1, which is 5 7% better than for the other MFs.

Intraocular pressure and biomechanical corneal properties measure by ocular response analyser in patients with primary congenital glaucoma.

PubMed

Perucho-González, Lucía; Martínez de la Casa, Jose María; Morales-Fernández, Laura; Bañeros-Rojas, Paula; Saenz-Francés, Federico; García-Feijoó, Julían

2016-08-01

To measure the differences in corneal hysteresis (CH) and corneal resistance factor (CRF) in primary congenital glaucoma (PCG) and in control subjects using ocular response analyser (ORA) and also to compare intraocular pressure (IOP) measurements given by ORA against IOP given by Perkins tonometer, a handheld version of Goldman applanation tonometer (GAT), to determine correlation. One hundred and eighteen eyes of 78 patients with PCG (group I) and 103 eyes of 53 controls (group II) were evaluated using ORA. In all participants, IOP was measured using the Perkins tonometer. The ORA device uses applanation pressure peaks to generate the corneal-compensated IOP (IOPcc), which is reportedly independent of corneal thickness, and the measurement of Goldman-correlated IOP (IOPg), which is influenced by corneal thickness. The measures in group I were as follows: IOPcc 20.92 ± 5.33; IOPg 18.87 ± 6.67; CH 8.51 ± 2.25; CRF 9.85 ± 3.03; and IOP measured by Goldman 18.32 ± 5.13. The measures in group II were as follows: IOPcc 14.33 ± 2.91; IOPg 14.77 ± 3.00; CH 11.37 ± 1.61; CRF 11.02 ± 1.74; and IOP measured by Goldman 13.74 ± 2.42. The differences of all parameters compared between both groups were statistically significant (p < 0.001 for CH and for all IOP measures and p = 0.001 for CRF). The values of IOPcc, IOPg and IOP measured with Goldman were higher in group I than the values in group II. However, CH and CRF values were lower in group I. A decrease in CH and CRF has been observed in patients with PCG compared to controls. Future research should assess how these parameters are modified in PCG and whether they could provide more information about progression. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

The acquisition of conditioned responding.

PubMed

Harris, Justin A

2011-04-01

This report analyzes the acquisition of conditioned responses in rats trained in a magazine approach paradigm. Following the suggestion by Gallistel, Fairhurst, and Balsam (2004), Weibull functions were fitted to the trial-by-trial response rates of individual rats. These showed that the emergence of responding was often delayed, after which the response rate would increase relatively gradually across trials. The fit of the Weibull function to the behavioral data of each rat was equaled by that of a cumulative exponential function incorporating a response threshold. Thus, the growth in conditioning strength on each trial can be modeled by the derivative of the exponential--a difference term of the form used in many models of associative learning (e.g., Rescorla & Wagner, 1972). Further analyses, comparing the acquisition of responding with a continuously reinforced stimulus (CRf) and a partially reinforced stimulus (PRf), provided further evidence in support of the difference term. In conclusion, the results are consistent with conventional models that describe learning as the growth of associative strength, incremented on each trial by an error-correction process.

Evidence for possible biological advantages of the newly emerging HIV-1 circulating recombinant form from Malaysia - CRF33_01B in comparison to its progenitors - CRF01_AE and subtype B.

PubMed

Lau, Katherine A; Wang, Bin; Miranda-Saksena, Monica; Boadle, Ross; Kamarulzaman, Adeeba; Ng, Kee-Peng; Saksena, Nitin K

2010-04-01

In Malaysia, co-circulation of CRF01_AE and subtype B has resulted in the emergence of the second generation derivative; CRF33_01B in approximately 20% of its HIV-1 infected individuals. Our objective was to identify possible biological advantages that CRF33_01B possesses over its progenitors. Biological and molecular comparisons of CRF33_01B against its parental subtypes clearly show that CRF33_01B replicated better in activated whole peripheral blood mononuclear cells (PBMCs) and CD4+ T-lymphocytes, but not monocyte-derived macrophages (MDMs). Also, its acquired fitness was greater than CRF01_AE but not subtype B. Moreover, CRF33_01B has higher rate of apoptotic cell death and syncytia induction compared to subtype B. These adaptive and survival abilities could have been acquired by CRF33_01B due to the incorporation of subtype B fragments into the gag-RT region of its full-length genome. Our studies confirm the previously held belief that HIV-1 strains may harbor enhanced biological fitness upon recombination. We therefore estimate a possible gradual replacement of the current predominance of CRF01_AE, as well as wider dissemination of CRF33_01B, together with the identification of other new CRF01_AE/B inter-subtype recombinants in Malaysia.

Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors

PubMed Central

Ivy, Autumn S.; Rex, Christopher S.; Chen, Yuncai; Dubé, Céline; Maras, Pamela M.; Grigoriadis, Dimitri E.; Gall, Christine M.; Lynch, Gary; Baram, Tallie Z.

2010-01-01

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF1) located on pyramidal cell dendrites. Additionally, chronic CRF1 occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH-expression is augmented in hippocampus of middle-aged CES rats, and then tested if the morphological defects and poor memory performance in these animals involve excessive activation of CRF1 receptors. Central or peripheral administration of a CRF1 blocker following the stress period improved memory performance of CES rats in novel object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF1 interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF1 occupancy post-hoc normalized hippocampal function during middle-age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress. PMID:20881118

Ablation depth and its effects on corneal biomechanical changes in laser in situ keratomileusis and epipolis laser in situ keratomileusis.

PubMed

Zhang, Lin; Wang, Yan; Yang, Xiaoyan

2014-04-01

To assess the corneal biomechanical parameters prior to and following laser in situ keratomileusis (LASIK) and epipolis laser in situ keratomileusis (epi-LASIK) and evaluate the probable correlative factors. Corneal hysteresis (CH), corneal resistance factor (CRF) and other biomechanical metrics were measured and evaluated with an ocular response analyzer preoperatively and 1 month postoperatively. Compared with preoperative values, CH and CRF decreased significantly after surgery in both groups (P = 0.000). The LASIK group exhibited a positive correlation between ablation depth (AD) and ∆CH/∆CRF with a strong r value (r = 0.543, P = 0.000; r = 0.574, P = 0.000). In the epi-LASIK group, however, the correlation was much weaker (r = -0.090, P = 0.682; r = 0.093, P = 0.673), although there were no significant differences between LASIK and epi-LASIK groups in postoperative CH (P = 0.730) and CRF (P = 0.736), and in the changes between CH (P = 0.539) and CRF (P = 0.881). Corneal biomechanical changes correlated with AD in LASIK but not in epi-LASIK, and it appeared that patients with identical demographics and similar attempted corrections are more likely to face a greater danger when undergoing LASIK than epi-LASIK. Therefore, the surface ablation procedure was recommended instead of lamellar ablation especially for correcting high myopia from a biomechanical viewpoint.

Cardiac CRFR1 Expression Is Elevated in Human Heart Failure and Modulated by Genetic Variation and Alternative Splicing

PubMed Central

Lewis, Kathy A.; Perrin, Marilyn H.; Sweet, Wendy E.; Moravec, Christine S.; Tang, W. H. Wilson; Huising, Mark O.; Troughton, Richard W.; Cameron, Vicky A.

2016-01-01

Corticotropin-releasing factor (CRF) and the CRF-related peptides, urocortin (Ucn)-1, Ucn2, and Ucn3 signal through receptors CRFR1 and CRFR2 to restore homeostasis in response to stress. The Ucns exert potent cardioprotective effects and may have clinical utility in heart failure. To explore the activity of this system in the heart, we measured the levels of myocardial gene expression of the CRF/Ucn family of ligands/receptors and investigated genetic variation and alternative splicing of CRFR1 in 110 heart failure patients and 108 heart donors. Using quantitative real-time PCR, we detected CRFR1, CRFR2, CRF, Ucn1, Ucn2, and Ucn3 in all samples. CRFR2α was the most abundant receptor and Ucn3 the most abundant ligand, both in patients and donors. Compared with donors, cardiac expression of CRFR1, CRF, and Ucn3 was higher (P < .001) and CRFR2α lower (P = .012) in patients. In patients and donors, genetic variation within CRFR1, represented by the chromosome 17q21.31 inversion polymorphism, was associated with markedly higher CRFR1 expression (P < .001), making CRFR1 and CRFR2α expression almost equivalent in some patients. A novel, truncated splice variant of CRFR1, designated CRFR1j, was identified and shown to exert a dominant-negative effect on CRFR1 signaling in vitro. The novel variant was expressed in a greater proportion of patients (60%) than donors (3%, P < .001). In summary, cardiac expression of CRFR1, CRF, and Ucn3 genes is elevated in heart failure and may contribute to the activation of the CRF/Ucn system in these patients. A common variant within the CRFR1 gene and a novel CRFR1 splice variant may modulate CRFR1 expression and signaling. PMID:27754786

Role of Bed Nucleus of the Stria Terminalis Corticotrophin-Releasing Factor Receptors in Frustration Stress-Induced Binge-Like Palatable Food Consumption in Female Rats with a History of Food Restriction

PubMed Central

Micioni Di Bonaventura, Maria Vittoria; Ciccocioppo, Roberto; Romano, Adele; Bossert, Jennifer M.; Rice, Kenner C.; Ubaldi, Massimo; St. Laurent, Robyn; Gaetani, Silvana; Massi, Maurizio; Shaham, Yavin

2014-01-01

We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This “frustration stress” manipulation also activates the hypothalamic–pituitary–adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10–20 mg/kg) and BNST (25–50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist d-Phe-CRF(12–41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders. PMID:25143612

Role of bed nucleus of the stria terminalis corticotrophin-releasing factor receptors in frustration stress-induced binge-like palatable food consumption in female rats with a history of food restriction.

PubMed

Micioni Di Bonaventura, Maria Vittoria; Ciccocioppo, Roberto; Romano, Adele; Bossert, Jennifer M; Rice, Kenner C; Ubaldi, Massimo; St Laurent, Robyn; Gaetani, Silvana; Massi, Maurizio; Shaham, Yavin; Cifani, Carlo

2014-08-20

We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders. Copyright © 2014 the authors 0270-6474/14/3411316-09$15.00/0.

Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

PubMed Central

Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I.

2015-01-01

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID:25926444

The association of oxidant-antioxidant status in patients with chronic renal failure.

PubMed

Aziz, Manal A; Majeed, Ghanim H; Diab, Kareem S; Al-Tamimi, Raid J

2016-01-01

Oxidative stress has been linked to disease progression, including chronic renal failure (CRF). The aim of the present study was to determine malondialdehyde (MDA) as a sign of lipid peroxidation, and to investigate the association between antioxidant activities and three trace elements, in 49 patients with CRF. The erythrocyte and plasma trace elements [selenium (Se), zinc (Zn), and copper (Cu)] and antioxidant defense levels were determined: glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), vitamins E and C. The obtained values were compared with 42 age- and sex-matched healthy controls. There were significantly lower mean values of plasma Se, GPx, vitamins E and C, erythrocyte Se, SOD and CAT levels in the patient group compared to the control group (p < 0.001). Plasma MDA showed a significant increase in all CRF patients in comparison with controls. No significant difference was found in plasma Cu, Zn, and erythrocyte GPx, Cu and Zn levels between patient and control groups. These findings indicate oxidative stress is present in patients of CRF, and may serve to establish a simple protocol for evaluation of renal function.

[Effects of controlled release blend bulk urea on soil nitrogen and soil enzyme activity in wheat and rice fields].

PubMed

Zhang, Jing Sheng; Wang, Chang Quan; Li, Bing; Liang, Jing Yue; He, Jie; Xiang, Hao; Yin, Bin; Luo, Jing

2017-06-18

A field experiment was conducted to investigate the effect of controlled-release fertilizer (CRF) combined with urea (UR) on the soil fertility and environment in wheat-rice rotation system. Changes in four forms of nitrogen (total nitrogen, ammonium nitrogen, nitrate nitrogen, and microbial biomass nitrogen) and in activities of three soil enzymes participating in nitrogen transformation (urease, protease, and nitrate reductase) were measured in seven fertilization treatments (no fertilization, routine fertilization, 10%CRF+90%UR, 20%CRF+80%UR, 40%CRF+60%UR, 80%CRF+20%UR, and 100%CRF). The results showed that soil total nitrogen was stable in the whole growth period of wheat and rice. There was no significant difference among the treatments of over 20% CRF in soil total nitrogen content of wheat and rice. The soil inorganic nitrogen content was increased dramatically in treatments of 40% or above CRF during the mid-late growing stages of wheat and rice. With the advance of the growth period, conventional fertilization significantly decreased soil microbial biomass nitrogen, but the treatments of 40% and above CRF increased the soil microbial biomass nitrogen significantly. The soil enzyme activities were increased with over 40% of CRF in the mid-late growing stage of wheat and rice. By increasing the CRF ratio, the soil protease activity and nitrate reductase activity were improved gradually, and peaked in 100% CRF. The treatments of above 20% CRF could decrease the urease activity in tillering stage of rice and delay the peak of ammonium nitrogen, which would benefit nitrogen loss reduction. The treatments of 40% and above CRF were beneficial to improving soil nitrogen supply and enhancing soil urease and protease activities, which could promote the effectiveness of nitrogen during the later growth stages of wheat and rice. The 100% CRF treatment improved the nitrate reductase activity significantly during the later stage of wheat and rice. Compared with the treatments of 40%-80% CRF, 100% CRF reduced the soil nitrate content of 20-40 cm soil layer in wheat significantly suggesting it could reduce the loss of nitrogen.

Effects of acute and chronic stress on telencephalic neurochemistry and gene expression in rainbow trout (Oncorhynchus mykiss).

PubMed

Moltesen, Maria; Laursen, Danielle Caroline; Thörnqvist, Per-Ove; Andersson, Madelene Åberg; Winberg, Svante; Höglund, Erik

2016-12-15

By filtering relevant sensory inputs and initiating stress responses, the brain is an essential organ in stress coping and adaptation. However, exposure to chronic or repeated stress can lead to allostatic overload, where neuroendocrinal and behavioral reactions to stress become maladaptive. This work examines forebrain mechanisms involved in allostatic processes in teleost fishes. Plasma cortisol, forebrain serotonergic (5-HTergic) neurochemistry, and mRNA levels of corticotropin-releasing factor (CRF), CRF-binding protein (CRF-BP), CRF receptors (CRFR1 and CRFR2), mineralocorticoid receptor (MR), glucocorticoid receptors (GR1 and GR2) and serotonin type 1A (5-HT 1A ) receptors (5-HT 1Aα and 5-HT 1Aβ ) were investigated at 1 h before and 0, 1 and 4 h after acute stress, in two groups of rainbow trout held in densities of 25 and 140 kg m -3 for 28 days. Generally, being held at 140 kg m -3 resulted in a less pronounced cortisol response. This effect was also reflected in lower forebrain 5-HTergic turnover, but not in mRNA levels in any of the investigated genes. This lends further support to reports that allostatic load causes fish to be incapable of mounting a proper cortisol response to an acute stressor, and suggests that changes in forebrain 5-HT metabolism are involved in allostatic processes in fish. Independent of rearing densities, mRNA levels of 5-HT 1Aα and MR were downregulated 4 h post-stress compared with values 1 h post-stress, suggesting that these receptors are under feedback control and take part in the downregulation of the hypothalamic-pituitary-interrenal (HPI) axis after exposure to an acute stressor. © 2016. Published by The Company of Biologists Ltd.

A comparative study of the response of modeled non-drizzling stratocumulus to meteorological and aerosol perturbations

NASA Astrophysics Data System (ADS)

Petters, J. L.; Jiang, H.; Feingold, G.; Rossiter, D. L.; Khelif, D.; Sloan, L. C.; Chuang, P. Y.

2013-03-01

The impact of changes in aerosol and cloud droplet concentration (Na and Nd) on the radiative forcing of stratocumulus-topped boundary layers (STBLs) has been widely studied. How these impacts compare to those due to variations in meteorological context has not been investigated in a systematic fashion for non-drizzling overcast stratocumulus. In this study we examine the impact of observed variations in meteorological context and aerosol state on daytime, non-drizzling overcast stratiform evolution, and determine how resulting changes in cloud properties compare. Using large-eddy simulation (LES) we create a model base case of daytime southeast Pacific coastal stratocumulus, spanning a portion of the diurnal cycle (early morning to near noon) and constrained by observations taken during the VOCALS (VAMOS Ocean-Atmosphere-Land Study) field campaign. We perturb aerosol and meteorological properties around this base case to investigate the stratocumulus response. We determine perturbations in the cloud top jumps in potential temperature θ and total water mixing ratio qt from ECMWF Re-analysis Interim data, and use a set of Nd values spanning the observable range. To determine the cloud response to these meteorological and aerosol perturbations, we compute changes in liquid water path (LWP), bulk optical depth (τ) and cloud radiative forcing (CRF). We find that realistic variations in the thermodynamic jump properties can elicit a response in the cloud properties of τ and shortwave (SW) CRF that are on the same order of magnitude as the response found due to realistic changes in aerosol state (i.e Nd). In response to increases in Nd, the cloud layer in the base case thinned due to increases in evaporative cooling and entrainment rate. This cloud thinning somewhat mitigates the increase in τ resulting from increases in Nd. On the other hand, variations in θ and qt jumps did not substantially modify Nd. The cloud layer thickens in response to an increase in the θ jump and thins in response to an increase in the qt jump, both resulting in a τ and SW CRF response comparable to those found from perturbations in Nd. Longwave CRF was not substantially altered by the perturbations we tested. We find that realistic variations in meteorological context can elicit a response in CRF and τ on the same order of magnitude as, and at times larger than, that response found due to realistic changes in aerosol state. We estimate the limits on variability of cloud top jump properties required for accurate observation of aerosol SW radiative impacts on stratocumulus, and find strict constraints: less than 1 K and 1 g kg-1 in the early morning hours, and order 0.1 K and 0.1 g kg-1 close to solar noon. These constraints suggest that accurately observing aerosol radiative impacts in stratocumulus may be challenging as co-variation of meteorological properties may obfuscate aerosol-cloud interactions.

Contextual Modulation is Related to Efficiency in a Spiking Network Model of Visual Cortex.

PubMed

Sharifian, Fariba; Heikkinen, Hanna; Vigário, Ricardo; Vanni, Simo

2015-01-01

In the visual cortex, stimuli outside the classical receptive field (CRF) modulate the neural firing rate, without driving the neuron by themselves. In the primary visual cortex (V1), such contextual modulation can be parametrized with an area summation function (ASF): increasing stimulus size causes first an increase and then a decrease of firing rate before reaching an asymptote. Earlier work has reported increase of sparseness when CRF stimulation is extended to its surroundings. However, there has been no clear connection between the ASF and network efficiency. Here we aimed to investigate possible link between ASF and network efficiency. In this study, we simulated the responses of a biomimetic spiking neural network model of the visual cortex to a set of natural images. We varied the network parameters, and compared the V1 excitatory neuron spike responses to the corresponding responses predicted from earlier single neuron data from primate visual cortex. The network efficiency was quantified with firing rate (which has direct association to neural energy consumption), entropy per spike and population sparseness. All three measures together provided a clear association between the network efficiency and the ASF. The association was clear when varying the horizontal connectivity within V1, which influenced both the efficiency and the distance to ASF, DAS. Given the limitations of our biophysical model, this association is qualitative, but nevertheless suggests that an ASF-like receptive field structure can cause efficient population response.

Effect of femtosecond and microkeratome flaps creation on the cornea biomechanics during laser in situ keratomileusis: one year follow-up

PubMed Central

Sun, Qian; Deng, Zheng-Zheng; Zhou, Yue-Hua; Zhang, Jing; Peng, Xiao-Yan

2016-01-01

AIM To compare the corneal biomechanical outcomes at one year after laser in situ keratomileusis (LASIK) with the flaps created by Ziemer and Moria M2 microkeratome with 110 head and -20 blade. METHODS Totally 100 eyes of 50 consecutive patients were enrolled in this prospective study and divided into two groups for corneal flaps created by ZiemerFemto LDV and Moria M2 microkeratome with 110 head and -20 blade. Corneal biomechanical properties including cornea resistance factor (CRF) and cornea hysteresis (CH) were measured before and 1, 3, 6, 12mo after surgery by ocular response analyzer. Central cornea thickness and corneal flap thickness were measured by optical coherence tomography. RESULTS The ablation depth (P=0.693), residual corneal thickness (P=0.453), and postoperative corneal curvature (P=0.264) were not significant different between Ziemer group and Moria 110-20 group after surgery. The residual stromal bed thickness, corneal flap thickness, CH and CRF at 12mo after surgery were significant different between Ziemer group and Moria 110-20 group (P<0.01);Ziemer group gained better corneal biomechanical results. The CRF and CH increased gradually from 1 to 12mo after surgery in Ziemer group, increased from 1 to 6mo but decreased from 6 to 12mo in Moria 110-20 group. Both CRF and CH at one year after surgery increased with the increasing of residual cornea thickness; pre-LASIK CRF, CRF also increased with residual stromal bed thickness, while CH decreased with the increasing of pre-LASIK intraocular pressure and cornea flap thickness (P<0.01). CONCLUSION In one year follow-up, femtosecond laser can provide better cornea flaps with stable cornea biomechanics than mechanical microkeratome. PMID:27803856

The Association Between Measures of Fitness and Metabolic Health in Treatment-Seeking Youth with Obesity.

PubMed

Guseman, Emily Hill; Cauffman, Samuel P; Tucker, Jared M; Smith, Lucie; Eisenmann, Joey C; Stratbucker, William

2017-04-01

Both cardiorespiratory fitness (CRF) and measures of muscular fitness are associated with metabolic syndrome in adults. However, limited information exists about these relationships in youth with severe obesity who are at increased risk of metabolic dysfunction. The purpose of this study was to examine the relationship between fitness and metabolic health in treatment-seeking youth with obesity. Data for this analysis were collected at the time of baseline visits at a stage 3 pediatric weight management center. Maximal voluntary contractions were obtained by using isometric hand-grip dynamometry, and CRF was obtained from a maximal treadmill test. Resting blood pressure and fasting measures of blood lipids, glucose, and insulin were used to calculate a continuous metabolic syndrome score (cMetS); homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting insulin and glucose. Relationships between measures of fitness and metabolic health were evaluated by using partial correlations adjusted for age. Sixty-nine participants (21 boys, 48 girls) were included in this analysis. Of these, 46% (n = 32) met the criteria for metabolic syndrome. No differences were found between boys and girls for any variable analyzed. Muscular strength was positively associated with cMetS (r = 0.35), though this association weakened after adjustment for body mass index percentile. CRF was inversely associated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = -0.26) and fasting insulin (r = -0.27). Body fat percentage was positively associated with insulin (r = 0.36). No significant relationship was found between CRF and cMetS. Contrary to previous studies, CRF was not associated with metabolic syndrome in this group. Muscular strength, however, was associated with cMetS. Notably, CRF was associated with elevated HOMA-IR, which may be seen as a precursor to metabolic syndrome. These results suggest that CRF and muscular strength influence metabolic function independently.

Increased nitric oxide production in platelets from severe chronic renal failure patients.

PubMed

Siqueira, Mariana Alves de Sá; Brunini, Tatiana M C; Pereira, Natália Rodrigues; Martins, Marcela Anjos; Moss, Monique Bandeira; Santos, Sérgio F; Lugon, Jocemir R; Mendes-Ribeiro, Antônio C

2011-02-01

Nitric oxide (NO) production occurs through oxidation of the amino acid L-arginine by NO synthase (NOS). NO inhibits platelet activation by increasing the levels of cyclic guanosine monophosphate (cGMP), thus maintaining vascular homeostasis. Our group previously demonstrated (da Silva et al. 2005) an enhancement of the L-arginine-NO-cGMP pathway in platelets taken from chronic renal failure (CRF) patients on haemodialysis associated with reduced platelet aggregation. We investigate the platelet L-arginine-NO-cGMP pathway, platelet function, and inflammation from patients in CRF on conservative treatment. A total of 42 CRF patients and 42 controls (creatinine clearance = 27 ± 3 vs. 93 ± 1 mL per min per 1.73 m2, respectively) participated in this study. NOS activity and expression and cGMP concentration were measured in platelets. Platelet aggregation induced by collagen or ADP was evaluated and plasma levels of fibrinogen were determined by the Clauss method. A marked increase in basal NOS activity was seen in undialysed CRF patients compared with controls, accompanied by an elevation of fibrinogen plasma levels. There were no differences in expression of NOS and in cGMP levels. In this context, platelet aggregation was not affected. We provide the first evidence of increased intraplatelet NO biosynthesis in undialysed CRF patients, which can be an early marker of future haemostatic abnormalities during dialysis treatment.

Impact of Chronic Renal Failure on Safety and Effectiveness of Paclitaxel-Eluting Stents for Femoropopliteal Artery Disease: Subgroup Analysis from Zilver PTX Post-Market Surveillance Study in Japan.

PubMed

Ogawa, Yukihisa; Yokoi, Hiroyoshi; Ohki, Takao; Kichikawa, Kimihiko; Nakamura, Masato; Komori, Kimihiro; Nanto, Shinsuke; O'Leary, Erin E; Lottes, Aaron E; Saunders, Alan T; Dake, Michael D

2017-11-01

Favorable long-term outcomes of the Zilver PTX drug-eluting stent (DES) in femoropopliteal lesions have been demonstrated. Chronic renal failure (CRF) has been shown to be a risk factor for restenosis and decreased limb salvage. The results of the DES in patients with CRF have not previously been reported. This study compares the results with the DES in patients with CRF and those without CRF. This retrospective analysis from the Zilver PTX Japan Post-Market Surveillance Study included 321 patients with CRF and 584 patients without CRF. Outcomes included freedom from target lesion revascularization (TLR) and patency. Of the patients included in this subgroup analysis, 2-year data were available for 209 patients in the CRF group and 453 patients in the non-CRF group. The two groups were similar in terms of lesion length and the frequency of in-stent restenosis. Critical limb ischemia, severe calcification, and diabetes were more common in patients with CRF, whereas total occlusion was more common in patients without CRF. Freedom from TLR rates were 81.4 versus 84.9% (p = 0.24), and patency rates were 70.7 versus 70.3% (p = 0.95) in patients with and without CRF at 2 years, respectively. This is the first comparative study of the DES in femoropopliteal artery lesions in patients with and without CRF. These results indicate that the DES placed in femoropopliteal artery lesions of CRF patients is safe and effective with similar patency and TLR rates to patients without CRF. Level 3, Post-Market Surveillance Study.

Molecular epidemiology of HIV type 1 infection in Iran: genomic evidence of CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use.

PubMed

Jahanbakhsh, Fatemeh; Ibe, Shiro; Hattori, Junko; Monavari, Seyed Hamid Reza; Matsuda, Masakazu; Maejima, Masami; Iwatani, Yasumasa; Memarnejadian, Arash; Keyvani, Hossein; Azadmanesh, Kayhan; Sugiura, Wataru

2013-01-01

To understand the molecular epidemiology of HIV-1 infection in Iran, we conducted the first study to analyze the genome sequence of Iranian HIV-1 isolates. For this cross-sectional study, we enrolled 10 HIV-1-infected individuals associated with injection drug use from Tehran, Shiraz, and Kermanshah. Near full-length genome sequences obtained from their plasma samples were used for phylogenetic tree and similarity plotting analyses. Among 10 isolates, nine were clearly identified as CRF35_AD and the remaining one as CRF01_AE. Interestingly, five of our Iranian CRF35_AD isolates made two clusters with 10 Afghan CRF35_AD isolates in a phylogenetic tree, indicating epidemiological connections among injection drug users in Iran and Afghanistan. In contrast, our CRF01_AE isolate had no genetic relationship with any other CRF01_AE isolates worldwide, even from Afghanistan. This study provides the first genomic evidence of HIV-1 CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use in Iran.

Midlife and Late-Life Cardiorespiratory Fitness and Brain Volume Changes in Late Adulthood: Results From the Baltimore Longitudinal Study of Aging

PubMed Central

Studenski, Stephanie A.; Resnick, Susan M.; Davatzikos, Christos; Ferrucci, Luigi

2016-01-01

Background. Higher cardiorespiratory fitness (CRF) is cross-sectionally associated with more conserved brain volume in older age, but longitudinal studies are rare. This study examined whether higher midlife CRF was prospectively associated with slower atrophy, which in turn was associated with higher late-life CRF. Methods. Brain volume by magnetic resonance imaging was determined annually from 1994 to 2003 in 146 participants (M baseline age = 69.6 years). Peak oxygen uptake on a treadmill yielded estimated midlife CRF in 138 and late-life CRF in 73 participants. Results. Higher midlife CRF was associated with greater middle temporal gyrus, perirhinal cortex, and temporal and parietal white matter, but was not associated with atrophy progression. Slower atrophy in middle frontal and angular gyri was associated with higher late-life CRF, independent of CRF at baseline magnetic resonance imaging. Conclusions. Higher midlife CRF may play a role in preserving middle and medial temporal volumes in late adulthood. Slower atrophy in middle frontal and angular gyri may predict late-life CRF. PMID:25896993

Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.

PubMed

Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I; Ferré, Sergi; McCormick, Peter J

2015-04-29

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. Copyright © 2015 the authors 0270-6474/15/356639-15$15.00/0.

Interactions of Stress and CRF in Ethanol-Withdrawal Induced Anxiety in Adolescent and Adult Rats

PubMed Central

Wills, Tiffany A.; Knapp, Darin J.; Overstreet, David H.; Breese, George R.

2010-01-01

Background Repeated stress or administration of corticotropin-releasing factor (CRF) prior to ethanol exposure sensitizes anxiety-like behavior in adult rats. Current experiments determined whether adolescent rats were more sensitive to these challenges in sensitizing ethanol withdrawal-induced anxiety and altering CRF levels in brain during withdrawal. Methods Male adult and adolescent Sprague–Dawley rats were restraint stressed (1 hour) twice 1 week apart prior to a single 5-day cycle of ethanol diet (ED; stress/withdrawal paradigm). Other rats received control diet (CD) and three 1-hour restraint stress sessions. Rats were then tested 5, 24, or 48 hours after the final withdrawal for anxiety-like behavior in the social interaction (SI) test. In other experiments, adolescent rats were given two microinjections of CRF icv 1 week apart followed by 5-days of either CD or ED and tested in social interaction 5 hours into withdrawal. Finally, CRF immunoreactivity was measured in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) after rats experienced control diet, repeated ethanol withdrawals, or stress/withdrawal. Results Rats of both ages had reduced SI following the stress/withdrawal paradigm, and this effect recovered within 24 hours. Higher CRF doses were required to reduce SI in adolescents than previously reported in adults. CRF immunohistochemical levels were higher in the PVN and CeA of CD-exposed adolescents. In adolescent rats, repeated ethanol withdrawals decreased CRF in the CeA but was not associated with decreased CRF cell number. There was no change in CRF from adult treatments. Conclusions In the production of anxiety-like behavior, adolescent rats have equal sensitivity with stress and lower sensitivity with CRF compared to adults. Further, adolescents had higher basal levels of CRF within the PVN and CeA and reduced CRF levels following repeated ethanol withdrawals. This reduced CRF within the CeA could indicate increased release of CRF, and future work will determine how this change relates to behavior. PMID:20586753

Enhanced motivation for food reward induced by stress and attenuation by corticotrophin-releasing factor receptor antagonism in rats: implications for overeating and obesity.

PubMed

Liu, Xiu

2015-06-01

Overeating beyond individuals' homeostatic needs critically contributes to obesity. The neurobehavioral mechanisms underlying the motivation to consume excessive foods with high calories are not fully understood. The present study examined whether a pharmacological stressor, yohimbine, enhances the motivation to procure food reward with an emphasis on comparisons between standard lab chow and high-fat foods. The effects of corticotropin-releasing factor (CRF) receptor blockade by a CRF1-selective antagonist NBI on the stress-enhanced motivation for food reward were also assessed. Male Sprague-Dawley rats with chow available ad libitum in their home cages were trained to press a lever under a progressive ratio schedule for deliveries of either standard or high-fat food pellets. For testing yohimbine stress effects, rats received an intraperitoneal administration of yohimbine 10 min before start of the test sessions. For testing effects of CRF1 receptor blockade on stress responses, NBI was administered 20 min prior to yohimbine challenge. The rats emitted higher levels of lever responses to procure the high-fat food pellets compared with their counterparts on standard food pellets. Yohimbine challenge facilitated lever responses for the reward in all of the rats, whereas the effect was more robust in the rats on high-fat food pellets compared with their counterparts on standard food pellets. An inhibitory effect of pretreatment with NBI was observed on the enhancing effect of yohimbine challenge but not on the responses under baseline condition without yohimbine administration. Stress challenge significantly enhanced the motivation of satiated rats to procure extra food reward, especially the high-fat food pellets. Activation of CRF1 receptors is required for the stress-enhanced motivation for food reward. These results may have implications for our better understanding of the biobehavioral mechanisms of overeating and obesity.

Pedunculopontine tegmental nucleus lesions impair stimulus--reward learning in autoshaping and conditioned reinforcement paradigms.

PubMed

Inglis, W L; Olmstead, M C; Robbins, T W

2000-04-01

The role of the pedunculopontine tegmental nucleus (PPTg) in stimulus-reward learning was assessed by testing the effects of PPTg lesions on performance in visual autoshaping and conditioned reinforcement (CRf) paradigms. Rats with PPTg lesions were unable to learn an association between a conditioned stimulus (CS) and a primary reward in either paradigm. In the autoshaping experiment, PPTg-lesioned rats approached the CS+ and CS- with equal frequency, and the latencies to respond to the two stimuli did not differ. PPTg lesions also disrupted discriminated approaches to an appetitive CS in the CRf paradigm and completely abolished the acquisition of responding with CRf. These data are discussed in the context of a possible cognitive function of the PPTg, particularly in terms of lesion-induced disruptions of attentional processes that are mediated by the thalamus.

Lack of muscle contractile property changes at the time of perceived physical exhaustion suggests central mechanisms contributing to early motor task failure in patients with cancer-related fatigue.

PubMed

Kisiel-Sajewicz, Katarzyna; Davis, Mellar P; Siemionow, Vlodek; Seyidova-Khoshknabi, Dilara; Wyant, Alexandria; Walsh, Declan; Hou, Juliet; Yue, Guang H

2012-09-01

Fatigue is one of the most common symptoms reported by cancer survivors, and fatigue worsens when patients are engaged in muscle exertion, which results in early motor task failure. Central fatigue plays a significant role, more than muscle (peripheral) fatigue, in contributing to early task failure in cancer-related fatigue (CRF). The purpose of this study was to determine if muscle contractile property alterations (reflecting muscle fatigue) occurred at the end of a low-intensity muscle contraction to exhaustion and if these properties differed between those with CRF and healthy controls. Ten patients (aged 59.9±10.6 years, seven women) with advanced solid cancer and CRF and 12 age- and gender-matched healthy controls (aged 46.6±12.8 years, nine women) performed a sustained contraction of the right arm elbow flexion at 30% maximal level until exhaustion. Peak twitch force, time to peak twitch force, rate of peak twitch force development, and half relaxation time derived from electrical stimulation-evoked twitches were analyzed pre- and post-sustained contraction. CRF patients reported significantly greater fatigue as measured by the Brief Fatigue Inventory and failed the motor task earlier, 340±140 vs. 503±155 seconds in controls. All contractile property parameters did not change significantly in CRF but did change significantly in controls. CRF patients perceive physical exhaustion sooner during a motor fatigue task with minimal muscular fatigue. The observation supports that central fatigue is a more significant factor than peripheral fatigue in causing fatigue feelings and limits motor function in cancer survivors with fatigue symptoms. Copyright © 2012. Published by Elsevier Inc.

High-Dose Asian Ginseng (Panax Ginseng) for Cancer-Related Fatigue: A Preliminary Report.

PubMed

Yennurajalingam, Sriram; Reddy, Akhila; Tannir, Nizar M; Chisholm, Gary B; Lee, Richard Tsong; Lopez, Gabriel; Escalante, Carmen P; Manzullo, Ellen F; Frisbee Hume, Susan; Williams, Janet L; Cohen, Lorenzo; Bruera, Eduardo

2015-09-01

Cancer-related fatigue (CRF) is the most common and severe symptom in patients with cancer. The number and efficacy of available treatments for CRF are limited. The objective of this preliminary study was to assess the safety of high-dose Panax ginseng (PG) for CRF. In this prospective, open-label study, 30 patients with CRF (≥4/10) received high-dose PG at 800 mg orally daily for 29 days. Frequency and type of side effects were determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. Scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale, Edmonton Symptom Assessment System (ESAS), and Hospital Anxiety and Depression Scale (HADS) were assessed at baseline, day 15, and day 29. Global Symptom Evaluation (GSE) was assessed at day 29. Of the 30 patients enrolled, 24 (80%) were evaluable. The median age was 58 years; 50% were females, and 84% were white. No severe (≥grade 3) adverse events related to the study drug were reported. Of the 24 evaluable patients, 21 (87%) had an improved (by ≥3 points) FACIT-F score by day 15. The mean ESAS score (standard deviation) for well-being improved from 4.67 (2.04) to 3.50 (2.34) (P = .01374), and mean score for appetite improved from 4.29 (2.79) to 2.96 (2.46) (P = .0097). GSE score of PG for fatigue was ≥3 in 15/24 patients (63%) with median improvement of 5. PG is safe and improves CRF fatigue as well as overall quality of life, appetite, and sleep at night. Randomized controlled trials of PG for CRF are justified. © The Author(s) 2015.

Presence of corticotrophin-releasing factor and/or tyrosine hydroxylase in cells of a neural brain-testicular pathway that are labelled by a transganglionic tracer.

PubMed

James, P; Rivier, C; Lee, S

2008-02-01

Our laboratory has shown that male testosterone levels are not solely controlled by the release of hypothalamic gonadotrophin-releasing hormone and pituitary luteinising hormone, but are also regulated by a multisynaptic pathway connecting the brain and the testis that interferes with the testosterone response to gonadotrophins. This pathway, which is independent of the pituitary gland, is activated by an i.c.v. injection of either the stress-related peptide corticotrophin-releasing factor (CRF) or of beta-adrenoceptor agonists, both of which alter androgen release and decrease levels of the peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein within Leydig cells. Our original studies used the retrograde transganglionic tracer pseudorabies virus (PRV) to map progression of the virus from the testes to upper brain levels. The present study aimed to extend this work by identifying the regions where CRF and catecholamine neurones represented components of the stress-activated, brain-testicular pathway that prevents testosterone increases. To this end, anaesthetised adult male rats received an intra-testicular injection of PRV. Using immunofluorescence, we identified co-labelling of PRV and either CRF or tyrosine hydroxylase (TH), the enzyme responsible for biogenic amine synthesis. Co-labelling of PRV and CRF was found in the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus (PVN) and the central amygdala. Co-labelling of PRV and TH was found in the PVN, substantia nigra, A7/Kölliker-Fuse area, area of A5, locus coeruleus, nucleus of solitary tract, area of C3, area of C2 and the area of C1/A1. These results indicate that most cell groups of the ventral noradrenergic pathway have neurones that are a part of the brain-testicular pathway. This suggests that the stress hormones CRF and catecholamines may act as neurotransmitters that signal the pathway to inhibit increases in plasma testosterone levels.

Does stress induce bowel dysfunction?

PubMed

Chang, Yu-Ming; El-Zaatari, Mohamad; Kao, John Y

2014-08-01

Psychological stress is known to induce somatic symptoms. Classically, many gut physiological responses to stress are mediated by the hypothalamus-pituitary-adrenal axis. There is, however, a growing body of evidence of stress-induced corticotrophin-releasing factor (CRF) release causing bowel dysfunction through multiple pathways, either through the HPA axis, the autonomic nervous systems, or directly on the bowel itself. In addition, recent findings of CRF influencing the composition of gut microbiota lend support for the use of probiotics, antibiotics, and other microbiota-altering agents as potential therapeutic measures in stress-induced bowel dysfunction.

Optimising mobile phase composition, its flow-rate and column temperature in HPLC using taboo search.

PubMed

Guillaume, Y C; Peyrin, E

2000-03-06

A chemometric methodology is proposed to study the separation of seven p-hydroxybenzoic esters in reversed phase liquid chromatography (RPLC). Fifteen experiments were found to be necessary to find a mathematical model which linked a novel chromatographic response function (CRF) with the column temperature, the water fraction in the mobile phase and its flow rate. The CRF optimum was determined using a new algorithm based on Glover's taboo search (TS). A flow-rate of 0.9 ml min(-1) with a water fraction of 0.64 in the ACN-water mixture and a column temperature of 10 degrees C gave the most efficient separation conditions. The usefulness of TS was compared with the pure random search (PRS) and simplex search (SS). As demonstrated by calculations, the algorithm avoids entrapment in local minima and continues the search to give a near-optimal final solution. Unlike other methods of global optimisation, this procedure is generally applicable, easy to implement, derivative free, conceptually simple and could be used in the future for much more complex optimisation problems.

Midlife and Late-Life Cardiorespiratory Fitness and Brain Volume Changes in Late Adulthood: Results From the Baltimore Longitudinal Study of Aging.

PubMed

Tian, Qu; Studenski, Stephanie A; Resnick, Susan M; Davatzikos, Christos; Ferrucci, Luigi

2016-01-01

Higher cardiorespiratory fitness (CRF) is cross-sectionally associated with more conserved brain volume in older age, but longitudinal studies are rare. This study examined whether higher midlife CRF was prospectively associated with slower atrophy, which in turn was associated with higher late-life CRF. Brain volume by magnetic resonance imaging was determined annually from 1994 to 2003 in 146 participants (M baseline age = 69.6 years). Peak oxygen uptake on a treadmill yielded estimated midlife CRF in 138 and late-life CRF in 73 participants. Higher midlife CRF was associated with greater middle temporal gyrus, perirhinal cortex, and temporal and parietal white matter, but was not associated with atrophy progression. Slower atrophy in middle frontal and angular gyri was associated with higher late-life CRF, independent of CRF at baseline magnetic resonance imaging. Higher midlife CRF may play a role in preserving middle and medial temporal volumes in late adulthood. Slower atrophy in middle frontal and angular gyri may predict late-life CRF. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.

Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-inducedmore » increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.« less

A newly emerging HIV-1 recombinant lineage (CRF58_01B) disseminating among people who inject drugs in Malaysia.

PubMed

Chow, Wei Zhen; Takebe, Yutaka; Syafina, Nur Ezreen; Prakasa, Malarvelli Soorya; Chan, Kok Gan; Al-Darraji, Haider Abdulrazzaq Abed; Koh, Clayton; Kamarulzaman, Adeeba; Tee, Kok Keng

2014-01-01

The HIV epidemic is primarily characterised by the circulation of HIV-1 group M (main) comprising of 11 subtypes and sub-subtypes (A1, A2, B-D, F1, F2, G, H, J, and K) and to date 55 circulating recombinant forms (CRFs). In Southeast Asia, active inter-subtype recombination involving three main circulating genotypes--subtype B (including subtype B', the Thai variant of subtype B), CRF01_AE, and CRF33_01B--have contributed to the emergence of novel unique recombinant forms. In the present study, we conducted the molecular epidemiological surveillance of HIV-1 gag-RT genes among 258 people who inject drugs (PWIDs) in Kuala Lumpur, Malaysia, between 2009 and 2011 whereby a novel CRF candidate was recently identified. The near full-length genome sequences obtained from six epidemiologically unlinked individuals showed identical mosaic structures consisting of subtype B' and CRF01_AE, with six unique recombination breakpoints in the gag-RT, pol, and env regions. Among the high-risk population of PWIDs in Malaysia, which was predominantly infected by CRF33_01B (>70%), CRF58_01B circulated at a low but significant prevalence (2.3%, 6/258). Interestingly, the CRF58_01B shared two unique recombination breakpoints with other established CRFs in the region: CRF33_01B, CRF48_01B, and CRF53_01B in the gag gene, and CRF15_01B (from Thailand) in the env gene. Extended Bayesian Markov chain Monte Carlo sampling analysis showed that CRF58_01B and other recently discovered CRFs were most likely to have originated in Malaysia, and that the recent spread of recombinant lineages in the country had little influence from neighbouring countries. The isolation, genetic characterization, and evolutionary features of CRF58_01B among PWIDs in Malaysia signify the increasingly complex HIV-1 diversity in Southeast Asia that may hold an implication on disease treatment, control, and prevention.

Natural stimulation of the nonclassical receptive field increases information transmission efficiency in V1.

PubMed

Vinje, William E; Gallant, Jack L

2002-04-01

We have investigated how the nonclassical receptive field (nCRF) affects information transmission by V1 neurons during simulated natural vision in awake, behaving macaques. Stimuli were centered over the classical receptive field (CRF) and stimulus size was varied from one to four times the diameter of the CRF. Stimulus movies reproduced the spatial and temporal stimulus dynamics of natural vision while maintaining constant CRF stimulation across all sizes. In individual neurons, stimulation of the nCRF significantly increases the information rate, the information per spike, and the efficiency of information transmission. Furthermore, the population averages of these quantities also increase significantly with nCRF stimulation. These data demonstrate that the nCRF increases the sparseness of the stimulus representation in V1, suggesting that the nCRF tunes V1 neurons to match the highly informative components of the natural world.

Molecular Diversity of HIV-1 among People Who Inject Drugs in Kuala Lumpur, Malaysia: Massive Expansion of Circulating Recombinant Form (CRF) 33_01B and Emergence of Multiple Unique Recombinant Clusters

PubMed Central

Chow, Wei Zhen; Ng, Kim Tien; Yong, Yean Kong; Azmel, Azureen; Takebe, Yutaka; Al-Darraji, Haider Abdulrazzaq Abed; Kamarulzaman, Adeeba; Tee, Kok Keng

2013-01-01

Since the discovery of HIV-1 circulating recombinant form (CRF) 33_01B in Malaysia in the early 2000 s, continuous genetic diversification and active recombination involving CRF33_01B and other circulating genotypes in the region including CRF01_AE and subtype B′ of Thai origin, have led to the emergence of novel CRFs and unique recombinant forms. The history and magnitude of CRF33_01B transmission among various risk groups including people who inject drugs (PWID) however have not been investigated despite the high epidemiological impact of CRF33_01B in the region. We update the most recent molecular epidemiology of HIV-1 among PWIDs recruited in Malaysia between 2010 and 2011 by population sequencing and phylogenetic analysis of 128 gag-pol sequences. HIV-1 CRF33_01B was circulating among 71% of PWIDs whilst a lower prevalence of other previously dominant HIV-1 genotypes [subtype B′ (11%) and CRF01_AE (5%)] and CRF01_AE/B′ unique recombinants (13%) were detected, indicating a significant shift in genotype replacement in this population. Three clusters of CRF01_AE/B′ recombinants displaying divergent yet phylogenetically-related mosaic genomes to CRF33_01B were identified and characterized, suggestive of an abrupt emergence of multiple novel CRF clades. Using rigorous maximum likelihood approach and the Bayesian Markov chain Monte Carlo (MCMC) sampling of CRF33_01Bpol sequences to elucidate the past population dynamics, we found that the founder lineages of CRF33_01B were likely to have first emerged among PWIDs in the early 1990 s before spreading exponentially to various high and low-risk populations (including children who acquired infections from their mothers) and later on became endemic around the early 2000 s. Taken together, our findings provide notable genetic evidence indicating the widespread expansion of CRF33_01B among PWIDs and into the general population. The emergence of numerous previously unknown recombinant clades highlights the escalating genetic complexity of HIV-1 in the Southeast Asian region. PMID:23667490

Molecular diversity of HIV-1 among people who inject drugs in Kuala Lumpur, Malaysia: massive expansion of circulating recombinant form (CRF) 33_01B and emergence of multiple unique recombinant clusters.

PubMed

Chow, Wei Zhen; Ong, Lai Yee; Razak, Siti Humaira; Lee, Yeat Mei; Ng, Kim Tien; Yong, Yean Kong; Azmel, Azureen; Takebe, Yutaka; Al-Darraji, Haider Abdulrazzaq Abed; Kamarulzaman, Adeeba; Tee, Kok Keng

2013-01-01

Since the discovery of HIV-1 circulating recombinant form (CRF) 33_01B in Malaysia in the early 2000 s, continuous genetic diversification and active recombination involving CRF33_01B and other circulating genotypes in the region including CRF01_AE and subtype B' of Thai origin, have led to the emergence of novel CRFs and unique recombinant forms. The history and magnitude of CRF33_01B transmission among various risk groups including people who inject drugs (PWID) however have not been investigated despite the high epidemiological impact of CRF33_01B in the region. We update the most recent molecular epidemiology of HIV-1 among PWIDs recruited in Malaysia between 2010 and 2011 by population sequencing and phylogenetic analysis of 128 gag-pol sequences. HIV-1 CRF33_01B was circulating among 71% of PWIDs whilst a lower prevalence of other previously dominant HIV-1 genotypes [subtype B' (11%) and CRF01_AE (5%)] and CRF01_AE/B' unique recombinants (13%) were detected, indicating a significant shift in genotype replacement in this population. Three clusters of CRF01_AE/B' recombinants displaying divergent yet phylogenetically-related mosaic genomes to CRF33_01B were identified and characterized, suggestive of an abrupt emergence of multiple novel CRF clades. Using rigorous maximum likelihood approach and the Bayesian Markov chain Monte Carlo (MCMC) sampling of CRF33_01Bpol sequences to elucidate the past population dynamics, we found that the founder lineages of CRF33_01B were likely to have first emerged among PWIDs in the early 1990 s before spreading exponentially to various high and low-risk populations (including children who acquired infections from their mothers) and later on became endemic around the early 2000 s. Taken together, our findings provide notable genetic evidence indicating the widespread expansion of CRF33_01B among PWIDs and into the general population. The emergence of numerous previously unknown recombinant clades highlights the escalating genetic complexity of HIV-1 in the Southeast Asian region.

Genetic Characterization of a Novel HIV-1 Circulating Recombinant Form (CRF74_01B) Identified among Intravenous Drug Users in Malaysia: Recombination History and Phylogenetic Linkage with Previously Defined Recombinant Lineages.

PubMed

Cheong, Hui Ting; Chow, Wei Zhen; Takebe, Yutaka; Chook, Jack Bee; Chan, Kok Gan; Al-Darraji, Haider Abdulrazzaq Abed; Koh, Clayton; Kamarulzaman, Adeeba; Tee, Kok Keng

2015-01-01

In many parts of Southeast Asia, the HIV-1 epidemic has been driven by the sharing of needles and equipment among intravenous drug users (IDUs). Over the last few decades, many studies have proven time and again that the diversity of HIV-1 epidemics can often be linked to the route of infection transmission. That said, the diversity and complexity of HIV-1 molecular epidemics in the region have been increasing at an alarming rate, due in part to the high tendency of the viral RNA to recombine. This scenario was exemplified by the discovery of numerous circulating recombinant forms (CRFs), especially in Thailand and Malaysia. In this study, we characterized a novel CRF designated CRF74_01B, which was identified in six epidemiologically unlinked IDUs in Kuala Lumpur, Malaysia. The near-full length genomes were composed of CRF01_AE and subtype B', with eight breakpoints dispersed in the gag-pol and nef regions. Remarkably, this CRF shared four and two recombination hotspots with the previously described CRF33_01B and the less prevalent CRF53_01B, respectively. Genealogy-based Bayesian phylogenetic analysis of CRF74_01B genomic regions showed that it is closely related to both CRF33_01B and CRF53_01B. This observation suggests that CRF74_01B was probably a direct descendent from specific lineages of CRF33_01B, CRF53_01B and subtype B' that could have emerged in the mid-1990s. Additionally, it illustrated the active recombination processes between prevalent HIV-1 subtypes and recombinants in Malaysia. In summary, we report a novel HIV-1 genotype designated CRF74_01B among IDUs in Kuala Lumpur, Malaysia. The characterization of the novel CRF74_01B is of considerable significance towards the understanding of the genetic diversity and population dynamics of HIV-1 circulating in the region.

Corticotropin-releasing factor stimulates colonic motility via muscarinic receptors in the rat

PubMed Central

Kim, Kyung-Jo; Kim, Ki Bae; Yoon, Soon Man; Han, Joung-Ho; Chae, Hee Bok; Park, Seon Mee; Youn, Sei Jin

2017-01-01

AIM To measure exogenous corticotropin-releasing factor (CRF)-induced motility of the isolated rat colon and to demonstrate the effect of pharmacologic inhibition on CRF-induced motility. METHODS The isolated vascularly-perfused rat colon was used. Luminal pressure was monitored via microtip catheter pressure transducers in the proximal and distal colon. At first, exogenous CRF was administered in a stepwise manner and the concentration of CRF yielding maximal colonic motility was selected. After recording basal colonic motility, hexamethonium, phentolamine, propranolol, atropine and tetrodotoxin were infused into the isolated colon. Initially, only the test drug was infused; then, CRF was added. The motility index was expressed as percentage change over basal level. RESULTS Administration of 1.4, 14.4, 144 and 288 pmol/L CRF progressively increased colonic motility in the proximal and distal colon. Infusion of atropine or tetrodotoxin reduced CRF-induced motility of both the proximal and distal colon, whereas hexamethonium, phentolamine and propranolol had no effect. CONCLUSION CRF-induced colonic motility appears to be mediated by local cholinergic signaling via muscarinic receptors. Muscarinic receptors are potential targets for counteracting CRF-induced colonic hypermotility. PMID:28638222

Secular change in cardiorespiratory fitness of men: Cooper Center Longitudinal Study.

PubMed

Willis, Benjamin L; Morrow, James R; Jackson, Allen W; Defina, Laura F; Cooper, Kenneth H

2011-11-01

Cardiorespiratory fitness (CRF) has been shown to be an independent predictor of all-cause and cardiovascular mortality, as well as health outcomes such as cardiovascular disease, hypertension, diabetes mellitus, and metabolic syndrome. During the last four decades, national guidelines for physical activity and fitness have emerged in an ongoing effort to improve health outcomes through enhanced CRF risk profiles. The purpose of the study was to describe the secular trend in CRF as a function of decade and age in a large cohort of men during the past 40 yr. A cross-sectional analysis of baseline fitness data collected during comprehensive medical examinations of 52,785 men age 20-74 yr evaluated at the Cooper Clinic in Dallas, TX, from 1970 to 2009 who completed a maximum treadmill exercise test for estimation of aerobic capacity was conducted. Comparisons were made between mean fitness levels in each decade stratified by five age groups. Mean CRF in MET from estimated V·O 2max has increased overall approximately 1 MET during a 40-yr period for each of the five age groups (P < 0.0001). The greatest change occurred during the 1970s to 1980s with minimal subsequent increase and a small decline commencing in the last decade especially in younger men. In a large cohort of men, average CRF has improved during the last 40 yr with a slight decline in the favorable trend notable in the most recent decade.

Interconnection of electronic medical record with clinical data management system by CDISC ODM.

PubMed

Matsumura, Yasushi; Hattori, Atsushi; Manabe, Shiro; Takeda, Toshihiro; Takahashi, Daiyo; Yamamoto, Yuichiro; Murata, Taizo; Mihara, Naoki

2014-01-01

EDC system has been used in the field of clinical research. The current EDC system does not connect with electronic medical record system (EMR), thus a medical staff has to transcribe the data in EMR to EDC system manually. This redundant process causes not only inefficiency but also human error. We developed an EDC system cooperating with EMR, in which the data required for a clinical research form (CRF) is transcribed automatically from EMR to electronic CRF (eCRF) and is sent via network. We call this system as "eCRF reporter". The interface module of eCRF reporter can retrieves the data in EMR database including patient biography data, laboratory test data, prescription data and data entered by template in progress notes. The eCRF reporter also enables users to enter data directly to eCRF. The eCRF reporter generates CDISC ODM file and PDF which is a translated form of Clinical data in ODM. After storing eCRF in EMR, it is transferred via VPN to a clinical data management system (CDMS) which can receive the eCRF files and parse ODM. We started some clinical research by using this system. This system is expected to promote clinical research efficiency and strictness.

Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1

NASA Astrophysics Data System (ADS)

Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ågren, Hans; Tu, Yaoquan

2015-01-01

The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr6.63 forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr6.63 to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr3566.63 allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1.

PubMed

Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ågren, Hans; Tu, Yaoquan

2015-01-28

The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

Periodontal parameters and BANA test in patients with chronic renal failure undergoing hemodialysis

PubMed Central

TORRES, Sérgio Aparecido; ROSA, Odila Pereira da Silva; HAYACIBARA, Mitsue Fujimaki; GUIMARÃES, Maria do Carmo Machado; HAYACIBARA, Roberto M.; BRETZ, Walter Antônio

2010-01-01

Objectives The aim of this study was to analyze the periodontal parameters of patients with chronic renal failure. Material and Methods The periodontal status of 16 Brazilian patients aged 29 to 53 (41.7±7.2) years with chronic renal failure (CRF) and another matched group of 14 healthy controls with periodontitis was assessed clinically and microbiologically. Probing pocket depth (PPD), gingival recession (GR), dental plaque index (PLI), gingival index (GI), and dental calculus index (CI) were the clinical parameters recorded for the entire dentition (at least 19 teeth), while the anaerobic periodontopathogen colonization in four sites with the highest PPD was evaluated using the BANA test (“PerioScan”; Oral B). Results The results for the CRF group and control group, respectively were: PPD: 1.77±0.32 and 2.65±0.53; GR: 0.58±0.56 and 0.51±0.36; PLI: 1.64±0.56 and 1.24±0.67; GI: 0.64±0.42 and 0.93±0.50; CI: 1.17±0.54 and 0.87±0.52. Comparison between groups using the "t" test revealed a significantly increased PPD (p<0.001) in the control group. Comparison of the other clincial parameters by the Mann-Whitney test showed differences only for PLI, which was significantly higher (p<0.05) in the CRF group. Spearman's test applied to each group showed a positive correlation among all clinical parameters, except for GR (p<0.05). None of the groups showed any correlation between GR and GI, while a significant negative correlation between GR and PPD was observed for the CRF group. The percentage of BANA-positive sites was 35.9% for the CRF group and 35.7% for the control group. The BANA test correlated positively with PPD only in the control group and with GR only in the CRF group. Conclusions In spite of a higher PLI and dense anaerobic microbial population even in shallow PPD, patients with CRF exhibited better periodontal conditions than periodontitis patients, which is an evidence of altered response to local irritants. PMID:20857011

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

PubMed Central

Clark, Michael S.; McDevitt, Ross A.; Hoplight, Blair J.; Neumaier, John F.

2007-01-01

Corticotropin releasing factor (CRF) family peptides play key roles in integrating neural responses to stress. Both major CRF receptors have been pharmacologically identified in the dorsal raphe nucleus (DRN), a stress sensitive and internally heterogeneous nucleus supplying many forebrain regions with serotonergic input. Despite the involvement of chronic stress and serotonergic dysfunction in human mood and anxiety disorders, little is known about the effects of chronic CRF receptor activation on the DRN. We infused ovine CRF (1ng/hr), urocortin II (UCNII, 1ng/hr), or vehicle alone into rat DRN over 6 days. During infusion, animals were allowed to freely explore an open field for 15 minutes on each of two days, with the addition of a novel object on the second day. Following behavioral testing, 5-HT1A, 5-HT1B, serotonin transporter (SERT), and tryptophan hydroxylase-2 (Tph2) expression were examined through the DRN by in situ hybridization. Ovine CRF infusion resulted in significantly decreased novel object touches, climbs, as well as increased latency to first novel object contact. UCNII had a similar but less dramatic effect, decreasing only climbing behavior. Both ovine CRF and UCNII blunted the decrease in corner time expected on re-exposure to the open field. Both peptides also produced regionally specific changes in gene expression: 5-HT1A expression was increased 30% in the mid-rostral ventromedial DRN, while SERT was decreased by 30% in the mid-caudal shell dorsomedial DRN. There also appeared to be a shift in the relative level of Tph2 expression between the ventromedial and core dorsomedial DRN at the mid-rostral level. Changes in 5-HT1A, SERT, and relative Tph2 mRNA abundance were correlated with novel object exploration. These findings suggest chronic intra-DRN administration of CRF agonists decreases exploratory behavior, while producing subregionally limited changes in serotonergic gene expression. These studies may be relevant to mechanisms underlying behavioral changes after chronic stress. PMID:17467184

Nonpharmacologic approach to fatigue in patients with cancer.

PubMed

Pachman, Deirdre R; Price, Katharine A; Carey, Elise C

2014-01-01

Cancer-related fatigue is a common yet underappreciated problem with a significant impact on functional ability and quality of life. Practice guidelines mandate that all cancer patients and survivors be screened for cancer-related fatigue (CRF) at regular intervals. Comorbidities that could contribute to fatigue should be treated, and patients with moderate to severe fatigue should undergo a comprehensive evaluation. Nonpharmacologic interventions are important tools to combat CRF and should be incorporated into routine practice. Physical activity, educational interventions, and cognitive-behavioral therapy have the most supportive data and can be recommended to patients with confidence. From a practical standpoint, general education on CRF is something that most care providers can readily offer patients as part of routine care. Other interventions that appear promising but are as yet lacking convincing evidence include mindfulness-based stress reduction, yoga, and acupuncture. Reiki, Qigong, hypnosis, and music therapy may be worthy of further investigation.

Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the "Superorganism Hypothesis"

PubMed Central

Coplan, Jeremy D.; Karim, Asif; Rozenboym, Anna; Smith, Eric L. P.; Kral, John G.; Rosenblum, Leonard A.

2017-01-01

Introduction Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response. Methods Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Results Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure. Comment In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.” PMID:28880949

[Study on the molecular-epidemiological characteristics of HIV-1 in Shenzhen, 1992-2008].

PubMed

Zhao, Guang-lu; Yu, Wei; Zhang, Juan-juan; Chen, Lin; Feng, Tie-jian; Wang, Feng; Hong, Fu-chang; Wang, Xiao-hui; Li, Qing

2012-01-01

To investigate the epidemiological characteristics of HIV-1 subtype in Shenzhen from 1992 to 2008. 489 HIV-1 positive plasma samples were collected from 1992 to 2008 in Shenzhen. HIV-1 env genes were amplified by nested-PCR from RNA. Phylogenetic analysis was performed on data regarding the nucleotide sequence. A total of 464 sequences were amplified and genotyped. Data from this study revealed that CRF01_AE was a predominant HIV-1 subtype in Shenzhen (64.4%, 299/464), followed by subtypes CRF_BC (17.5%, 81/464), B' (14.7%, 68/464) and B (2.4%, 11/464). Subtype C (0.4%, 2/464), A1 (0.2%, 1/464), CRF02_AG (0.2%, 1/464) and CRF06_cpx (0.2%, 1/464) were also prevalent in Shenzhen. CRF01_AE and CRF_BC were predominant among heterosexuals, homosexuals and injection drug users, while B' was predominant among blood donors. Results from phylogenetic tree analysis showed that some of the HIV-1 clusters had been defined in CRF01_AE strains at different time or groups with different transmission routes. Cross-infections were also seen. CRF01_AE was the predominant HIV-1 subtype in Shenzhen while CRF_BC, B, B', C, A1, CRF02_AG and a small amount of CRF06_cpx or recombinant subtypes were prevalent in this city. Different subtypes showed great variation in the process of epidemics.

Cardiorespiratory Fitness and Highly Sensitive Cardiac Troponin Levels in a Preventive Medicine Cohort.

PubMed

DeFina, Laura F; Willis, Benjamin L; Radford, Nina B; Christenson, Robert H; deFilippi, Christopher R; de Lemos, James A

2016-11-28

Cardiorespiratory fitness (CRF) and highly sensitive cardiac troponin T (hs-cTnT) are associated with risk of all-cause and cardiovascular mortality as well as incident heart failure. A link of low CRF to subclinical cardiac injury may explain this association. We hypothesized that CRF would be inversely associated with hs-cTnT measured in healthy adults over age 50. We evaluated 2498 participants (24.7% female, mean age 58.7 years) from the Cooper Center Longitudinal Study between August 2008 and January 2012. Plasma specimens obtained shortly before CRF estimates by Balke treadmill testing were used for hs-cTnT assays. CRF was grouped into low CRF (category 1), moderate CRF (categories 2-3), and high CRF (categories 4-5). Multivariable logistic regression was used to estimate the association of CRF with hs-cTnT. The prevalence of measurable hs-cTnT (≥3 ng/L) was 78.5%. In multivariable analyses, low-fit individuals were significantly more likely than high-fit individuals to have elevated hs-cTnT (≥14 ng/L) (odds ratio 2.47, 95% CI 1.10-5.36). In healthy older adults, CRF is inversely associated with hs-cTnT level adjusted for other risk factors. Prospective studies are needed to evaluate whether improving CRF is effective in preventing subclinical cardiac injury. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Aiming for a Better Understanding and Management of Cancer-Related Fatigue

PubMed Central

Neefjes, Elisabeth C.W.; van der Vorst, Maurice J.D.L.; Blauwhoff-Buskermolen, Susanne

2013-01-01

Cancer-related fatigue (CRF) is a serious symptom of patients with cancer and deteriorates their daily quality of life. Whereas fatigue is a common problem in the general population, with a prevalence of about 30%, up to 99% of patients with cancer have fatigue of more intense severity. CRF is directly related to the biology of cancer, but it can also be caused by anticancer treatment. We reviewed current evidence about the potential pathophysiological mechanisms causing CRF. Clinical methods to determine the presence and severity of CRF and potential treatment options to reduce CRF will be discussed. After reading this review, the reader will have knowledge of the current understanding of CRF and will be able to give evidence-based advice to patients with CRF. PMID:24037979

Increased expression of CRF and CRF-receptors in dorsal striatum, hippocampus, and prefrontal cortex after the development of nicotine sensitization in rats.

PubMed

Carboni, Lucia; Romoli, Benedetto; Bate, Simon T; Romualdi, Patrizia; Zoli, Michele

2018-05-29

Nicotine addiction supports tobacco smoking, a main preventable cause of disease and death in Western countries. It develops through long-term neuroadaptations in the brain reward circuit by modulating intracellular pathways and regulating gene expression. This study assesses the regional expression of the transcripts of the CRF transmission in a nicotine sensitization model, since it is hypothesised that the molecular neuroadaptations that mediate the development of sensitization contribute to the development of addiction. Rats received intraperitoneal nicotine administrations (0.4 mg/kg) once daily for either 1 day or over 5 days. Locomotor activity was assessed to evaluate the development of sensitization. The mRNA expression of CRF and CRF1 and CRF2 receptors was measured by qPCR in the ventral mesencephalon, ventral striatum, dorsal striatum (DS), prefrontal cortex (PFCx), and hippocampus (Hip). Acute nicotine administration increased locomotor activity in rats. In the sub-chronic group, locomotor activity progressively increased and reached a clear sensitization. Significant effects of sensitization on CRF mRNA levels were detected in the DS (increasing effect). Significantly higher CRF1 and CRF2 receptor levels after sensitization were detected in the Hip. Additionally, CRF2 receptor levels were augmented by sensitization in the PFCx, and treatment and time-induced increases were detected in the DS. Nicotine treatment effects were observed on CRF1R levels in the DS. This study suggests that the CRF transmission, in addition to its role in increasing withdrawal-related anxiety, may be involved in the development of nicotine-habituated behaviours through reduced control of impulses and the aberrant memory plasticity characterising addiction. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of hemodialysis and peritoneal dialysis on redox status in chronic renal failure patients: a comparative study.

PubMed

Mekki, Khedidja; Taleb, Warda; Bouzidi, Nassima; Kaddous, Abbou; Bouchenak, Malika

2010-09-03

To investigate the effects of hemodialysis (HD) and periotoneal dialysis (PD) on oxidative stress in chronic renal failure patients (CRF). 20 HD patients (M/F: 8/12, 36 ± 12 years) and 20 PD patients (M/F: 10/10, 40 ± 8 years) were compared with 20 end stage renal failure patients (CRF) (M/F: 4/16, 61 ± 13 years). Thiobarbituric acid reactive substances (TBARS) values were elevated in HD and decreased in PD compared to CRF (P < 0.05). TBARS-VLDL and TBARS-HDL2 were decreased in HD and PD, compared to CRF (p < 0.05). TBARS-LDL were higher in HD compared to CRF (p < 0.05). No significant difference in TBARS-HDL3 values between the three groups. Carbonyls were increased in HD (p < 0.05) and PD (p < 0.01) compared to CRF. Plasma superoxide dismutase activity (SOD) was decreased in HD compared to CRF and PD (P < 0.05). Glutathion peroxidase activity (GSH-Px) was decreased in HD and PD (P < 0.005), compared to CRF. Decrease in catalase activity was noted only in PD compared to CRF (P < 0.05). An increase in nitric oxide was noted in HD compared to CRF (p < 0.05). Albumin concentrations were higher in HD and PD compared to CRF (P < 0.001). Whereas uric acid concentrations were decreased in HD (P < 0.001) compared to CRF and PD. Bilirubin values were similar in all groups. Increased values of iron were noted in HD and PD, compared to PD (p < 0.001). HD and PD aggravate oxidative stress generated by uremia. HD accentuates lipid and protein peroxidation, while PD aggravates protein oxidation. However, the activity of antioxidant enzymes was altered by both dialysis treatments.

A Central Amygdala CRF Circuit Facilitates Learning about Weak Threats.

PubMed

Sanford, Christina A; Soden, Marta E; Baird, Madison A; Miller, Samara M; Schulkin, Jay; Palmiter, Richard D; Clark, Michael; Zweifel, Larry S

2017-01-04

Fear is a graded central motive state ranging from mild to intense. As threat intensity increases, fear transitions from discriminative to generalized. The circuit mechanisms that process threats of different intensity are not well resolved. Here, we isolate a unique population of locally projecting neurons in the central nucleus of the amygdala (CeA) that produce the neuropeptide corticotropin-releasing factor (CRF). CRF-producing neurons and CRF in the CeA are required for discriminative fear, but both are dispensable for generalized fear at high US intensities. Consistent with a role in discriminative fear, CRF neurons undergo plasticity following threat conditioning and selectively respond to threat-predictive cues. We further show that excitability of genetically isolated CRF-receptive (CRFR1) neurons in the CeA is potently enhanced by CRF and that CRFR1 signaling in the CeA is critical for discriminative fear. These findings demonstrate a novel CRF gain-control circuit and show separable pathways for graded fear processing. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic Diversity of HIV-1 in Tunisia.

PubMed

El Moussi, Awatef; Thomson, Michael M; Delgado, Elena; Cuevas, María Teresa; Nasr, Majda; Abid, Salma; Ben Hadj Kacem, Mohamed Ali; Benaissa Tiouiri, Hanene; Letaief, Amel; Chakroun, Mohamed; Ben Jemaa, Mounir; Hamdouni, Hayet; Tej Dellagi, Rafla; Kheireddine, Khaled; Boutiba, Ilhem; Pérez-Álvarez, Lucía; Slim, Amine

2017-01-01

In this study, the genetic diversity of HIV-1 in Tunisia was analyzed. For this, 193 samples were collected in different regions of Tunisia between 2012 and 2015. A protease and reverse transcriptase fragment were amplified and sequenced. Phylogenetic analyses were performed through maximum likelihood and recombination was analyzed by bootscanning. Six HIV-1 subtypes (B, A1, G, D, C, and F2), 5 circulating recombinant forms (CRF02_AG, CRF25_cpx, CRF43_02G, CRF06_cpx, and CRF19_cpx), and 11 unique recombinant forms were identified. Subtype B (46.4%) and CRF02_AG (39.4%) were the predominant genetic forms. A group of 44 CRF02_AG sequences formed a distinct Tunisian cluster, which also included four viruses from western Europe. Nine viruses were closely related to isolates collected in other African or in European countries. In conclusion, a high HIV-1 genetic diversity is observed in Tunisia and the local spread of CRF02_AG is first documented in this country.

A Newly Emerging HIV-1 Recombinant Lineage (CRF58_01B) Disseminating among People Who Inject Drugs in Malaysia

PubMed Central

Chow, Wei Zhen; Takebe, Yutaka; Syafina, Nur Ezreen; Prakasa, Malarvelli Soorya; Chan, Kok Gan; Al-Darraji, Haider Abdulrazzaq Abed; Koh, Clayton; Kamarulzaman, Adeeba; Tee, Kok Keng

2014-01-01

The HIV epidemic is primarily characterised by the circulation of HIV-1 group M (main) comprising of 11 subtypes and sub-subtypes (A1, A2, B–D, F1, F2, G, H, J, and K) and to date 55 circulating recombinant forms (CRFs). In Southeast Asia, active inter-subtype recombination involving three main circulating genotypes—subtype B (including subtype B′, the Thai variant of subtype B), CRF01_AE, and CRF33_01B—have contributed to the emergence of novel unique recombinant forms. In the present study, we conducted the molecular epidemiological surveillance of HIV-1 gag-RT genes among 258 people who inject drugs (PWIDs) in Kuala Lumpur, Malaysia, between 2009 and 2011 whereby a novel CRF candidate was recently identified. The near full-length genome sequences obtained from six epidemiologically unlinked individuals showed identical mosaic structures consisting of subtype B′ and CRF01_AE, with six unique recombination breakpoints in the gag-RT, pol, and env regions. Among the high-risk population of PWIDs in Malaysia, which was predominantly infected by CRF33_01B (>70%), CRF58_01B circulated at a low but significant prevalence (2.3%, 6/258). Interestingly, the CRF58_01B shared two unique recombination breakpoints with other established CRFs in the region: CRF33_01B, CRF48_01B, and CRF53_01B in the gag gene, and CRF15_01B (from Thailand) in the env gene. Extended Bayesian Markov chain Monte Carlo sampling analysis showed that CRF58_01B and other recently discovered CRFs were most likely to have originated in Malaysia, and that the recent spread of recombinant lineages in the country had little influence from neighbouring countries. The isolation, genetic characterization, and evolutionary features of CRF58_01B among PWIDs in Malaysia signify the increasingly complex HIV-1 diversity in Southeast Asia that may hold an implication on disease treatment, control, and prevention. PMID:24465513

Effects of RO 15-1788 on a running response rewarded on continuous or partial reinforcement schedules.

PubMed

Hawkins, M; Sinden, J; Martin, I; Gray, J A

1988-01-01

Two experiments were run in which rats were rewarded with food for running in a straight alley at one trial a day, followed by extinction of the running response. During acquisition of the response, reward was delivered either on a continuous reinforcement (CRF) or on a quasirandom 50% partial reinforcement (PRF) schedule. The groups given PRF were more resistant to extinction than those given CRF, the well-known partial reinforcement extinction effect. In Experiment 1 different groups of rats were injected during acquisition only with 1, 5 or 10 mg/kg of the benzodiazepine antagonist, RO 15-1788, or with placebo. In Experiment 2, 5 mg/kg RO 15-1788 or placebo were administered in a full cross-over design during acquisition, extinction or both. At the end of Experiment 2 only [3H]-flunitrazepam binding was measured in either the presence or absence of added gamma-aminobutyrate (GABA) in homogenates of hippocampi dissected from the animals that had received behavioural training. The drug affected running speeds during both acquisition and extinction in different ways depending upon the schedule of reinforcement (CRF or PRF) and also gave rise to enhanced GABA stimulation of [3H]-flunitrazepam binding. The results are discussed in relation to the hypothesis that the neurochemical pathways by which reinforcement schedules modify behaviour include a step influenced by benzodiazepine receptors.

Phylogenetic and Temporal Dynamics of Human Immunodeficiency Virus Type 1 CRF01_AE in China

PubMed Central

Su, Xueli; Lu, Hongyan; Pang, Xinghuo; Yan, Hong; Feng, Xia; He, Xiong; Zeng, Yi

2013-01-01

To explore the epidemic history of HIV-1 CRF01_AE in China, 408 fragments of gag gene sequences of CRF01_AE sampled in 2002–2010 were determined from different geographical regions and risk populations in China. Phylogenetic analysis indicates that the CRF01_AE sequences can be grouped into four clusters, suggesting that at least four genetically independent CRF01_AE descendants are circulating in China, of which two were closely related to the isolates from Thailand and Vietnam. Cluster 1 has the most extensive distribution in China. In North China, cluster 1 and cluster 4 were mainly transmitted through homosexuality.The real substance of the recent HIV-1 epidemic in men who have sex with men(MSM) of North China is a rapid spread of CRF01_AE, or rather two distinctive natives CRF01_AE.The time of the most recent common ancestor (tMRCA) of four CRF01_AE clusters ranged from the years 1990.9 to 2003.8 in different regions of China. This is the first phylogenetic and temporal dynamics study of HIV-1 CRF01_AE in China. PMID:23365653

Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1

PubMed Central

Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ågren, Hans; Tu, Yaoquan

2015-01-01

The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr6.63 forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr6.63 to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr3566.63 allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R. PMID:25628267

Relationship between cigarette smoking and other coronary risk factors in atherosclerosis: risk of cardiovascular disease and preventive measures.

PubMed

Leone, Aurelio

2003-01-01

Among the major Coronary Risk Factors (CRF) cigarette smoking has shown undoubtedly harmful effects on the heart and blood vessels either as active smoking (smoking a cigarette) or passive smoking (exposure to environmental tobacco smoke -ETS). The strong relationship between cigarette smoking and cardiovascular disease has been seen independent of the other CRF in a number of well-designated epidemiologic studies. However, a strong increase in the excess of cardiovascular risk has been defined along with the interaction of cigarette smoking and other major CRF. Thousands of pharmacologically active substances are present in tobacco smoke, and a large number of direct and indirect effects have been demonstrated. Different responses are also related to these types of exposure: active exposure or passive exposure. The cardiovascular risk increases with increasing levels of blood pressure and/or serum cholesterol and diabetes mellitus, and at each level of these three risk factors, distributed with different rates according to age and gender in individuals, the risk in active smokers or passive smokers is greater than the risk in nonsmokers. Further analytical and methodological observations are needed for better understanding of the chemical and biological synergism. Nevertheless, evidence is clear that cigarette smoking greatly increases the risk of cardiovascular diseases in individuals already at increased risk because of other CRF. Preventive measures must be absolutely conducted to prevent the CRF interaction. These are the changes in lifestyle (i.e. to give up smoking and make physical activity), drug administration, diet supplementation especially by those substances with antioxidant effects.

Does corneal hysteresis correlate with endothelial cell density?

PubMed

Akova-Budak, Berna; Kıvanç, Sertaç Argun

2015-05-21

Our aim was to determine if there is a correlation between corneal biomechanical properties, endothelial cell count, and corneal pachymetry in healthy corneas. Ninety-two eyes of all subjects underwent complete ocular examination, including intraocular pressure measurement by Goldmann applanation tonometer, objective refraction, and slit-lamp biomicroscopy. Topographic measurements and corneal pachymetry were performed using a Scheimpflug-based (Pentacam, Oculus, Germany) corneal topographer. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured with an Ocular Response Analyzer (ORA, Reichert Ophthalmic Instruments, Buffalo, NY). Endothelial cell count measurement was done using a specular microscope (CellChek, Konan, USA). Right eye values of the subjects were taken for the study. The mean CH was 11.5±1.7 mmHg and the mean CRF was 11.2±1.4 mmHg. Mean intraocular pressure was 15.3±2.3 mmHg. The mean endothelial cell count was 2754±205 cells/mm2. No correlation was found between biomechanical properties of cornea and endothelial cell count. There was a significant positive correlation between CH, CRF, and corneal thickness (p<0.001; r=0.79). The corneal biomechanical properties significantly correlated with corneal thickness. We found no correlation between CH and CRF with the endothelial cell density in normal subjects.

Subcellular plasticity of the corticotropin-releasing factor receptor in dendrites of the mouse bed nucleus of the stria terminalis following chronic opiate exposure.

PubMed

Jaferi, A; Lane, D A; Pickel, V M

2009-09-29

Chronic opiate administration alters the expression levels of the stress-responsive peptide, corticotropin-releasing factor (CRF), in the bed nucleus of the stria terminalis (BNST). This brain region contains CRF receptors that drive drug-seeking behavior exacerbated by stress. We used electron microscopy to quantitatively compare immunolabeling of the corticotropin-releasing factor receptor (CRFr) and CRF in the anterolateral bed nucleus of the stria terminalis (BSTal) of mice injected with saline or morphine in escalating doses for 14 days. We also compared the results with those in non-injected control mice. The tissue was processed for CRFr immunogold and CRF immunoperoxidase labeling. The non-injected controls had a significantly lower plasmalemmal density of CRFr immunogold particles in dendrites compared with mice receiving saline, but not those receiving morphine, injections. Compared with saline, however, mice receiving chronic morphine showed a significantly lower plasmalemmal, and greater cytoplasmic, density of CRFr immunogold in dendrites. Within the cytoplasmic compartment of somata and dendrites of the BSTal, the proportion of CRFr gold particles associated with mitochondria was three times as great in mice receiving morphine compared with saline. This subcellular distribution is consistent with morphine,- and CRFr-associated modulation of intracellular calcium release or oxidative stress. The between-group changes occurred without effect on the total number of dendritic CRFr immunogold particles, suggesting that chronic morphine enhances internalization or decreases delivery of the CRFr to the plasma membrane, a trafficking effect that is also affected by the stress of daily injections. In contrast, saline and morphine treatment groups showed no significant differences in the total number of CRF-immunoreactive axon terminals, or the frequency with which these terminals contacted CRFr-containing dendrites. This suggests that morphine does not influence axonal availability of CRF in the BSTal. The results have important implications for drug-associated adaptations in brain stress systems that may contribute to the motivation to continue drug use during dependence.

Effects of electroconvulsive seizures on depression-related behavior, memory and neurochemical changes in Wistar and Wistar-Kyoto rats.

PubMed

Kyeremanteng, C; MacKay, J C; James, J S; Kent, P; Cayer, C; Anisman, H; Merali, Z

2014-10-03

Investigations in healthy outbred rat strains have shown a potential role for brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis in the antidepressant and memory side effects of electroconvulsive therapy (ECT, or ECS in animals). The Wistar-Kyoto (WKY) rat strain is used as a genetic model of depression yet no studies to date have directly compared the impact of ECS on the WKY strain to its healthy outbred control (Wistar). The objective of this study is to examine behavioral (antidepressant and retrograde memory) and neurochemical (BDNF and HPA axis) changes immediately (1day) and at a longer delay (7days) after repeated ECS (5 daily administrations) in WKY and Wistar rats. Male Wistar and WKY rats received 5days of repeated ECS or sham treatment and were assessed 1 and 7days later for 1) depression-like behavior and mobility; 2) retrograde memory; and 3) brain BDNF protein, brain corticotropin-releasing factor (CRF) and plasma corticosterone levels. Both strains showed the expected antidepressant response and retrograde memory impairments at 1day following ECS, which were sustained at 7days. In addition, at 1day after ECS, Wistar and WKY rats showed similar elevations in brain BDNF and extra-hypothalamic CRF and no change in plasma corticosterone. At 7days after ECS, Wistar rats showed sustained elevations of brain BDNF and CRF, whereas WKY rats showed a normalization of brain BDNF, despite sustained elevations of brain CRF. The model of 5 daily ECS was effective at eliciting behavioral and neurochemical changes in both strains. A temporal association was observed between brain CRF levels, but not BDNF, and measures of antidepressant effectiveness of ECS and retrograde memory impairments suggesting that extra-hypothalamic CRF may be a potential important contributor to these behavioral effects after repeated ECS/ECT. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of Corneal Biomechanical Properties between Indian and Chinese Adults.

PubMed

Chua, Jacqueline; Nongpiur, Monisha E; Zhao, Wanting; Tham, Yih Chung; Gupta, Preeti; Sabanayagam, Charumathi; Aung, Tin; Wong, Tien Yin; Cheng, Ching-Yu

2017-09-01

To investigate the difference in corneal hysteresis (CH) and corneal resistance factor (CRF) between Indian and Chinese populations. Population-based cross-sectional study. Three hundred eighty-two Singaporean Indian persons and 764 Singaporean Chinese 50 years of age or older were included from the Singapore Indian Eye Study and Singapore Chinese Eye Study, respectively. Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for risk factor assessment. The CH and CRF were measured with the Ocular Response Analyzer (Reichert Ophthalmic Instruments, Buffalo, NY). Information on genetic ancestry was derived using principal component analysis. Linear regression models were used to investigate the association of CH and CRF with potential risk factors. Corneal hysteresis and CRF. After excluding participants with a history of intraocular surgery, a diagnosis of glaucoma suspect or glaucoma, refractive surgery, or presence of corneal abnormalities, CH and CRF readings were available for 382 Indian persons. For each Indian participant, 2 Chinese participants were selected and matched for age and gender (n = 764). There were no differences in the clinical measurements of CH (10.6±1.6 mmHg; P = 0.670) or CRF (10.3±1.7 mmHg; P = 0.103) between the ethnic groups. However, after adjusting for covariates, Indian persons had, on average, 0.18-mmHg higher CH levels than in Chinese (95% confidence interval [CI], 0.02-0.38; P = 0.031). Consistently, CH level was correlated significantly with genetic ancestry in the Southeast Asian population. Corneal resistance factor level was not associated independently with self-reported ethnicity (95% CI, -0.10 to 0.29; P = 0.335). Chinese have lower CH than Indian persons, and this disparity may reflect biomechanical differences of the cornea. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

[Left ventricular dysfunction measured in diabetic patients with chronic renal failure on continuous ambulatory peritoneal dialysis].

PubMed

Díaz-Arrieta, Gustavo; Mendoza-Hernández, María Elsa; Pacheco-Aranda, Erika; Rivas-Duro, Miguel; Robles-Parra, Héctor Manuel; Espinosa-Vázquez, Raúl Arturo; Hernández-Cabrera, Jorge

2010-01-01

In diabetic patients with chronic renal failure (CRF) treated with dialysis, the diastolic and systolic left ventricular dysfunction is frequent. The aim was to assess by echocardiography the prevalence of diastolic and systolic ventricular dysfunction in diabetic patients with CRF treated with continuous ambulatory peritoneal dialysis (CAPD). Sixty diabetic patients with CRF in CAPD were studied. The mean age was 54.5 +/- 12 years (27-78 years). The left ventricular filling pattern (LVFP) as a diastolic function parameter and left ventricular ejection fraction (LVEF) as a systolic function parameter were measured by transthoracic echocardiography. Descriptive statistical analysis was used. 27 (45 %) patients were women and 33 (55 %) were men. In 55 (91.7 %) left ventricular concentric hypertrophy was observed. Fifty-two patients (86.7 %) showed LVFP type I; three (5 %) had the type II; two (3.3 %) showed pseudonormal pattern and three (5 %) had a normal LVFP. The LVEF was 0.63 +/- 0.09 (CI = 0.41-0.82). Forty nine (81.7 %) patients had LVEF equal or greater than 0.55. The prevalence of diastolic left ventricular dysfunction was 95 % and the prevalence of systolic left ventricular dysfunction was 18.3%.

Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear.

PubMed

Elharrar, Einat; Warhaftig, Gal; Issler, Orna; Sztainberg, Yehezkel; Dikshtein, Yahav; Zahut, Roy; Redlus, Lior; Chen, Alon; Yadid, Gal

2013-12-01

Posttraumatic stress disorder (PTSD) is a severe, persistent psychiatric disorder in response to a traumatic event, causing intense anxiety and fear. These responses may increase over time upon conditioning with fear-associated cues, a phenomenon termed fear incubation. Corticotropin-releasing factor receptor type 1 (CRFR1) is involved in activation of the central stress response, while corticotropin-releasing factor receptor type 2 (CRFR2) has been suggested to mediate termination of this response. Corticotropin-releasing factor (CRF) receptors are found in stress-related regions, including the bed nucleus of stria terminalis (BNST), which is implicated in sustained fear. Fear-related behaviors were analyzed in rats exposed to predator-associated cues, a model of psychological trauma, over 10 weeks. Rats were classified as susceptible (PTSD-like) or resilient. Expression levels of CRF receptors were measured in the amygdala nuclei and BNST of the two groups. In addition, lentiviruses overexpressing CRFR2 were injected into the medial division, posterointermediate part of the BNST (BSTMPI) of susceptible and resilient rats and response to stress cues was measured. We found that exposure to stress and stress-associated cues induced a progressive increase in fear response of susceptible rats. The behavioral manifestations of these rats were correlated both with sustained elevation in CRFR1 expression and long-term downregulation in CRFR2 expression in the BSTMPI. Intra-BSTMPI injection of CRFR2 overexpressing lentiviruses attenuated behavioral impairments of susceptible rats. These results implicate the BNST CRF receptors in the mechanism of coping with stress. Our findings suggest increase of CRFR2 levels as a new approach for understanding stress-related atypical psychiatric syndromes such as PTSD. © 2013 Society of Biological Psychiatry.

Using a site-specific technical error to establish training responsiveness: a preliminary explorative study.

PubMed

Weatherwax, Ryan M; Harris, Nigel K; Kilding, Andrew E; Dalleck, Lance C

2018-01-01

Even though cardiorespiratory fitness (CRF) training elicits numerous health benefits, not all individuals have positive training responses following a structured CRF intervention. It has been suggested that the technical error (TE), a combination of biological variability and measurement error, should be used to establish specific training responsiveness criteria to gain further insight on the effectiveness of the training program. To date, most training interventions use an absolute change or a TE from previous findings, which do not take into consideration the training site and equipment used to establish training outcomes or the specific cohort being evaluated. The purpose of this investigation was to retrospectively analyze training responsiveness of two CRF training interventions using two common criteria and a site-specific TE. Sixteen men and women completed two maximal graded exercise tests and verification bouts to identify maximal oxygen consumption (VO 2 max) and establish a site-specific TE. The TE was then used to retrospectively analyze training responsiveness in comparison to commonly used criteria: percent change of >0% and >+5.6% in VO 2 max. The TE was found to be 7.7% for relative VO 2 max. χ 2 testing showed significant differences in all training criteria for each intervention and pooled data from both interventions, except between %Δ >0 and %Δ >+7.7% in one of the investigations. Training nonresponsiveness ranged from 11.5% to 34.6%. Findings from the present study support the utility of site-specific TE criterion to quantify training responsiveness. A similar methodology of establishing a site-specific and even cohort specific TE should be considered to establish when true cardiorespiratory training adaptations occur.

Targeting NPY, CRF/UCNs and NPS Neuropeptide Systems to Treat Alcohol Use Disorder (AUD).

PubMed

Rodriguez, Francisco D; Coveñas, Rafael

2017-01-01

The term Alcohol Use Disorder (AUD) incorporates different states of disease related to the recurrent use of alcohol and linked to the relevant impairment, disability and failure to perform major responsibilities in different realms. Many neurotransmitter systems are involved in the phases or states of alcoholism from reward mechanisms, associated to binge intoxication, to stress and anxiety linked to relapse and withdrawal. Some neuropeptides play a key function in the control of anxiety and stress, and establish a close relationship with the pathological mechanisms underlying alcohol addiction. Among them, Neuropeptide Y (NPY), Corticotropin-releasing factor (CRF)/Urocortins and Neuropeptide S (NPS) cross-talk, and are responsible for some of the maladaptation processes that the brain exhibits during the progression of the disease. In this study, we review the literature mainly focused on the participation of these neuropeptides in the pathophysiology of AUD, as well as on the use of antagonists designed to investigate signaling mechanisms initiated after ligand binding and their connection to biochemical adaptation events coupled to alcohol addiction. The possibility that these systems may serve as therapeutic objectives to mitigate or eliminate the harm that drinking ethanol generates, is also discussed. The peptide systems reviewed here, together with other neurotransmitter systems and their mutual relationships, are firm candidates to be targeted to treat AUD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Phylodynamic analysis of the dissemination of HIV-1 CRF01_AE in Vietnam.

PubMed

Liao, Huanan; Tee, Kok Keng; Hase, Saiki; Uenishi, Rie; Li, Xiao-Jie; Kusagawa, Shigeru; Thang, Pham Hong; Hien, Nguyen Tran; Pybus, Oliver G; Takebe, Yutaka

2009-08-15

To estimate the epidemic history of HIV-1 CRF01_AE in Vietnam and adjacent Guangxi, China, we determined near full-length nucleotide sequences of CRF01_AE from a total of 33 specimens collected in 1997-1998 from different geographic regions and risk populations in Vietnam. Phylogenetic and Bayesian molecular clock analyses were performed to estimate the date of origin of CRF01_AE lineages. Our study reconstructs the timescale of CRF01_AE expansion in Vietnam and neighboring regions and suggests that the series of CRF01_AE epidemics in Vietnam arose by the sequential introduction of founder strains into new locations and risk groups. CRF01_AE appears to have been present among heterosexuals in South-Vietnam for more than a decade prior to its epidemic spread in the early 1990s. In the late 1980s, the virus spread to IDUs in Southern Vietnam and subsequently in the mid-1990s to IDUs further north. Our results indicate the northward dissemination of CRF01_AE during this time.

[Molecular epidemiology and transmission of HIV-1 infection in Zhejiang province, 2015].

PubMed

Yang, J Z; Chen, W J; Zhang, W J; He, L; Zhang, J F; Pan, X H

2017-11-10

Objective: To understand the distribution of HIV-1 subtype diversity and its transmission characteristics in Zhejiang province. Methods: A total of 302 newly diagnosed HIV-1 positive patients were selected through stratified random sampling in Zhejiang in 2015. HIV-1 pol genes were sequenced successfully with reverse transcription PCR/nested PCR and phylogenetic analysis was conducted for 276 patients. Then a molecular epidemiologic study was performed combined with field epidemiological investigation. Results: Of 276 sequence samples analyzed, 122 CRF07_BC strains (44.2%), 103 CRF01_AE strains (37.3%), 17 CRF08_BC strains (6.1%), 9 B strains (3.2%), 6 CRF55_01B strains (2.2%), 5 C strains (1.8%), 1 CRF59_01B strain (0.4%), 1 CRF67_01B strain (0.4%), 1 A1 strain (0.4%), and 11 URFs strains (4.0%) were identified. Phylogenetic analysis revealed 16 clusters with only 15.1% (34/225) sequences involved among CRF07_BC and CRF01_AE strains. The clustered cases in MSM were higher than that in populations with other transmission routes. And clusters existed between the populations with different transmission routes. Conclusion: The major strains of HIV-1 in Zhejiang are CRF07_BC and CRF01_AE. The HIV subtypes showed more complexity in Zhejiang. It is necessary to strengthen the surveillance for HIV subtypes, carry out classified management and conduct effective prevention and control in the population at high risk.

Effect of Methylphenidate in Patients with Cancer-Related Fatigue: A Systematic Review and Meta-Analysis

PubMed Central

He, Hua; Qi, Enbo; Chen, Wen; Dong, Yan; Hou, Lijun

2014-01-01

Background Cancer-related fatigue (CRF) is a common symptom affecting patients with cancer. There are an increasing number of trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs and an up-to-date assessment of the evidence for its use is needed. Trials of methylphenidate for CRF provided inconsistent results. This meta-analysis was aimed at assessing the effect and safety of methylphenidate on CRF. Methods We comprehensively searched the Pubmed, EMBASE, PSYCHInfo and the Cochrane databases in order to identify published studies on the effect of methylphenidate on CRF. Primary outcomes included fatigue. Secondary outcomes included depression, cognition and adverse effects. Findings A meta-analysis was conducted on five randomized controlled trials and 498 patients were enrolled. Despite a large placebo effect observed in the studies included, pooled data suggested therapeutic effect of methylphenidate on CRF. Subgroup Analyses showed that the efficacy of methylphenidate on CRF is getting better with prolonging treatment duration, with a MD of −3.70 (95% CI −7.03– −0.37, p = 0.03) for long-time group and a MD of −2.49 (95% CI −6.01–1.03, p = 0.17) for short-time group. In general, there was no impact of methylphenidate on depression and cognition associated with CRF. Adverse events were similar between methylphenidate and placebo groups except that more patients reported vertigo, anxiety, anorexia and nausea in methylphenidate group compared to placebo group. Conclusion Existing trials of methylphenidate on CRF provided limited evidence for the use of methylphenidate to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF. PMID:24416225

Analysis of the Origin and Evolutionary History of HIV-1 CRF28_BF and CRF29_BF Reveals a Decreasing Prevalence in the AIDS Epidemic of Brazil

PubMed Central

Ristic, Natalia; Zukurov, Jean; Alkmim, Wagner; Diaz, Ricardo Sobhie; Janini, Luiz Mario; Chin, Mario P. S.

2011-01-01

Background HIV-1 subtype B and subtype F are prevalent in the AIDS epidemic of Brazil. Recombinations between these subtypes have generated at least four BF circulating recombinant forms (CRFs). CRF28_BF and CRF29_BF are among the first two BF recombinants being identified in Brazil and they contributed significantly to the epidemic. However, the evolution and demographic histories of the CRFs are unclear. Methodology/Principal Findings A collection of gag and pol sequences sampled within Brazil was screened for CRF28_BF-like and CRF29_BF-like recombination patterns. A Bayesian coalescent framework was employed to delineate the phylogenetic, divergence time and population dynamics of the virus having CRF28_BF-like and CRF29_BF-like genotype. These recombinants were phylogenetically related to each other and formed a well-supported monophyletic clade dated to 1988–1989. The effective number of infections by these recombinants grew exponentially over a five-year period after their emergence, but then decreased toward the present following a logistic model of population growth. The demographic pattern of both recombinants closely resembles those previously reported for CRF31_BC. Conclusions We revealed that HIV-1 recombinants of the CRF28_BF/CRF29_BF clade are still circulating in the Brazilian population. These recombinants did not exhibit a strong founder effect and showed a decreasing prevalence in the AIDS epidemic of Brazil. Our data suggested that multiple URFs may also play a role in shaping the epidemic of recombinant BF HIV-1 in the region. PMID:21390250

Sex differences in stress-related receptors: ″micro″ differences with ″macro″ implications for mood and anxiety disorders

PubMed Central

2013-01-01

Stress-related psychiatric disorders, such as unipolar depression and post-traumatic stress disorder (PTSD), occur more frequently in women than in men. Emerging research suggests that sex differences in receptors for the stress hormones, corticotropin releasing factor (CRF) and glucocorticoids, contribute to this disparity. For example, sex differences in CRF receptor binding in the amygdala of rats may predispose females to greater anxiety following stressful events. Additionally, sex differences in CRF receptor signaling and trafficking in the locus coeruleus arousal center combine to make females more sensitive to low levels of CRF, and less adaptable to high levels. These receptor differences in females could lead to hyperarousal, a dysregulated state associated with symptoms of depression and PTSD. Similar to the sex differences observed in CRF receptors, sex differences in glucocorticoid receptor (GR) function also appear to make females more susceptible to dysregulation after a stressful event. Following hypothalamic pituitary adrenal axis activation, GRs are critical to the negative feedback process that inhibits additional glucocorticoid release. Compared to males, female rats have fewer GRs and impaired GR translocation following chronic adolescent stress, effects linked to slower glucocorticoid negative feedback. Thus, under conditions of chronic stress, attenuated negative feedback in females would result in hypercortisolemia, an endocrine state thought to cause depression. Together, these studies suggest that sex differences in stress-related receptors shift females more easily into a dysregulated state of stress reactivity, linked to the development of mood and anxiety disorders. The implications of these receptor sex differences for the development of novel pharmacotherapies are also discussed. PMID:23336736

Effects of a controlled-release fertilizer on yield, nutrient uptake, and fertilizer usage efficiency in early ripening rapeseed (Brassica napus L.)*

PubMed Central

Tian, Chang; Zhou, Xuan; Liu, Qiang; Peng, Jian-wei; Wang, Wen-ming; Zhang, Zhen-hua; Yang, Yong; Song, Hai-xing; Guan, Chun-yun

2016-01-01

Background: Nitrogen (N), phosphorous (P), and potassium (K) are critical nutrient elements necessary for crop plant growth and development. However, excessive inputs will lead to inefficient usage and cause excessive nutrient losses in the field environment, and also adversely affect the soil, water and air quality, human health, and biodiversity. Methods: Field experiments were conducted to study the effects of controlled-release fertilizer (CRF) on seed yield, plant growth, nutrient uptake, and fertilizer usage efficiency for early ripening rapeseed (Xiangzayou 1613) in the red-yellow soil of southern China during 2011–2013. It was grown using a soluble fertilizer (SF) and the same amounts of CRF, such as SF1/CRF1 (3750 kg/hm2), SF2/CRF2 (3000 kg/hm2), SF3/CRF3 (2250 kg/hm2), SF4/CRF4 (1500 kg/hm2), SF5/CRF5 (750 kg/hm2), and also using no fertilizer (CK). Results: CRF gave higher seed yields than SF in both seasons by 14.51%. CRF4 and SF3 in each group achieved maximum seed yield (2066.97 and 1844.50 kg/hm2, respectively), followed by CRF3 (1929.97 kg/hm2) and SF4 (1839.40 kg/hm2). There were no significant differences in seed yield among CK, SF1, and CRF1 (P>0.05). CRF4 had the highest profit (7126.4 CNY/hm2) and showed an increase of 12.37% in seed yield, and it decreased by 11.01% in unit fertilizer rate compared with SF4. The branch number, pod number, and dry matter weight compared with SF increased significantly under the fertilization of CRF (P<0.05). The pod number per plant was the major contributor to seed yield. On the other hand, the N, P, and K uptakes increased at first and then decreased with increasing the fertilizer rate at maturity, and the N, P, and K usage efficiency decreased with increasing the fertilizer rate. The N, P, and K uptakes and usage efficiencies of the CRF were significantly higher than those of SF (P<0.05). The N accumulation and N usage efficiency of CRF increased by an average of 13.66% and 9.74 percentage points, respectively, compared to SF. In conclusion, CRF significantly promoted the growth of rapeseed with using total N as the base fertilizer, by providing sufficient N in the later growth stages, and last by reducing the residual N in the soil and increasing the N accumulation and N usage efficiency. PMID:27704747

Effects of a controlled-release fertilizer on yield, nutrient uptake, and fertilizer usage efficiency in early ripening rapeseed (Brassica napus L.).

PubMed

Tian, Chang; Zhou, Xuan; Liu, Qiang; Peng, Jian-Wei; Wang, Wen-Ming; Zhang, Zhen-Hua; Yang, Yong; Song, Hai-Xing; Guan, Chun-Yun

Nitrogen (N), phosphorous (P), and potassium (K) are critical nutrient elements necessary for crop plant growth and development. However, excessive inputs will lead to inefficient usage and cause excessive nutrient losses in the field environment, and also adversely affect the soil, water and air quality, human health, and biodiversity. Field experiments were conducted to study the effects of controlled-release fertilizer (CRF) on seed yield, plant growth, nutrient uptake, and fertilizer usage efficiency for early ripening rapeseed (Xiangzayou 1613) in the red-yellow soil of southern China during 2011-2013. It was grown using a soluble fertilizer (SF) and the same amounts of CRF, such as SF1/CRF1 (3750 kg/hm 2 ), SF2/CRF2 (3000 kg/hm 2 ), SF3/CRF3 (2250 kg/hm 2 ), SF4/CRF4 (1500 kg/hm 2 ), SF5/CRF5 (750 kg/hm 2 ), and also using no fertilizer (CK). CRF gave higher seed yields than SF in both seasons by 14.51%. CRF4 and SF3 in each group achieved maximum seed yield (2066.97 and 1844.50 kg/hm 2 , respectively), followed by CRF3 (1929.97 kg/hm 2 ) and SF4 (1839.40 kg/hm 2 ). There were no significant differences in seed yield among CK, SF1, and CRF1 (P>0.05). CRF4 had the highest profit (7126.4 CNY/hm 2 ) and showed an increase of 12.37% in seed yield, and it decreased by 11.01% in unit fertilizer rate compared with SF4. The branch number, pod number, and dry matter weight compared with SF increased significantly under the fertilization of CRF (P<0.05). The pod number per plant was the major contributor to seed yield. On the other hand, the N, P, and K uptakes increased at first and then decreased with increasing the fertilizer rate at maturity, and the N, P, and K usage efficiency decreased with increasing the fertilizer rate. The N, P, and K uptakes and usage efficiencies of the CRF were significantly higher than those of SF (P<0.05). The N accumulation and N usage efficiency of CRF increased by an average of 13.66% and 9.74 percentage points, respectively, compared to SF. In conclusion, CRF significantly promoted the growth of rapeseed with using total N as the base fertilizer, by providing sufficient N in the later growth stages, and last by reducing the residual N in the soil and increasing the N accumulation and N usage efficiency.

EXAMINING THE GENERALITY OF CHILDREN'S PREFERENCE FOR CONTINGENT REINFORCEMENT VIA EXTENSION TO DIFFERENT RESPONSES, REINFORCERS, AND SCHEDULES

PubMed Central

Luczynski, Kevin C; Hanley, Gregory P

2010-01-01

Studies that have assessed whether children prefer contingent reinforcement (CR) or noncontingent reinforcement (NCR) have shown that they prefer CR. Preference for CR has, however, been evaluated only under continuous reinforcement (CRF) schedules. The prevalence of intermittent reinforcement (INT) warrants an evaluation of whether preference for CR persists as the schedule of reinforcement is thinned. In the current study, we evaluated 2 children's preference for contingent versus noncontingent delivery of highly preferred edible items for academic task completion under CRF and INT schedules. Children (a) preferred CR to NCR under the CRF schedule, (b) continued to prefer CR as the schedule of reinforcement became intermittent, and (c) exhibited a shift in preference from CR to NCR as the schedule became increasingly thin. These findings extend the generality of and provide one set of limits to the preference for CR. Applied implications, variables controlling preferences, and future research are discussed. PMID:21358901

Increased rate of adenine incorporation into adenine nucleotide pool in erythrocytes of patients with chronic renal failure.

PubMed

Marlewski, M; Smolenski, R T; Szolkiewicz, M; Aleksandrowicz, Z; Rutkowski, B; Swierczynski, J

2000-11-01

Elevated purine nucleotide pool (mainly ATP) in erythrocytes of patients with chronic renal failure (CRF) is a known phenomenon, however the mechanism responsible for this abnormality is far from being clear. We hypothesize that the increased rate of adenine incorporation into adenine nucleotide pool is responsible for the elevated level of ATP in uremic erythrocytes. In chronically uremic patients we evaluated using HPLC technique: (a) plasma adenine concentration; (b) the rate of adenine incorporation into adenine nucleotide pool in uremic erythrocytes. Additionally, the effect of higher than physiological phosphate concentration (2.4 mM) and lower than physiological pH (7.1) on adenine incorporation into erythrocytes adenine nucleotide pool was investigated. Healthy volunteers with normal renal function served as control. The concentration of adenine in plasma of CRF patients was found to be significantly higher than in plasma of healthy subjects. In contrast, adenosine concentration was similar both in healthy humans and in CRF patients. In isolated erythrocytes of uremic patients (incubated in the medium pH 7.4, containing 1.2 mM inorganic phosphate) adenine was incorporated into adenine nucleotide pool at a rate approximately 2-fold higher than in erythrocytes from healthy subjects. The rate of adenosine incorporation into adenine nucleotide pool was similar in erythrocytes of both studied groups. Incubation of erythrocytes obtained from healthy subjects in the medium pH 7.4, containing 2.4 mM inorganic phosphate, caused the increase of adenine incorporation into adenine nucleotide pool by about 60%. Incubation of the cells in the pH 7.1 buffer containing 2. 4 mM inorganic phosphate increased the rate of adenine incorporation into adenylate approximately 2-fold as compared to erythrocytes incubated in the medium pH 7.4 containing 1.2 mM inorganic phosphate. Erythrocytes obtained from uremic patients and incubated in the pH 7.1 medium containing 2.4 mM phosphate incorporated adenine into adenine nucleotide pool at a rate similar to erythrocytes incubated in the medium pH 7.4 containing 1.2 mM phosphate. Erythrocytes obtained from either healthy subjects or from patients with CRF and incubated in the presence of higher than physiological concentration of inorganic phosphate (2.4 mM) and lower than physiological pH (7. 1) did not exhibit any increase in the rate of adenisine incorporation into adenine nucleotide pool. These results suggest that the increased rate of adenine incorporation into adenine nucleotide pool could be partially responsible for the increased concentration of ATP in uremic erythrocytes. Copyright 2000 S. Karger AG, Basel

The incidence of training responsiveness to cardiorespiratory fitness and cardiometabolic measurements following individualized and standardized exercise prescription: study protocol for a randomized controlled trial.

PubMed

Weatherwax, Ryan M; Harris, Nigel K; Kilding, Andrew E; Dalleck, Lance C

2016-12-19

There is individual variability to cardiorespiratory fitness (CRF) training, but the underlying cause is not well understood. Traditionally, a standardized approach to exercise prescription has utilized relative percentages of maximal heart rate, heart rate reserve (HRR), maximal oxygen uptake (VO 2 max), or VO 2 reserve to establish exercise intensity. However, this model fails to take into consideration individual metabolic responses to exercise and may attribute to the variability in training responses. It has been proposed that an individualized approach would take into consideration metabolic responses to exercises to increase responsiveness to training. In this randomized control trial, participants will undergo a 12-week exercise intervention using individualized (ventilatory thresholds) and standardized (HRR) methods to prescribe CRF training intensity. Following the intervention, participants will be categorized as responders or non-responders based on changes in maximal aerobic abilities. Participants who are non-responders will complete a second 12-week intervention in a crossover design to determine whether they can become responders with a differing exercise prescription. There are four main research outcomes: (1) determine the cohort-specific technical error to use in the categorization of response rate; (2) determine if an individualized intensity prescription is superior to a standard approach in regards to VO 2 max and cardiometabolic risk factors; (3) investigate the time course changes throughout 12 weeks of CRF training between the two intervention groups; and (4) determine if non-responders can become responders if the exercise prescription is modified. The findings from this research will provide evidence on the effectiveness of individualized exercise prescription related to training responsiveness of VO 2 max and cardiometabolic risk factors compared to a standardized approach and further our understanding of individual exercise responses. If the individualized approach proposed is deemed effective, it may change the way exercise specialists prescribe exercise intensity to enhance training responsiveness. ClinicalTrials.gov, NCT02868710 . Registered on 15 August 2016.

Stability of simple/complex classification with contrast and extraclassical receptive field modulation in macaque V1

PubMed Central

Henry, Christopher A.

2013-01-01

A key property of neurons in primary visual cortex (V1) is the distinction between simple and complex cells. Recent reports in cat visual cortex indicate the categorization of simple and complex can change depending on stimulus conditions. We investigated the stability of the simple/complex classification with changes in drive produced by either contrast or modulation by the extraclassical receptive field (eCRF). These two conditions were reported to increase the proportion of simple cells in cat cortex. The ratio of the modulation depth of the response (F1) to the elevation of response (F0) to a drifting grating (F1/F0 ratio) was used as the measure of simple/complex. The majority of V1 complex cells remained classified as complex with decreasing contrast. Near contrast threshold, an equal proportion of simple and complex cells changed their classification. The F1/F0 ratio was stable between optimal and large stimulus areas even for those neurons that showed strong eCRF suppression. There was no discernible overall effect of surrounding spatial context on the F1/F0 ratio. Simple/complex cell classification is relatively stable across a range of stimulus drives, produced by either contrast or eCRF suppression. PMID:23303859

A Novel Role of Peripheral Corticotropin-Releasing Hormone (CRH) on Dermal Fibroblasts

PubMed Central

Rassouli, Olga; Liapakis, George; Lazaridis, Iakovos; Sakellaris, George; Gkountelias, Kostas; Gravanis, Achille; Margioris, Andrew N.

2011-01-01

Corticotropin-releasing hormone, or factor, (CRH or CRF) exerts important biological effects in multiple peripheral tissues via paracrine/autocrine actions. The aim of our study was to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing. We show expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh−/−) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF1 antagonist antalarmin recapitulated the findings in the Crh−/− cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6. In conclusion, our findings show an important role of fibroblast-expressed CRH in the proliferation, migration, and cytokine production of these cells, processes associated with the skin response to injury. Our data suggest that the immunomodulatory effects of CRH may include an important, albeit not explored yet, role in epidermal tissue remodeling and regeneration and maintenance of tissue homeostasis. PMID:21765902

Increased adrenal steroid secretion in response to CRF in women with hypothalamic amenorrhea.

PubMed

Genazzani, A D; Bersi, C; Luisi, S; Fruzzetti, F; Malavasi, B; Luisi, M; Petraglia, F; Genazzani, A R

2001-09-01

To evaluate adrenal steroid hormone secretion in response to corticotropin-releasing factor (CRF) or to adrenocorticotropin hormone in women with hypothalamic amenorrhea. Controlled clinical study. Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Italy. Fifteen women with hypothalamic amenorrhea were enrolled in the study. Eight normal cycling women were used as control group. Blood samples were collected before and after an injection of ovine CRF (0.1 microg/kg iv bolus) or after synthetic ACTH (0.25 mg iv). Plasma levels of ACTH, 17-hydroxypregnenolone (17OHPe), progesterone (P), dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17OHP), cortisol (F), 11-deoxycortisol (S) and androstenedione (A). Basal plasma concentrations of ACTH, cortisol, 11-deoxycortisol, DHEA and 17OHPe were significantly higher in patients than in controls, whereas plasma levels of progesterone and 17-OHP were significantly lower in patients than in controls. In amenorrheic women the ratio of 17-OHPe/DHEA, of 17-OHPe/17-OHP and of 11-deoxycortisol/cortisol were significantly higher than in controls, while a significant reduction in the ratio of 17-OHP/androstenedione, of 17-OHP/11-deoxycortisol was obtained. In response to corticotropin-releasing factor test, plasma levels of ACTH, cortisol, 17-OHP, 11-deoxycortisol, DHEA and androstenedione were significantly lower in patients than in controls. In response to adrenocorticotropin hormone, plasma levels of 17-OHP, androstenedione and androstenedione/cortisol were significantly higher in patients than in controls. Patients suffering for hypothalamic amenorrhea showed an increased activation of hypothalamus-pituitary-adrenal (HPA) axis, as shown by the higher basal levels and by augmented adrenal hormone response to corticotropin-releasing factor administration. These data suggest a possible derangement of adrenal androgen enzymatic pathway.

[Genetic subtype and epidemiological feature of HIV-1 circulating strains among recently infected patients in Fujian province].

PubMed

Deng, Yongyue; Zhang, Chunyang; Yan, Yansheng; Yan, Pingping; Wu, Shouli

2014-06-01

In order to evaluate the distribution of genetic subtypes and epidemiological feature of HIV-1 circulating strains in Fujian province. Blood samples and epidemiological data were collected from 104 newly infected patients who were distinguished by BED-CEIA methodology, during 2011-2012. Viral sequences(n = 81) of HIV-1 gag, env, and pol segments were amplified by nested PCR. Subtypes B and four Circulating Recombinant Forms, (CRF01_AE, CRF07_BC, CRF08_BC and CRF55_01B) were found in the samples, CRF01_AE(45.68%)and CRF07_BC(35.80%) were the two main HIV-1 strains in Fujian province. Compared with previous data, the proportion of CRF07_BC rose significantly while it gradually decreased in CRF01_AE. Heterosexual contact was still the principal transmission route in Fujian province, but the number of infection among men-who-have-sex-with- men grew rapidly. Results from this study suggested that different subtypes of HIV-1 strain existed in Fujian province. The distribution of subtypes and the mode of transmission were changing with the progress of epidemic. Dynamic monitoring of the molecular epidemiology trends of HIV-1 infection should be enhanced.

Favorable cardiovascular risk factor profile is associated with lower healthcare expenditure and resource utilization among adults with diabetes mellitus free of established cardiovascular disease: 2012 Medical Expenditure Panel Survey (MEPS).

PubMed

Feldman, David I; Valero-Elizondo, Javier; Salami, Joseph A; Rana, Jamal S; Ogunmoroti, Oluseye; Osondu, Chukwuemeka U; Spatz, Erica S; Virani, Salim S; Blankstein, Ron; Blaha, Michael J; Veledar, Emir; Nasir, Khurram

2017-03-01

Given the prevalence and economic burden of diabetes mellitus (DM), we studied the impact of a favorable cardiovascular risk factor (CRF) profile on healthcare expenditures and resource utilization among individuals without cardiovascular disease (CVD), by DM status. 25,317 participants were categorized into 3 mutually-exclusive strata: "Poor", "Average" and "Optimal" CRF profiles (≥4, 2-3, 0-1 CRF, respectively). Two-part econometric models were utilized to study cost data. Mean age was 45 (48% male), with 54% having optimal, 39% average, and 7% poor CRF profiles. Individuals with DM were more likely to have poor CRF profile vs. those without DM (OR 7.7, 95% CI 6.4, 9.2). Individuals with DM/poor CRF profile had a mean annual expenditure of $9,006, compared to $6,461 among those with DM/optimal CRF profile (p < 0.001). A favorable CRF profile is associated with significantly lower healthcare expenditures and utilization in CVD-free individuals across DM status, suggesting that these individuals require aggressive individualized prescriptions targeting lifestyle modifications and therapeutic treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

Energy and nutrient intake of patients with mild-to-moderate chronic renal failure compared with healthy children: an Italian multicentre study.

PubMed

Rätsch, I M; Catassi, C; Verrina, E; Gusmano, R; Appiani, A; Bettinelli, A; Picca, S; Rizzoni, G; Fabian-Bach, C; Wingen, A M

1992-09-01

Nutritional counselling is important in the management of children with chronic renal failure (CRF). In 1988, a controlled European multicentre study was started to evaluate the effects of a low-protein diet on the progression of CRF in children. To assess the energy, macro- and micronutrient intake, 4-day weighed dietary records were obtained from 50 children with low to moderate CRF (creatinine clearance 65 to 15 ml/min per 1.73 m2) and from 93 healthy children. The mean energy intake was 90%-93% of the recommended dietary allowance for Italian children in controls and 76%-88% in CRF patients. The mean protein intake was 2.1-3.1 g/kg per day in controls and 1.6-2.7 g/kg per day in CRF patients. Overall, the energy intake was 10% and the protein intake 33% lower in CRF patients than in healthy children. Children with CRF consumed less cholesterol, calcium and phosphorus than healthy children. The lower spontaneous intake of energy, protein and other nutrients should be taken into account when planning the nutrition of children with CRF.

CRF: detection of CRISPR arrays using random forest.

PubMed

Wang, Kai; Liang, Chun

2017-01-01

CRISPRs (clustered regularly interspaced short palindromic repeats) are particular repeat sequences found in wide range of bacteria and archaea genomes. Several tools are available for detecting CRISPR arrays in the genomes of both domains. Here we developed a new web-based CRISPR detection tool named CRF (CRISPR Finder by Random Forest). Different from other CRISPR detection tools, a random forest classifier was used in CRF to filter out invalid CRISPR arrays from all putative candidates and accordingly enhanced detection accuracy. In CRF, particularly, triplet elements that combine both sequence content and structure information were extracted from CRISPR repeats for classifier training. The classifier achieved high accuracy and sensitivity. Moreover, CRF offers a highly interactive web interface for robust data visualization that is not available among other CRISPR detection tools. After detection, the query sequence, CRISPR array architecture, and the sequences and secondary structures of CRISPR repeats and spacers can be visualized for visual examination and validation. CRF is freely available at http://bioinfolab.miamioh.edu/crf/home.php.

Increased CRF signaling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal

PubMed Central

Zhao-Shea, Rubing; DeGroot, Steven R.; Liu, Liwang; Vallaster, Markus; Pang, Xueyan; Su, Qin; Gao, Guangping; Rando, Oliver J.; Martin, Gilles E.; George, Olivier; Gardner, Paul D.; Tapper, Andrew R.

2015-01-01

Increased anxiety is a predominant withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear. Here, we show that withdrawal-induced anxiety increases activity of neurons in the interpeduncular intermediate (IPI), a subregion of the interpeduncular nucleus (IPN). IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signaling, which modulated glutamatergic input from the medial habenula (MHb). Pharmacological blockade of IPN CRF1 receptors or optogenetic silencing of MHb input reduced IPI activation and alleviated withdrawal-induced anxiety; whereas IPN CRF infusion in mice increased anxiety. We identified a meso-interpeduncular circuit, consisting of ventral tegmental area (VTA) dopaminergic neurons projecting to the IPN, as a potential source of CRF. Knock-down of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal. These data indicate that increased CRF receptor signaling within a VTA-IPN-MHb circuit triggers anxiety during nicotine withdrawal. PMID:25898242

Graft biomechanical properties after penetrating keratoplasty in keratoconus.

PubMed

Feizi, Sepehr; Einollahi, Bahram; Yazdani, Shahin; Hashemloo, Ali

2012-08-01

To measure corneal graft biomechanical properties after penetrating keratoplasty (PKP) in a group of keratoconic eyes using the ocular response analyzer (ORA) and to evaluate the relationship between donor size, donor-recipient disparity and central graft thickness (CGT), and ORA parameters. This cross-sectional study was conducted on 34 eyes of 34 keratoconus patients who had undergone PKP. Corneal hysteresis (CH), corneal resistance factor (CRF), and cornea-compensated intraocular pressure were measured at least 6 months after complete suture removal. Two groups of donor-recipient disparity (0.25 vs. 0.50 mm) were compared using the independent t test. Multivariate regression analysis was used to investigate the correlation of donor trephine size and CGT with ORA parameters. Factors influencing intraocular pressure measured with the Goldmann applanation tonometer (IOP GAT) after PKP were determined using multiple regression analysis. Mean patient age and follow-up period were 29.6 ± 6.2 years and 82.4 ± 59.6 months, respectively. Mean CGT, CH, and CRF were 564.7 ± 36.9 μm, 10.1 ± 2.1 mm Hg, and 10.0 ± 2.3 mm Hg, respectively. CH and CRF had a significant positive correlation with donor trephine size and CGT. Significantly greater values of CH and CRF were observed in the 0.5-mm disparity group compared with the 0.25-mm disparity group. Among the studied parameters, only CH, CRF, and cornea-compensated intraocular pressure had a significant positive correlation with IOP GAT. Graft biomechanics seem to be closer to normal values with larger grafts and greater donor-recipient disparity. These metrics had a significant correlation with IOP GAT after PKP.

Epigenetic regulation of nociceptin/orphanin FQ and corticotropin-releasing factor system genes in frustration stress-induced binge-like palatable food consumption.

PubMed

Pucci, Mariangela; Micioni Di Bonaventura, Maria Vittoria; Giusepponi, Maria Elena; Romano, Adele; Filaferro, Monica; Maccarrone, Mauro; Ciccocioppo, Roberto; Cifani, Carlo; D'Addario, Claudio

2016-11-01

Evidence suggests that binge eating may be caused by a unique interaction between dieting and stress. We developed a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after a 15-minute exposure to the sight of the palatable food (frustration stress). The aim of the present study was to investigate the regulation of the stress neurohormone corticotropin-releasing factor (CRF) system and of the nociceptin/orphanin FQ (N/OFQ) system genes in selective rat brain regions, using our animal model. Food restriction by itself seems to be responsible in the hypothalamus for the downregulation on messenger RNA levels of CRF-1 receptor, N/OFQ and its receptor (NOP). For the latter, this alteration might be due to selective histone modification changes. Instead, CRF gene appears to be upregulated in the hypothalamus as well as in the ventral tegmental area only when rats are food restricted and exposed to frustration stress, and, of relevance, these changes appear to be due to a reduction in DNA methylation at gene promoters. Moreover, also CRF-1 receptor gene resulted to be differentially regulated in these two brain regions. Epigenetic changes may be viewed as adaptive mechanisms to environmental perturbations concurring to facilitate food consumption in adverse conditions, that is, in this study, under food restriction and stressful conditions. Our data on N/OFQ and CRF signaling provide insight on the use of this binge-eating model for the study of epigenetic modifications in controlled genetic and environmental backgrounds. © 2015 Society for the Study of Addiction.

Multi-Beam Approach for Accelerating Alignment and Calibration of HyspIRI-Like Imaging Spectrometers

NASA Technical Reports Server (NTRS)

Eastwood, Michael L.; Green, Robert O.; Mouroulis, Pantazis; Hochberg, Eric B.; Hein, Randall C.; Kroll, Linley A.; Geier, Sven; Coles, James B.; Meehan, Riley

2012-01-01

A paper describes an optical stimulus that produces more consistent results, and can be automated for unattended, routine generation of data analysis products needed by the integration and testing team assembling a high-fidelity imaging spectrometer system. One key attribute of the system is an arrangement of pick-off mirrors that provides multiple input beams (five in this implementation) to simultaneously provide stimulus light to several field angles along the field of view of the sensor under test, allowing one data set to contain all the information that previously required five data sets to be separately collected. This stimulus can also be fed by quickly reconfigured sources that ultimately provide three data set types that would previously be collected separately using three different setups: Spectral Response Function (SRF), Cross-track Response Function (CRF), and Along-track Response Function (ARF), respectively. This method also lends itself to expansion of the number of field points if less interpolation across the field of view is desirable. An absolute minimum of three is required at the beginning stages of imaging spectrometer alignment.

Cardiorespiratory benefits of group exercise among adults with serious mental illness.

PubMed

Jerome, Gerald J; Young, Deborah Rohm; Dalcin, Arlene T; Wang, Nae-Yuh; Gennusa, Joseph; Goldsholl, Stacy; Appel, Lawrence J; Daumit, Gail L

2017-10-01

This study examined cardiorespiratory fitness (CRF) among adults with serious mental illness (SMI) participating in group exercise classes. Overweight and obese adults with SMI were randomized to either a control condition or a weight management condition with group exercise classes (n = 222). Submaximal bicycle ergometry was used to assess CRF at baseline, 6 and 18 months. Those with ≥ 66% participation in the exercise classes had a lower heart rate response at 6 and 18 month follow-up. Participation in group exercise classes was associated with improved short and long term cardiovascular fitness among adults with SMI. Copyright © 2017 Elsevier B.V. All rights reserved.

Application of regenerative medicine for kidney diseases.

PubMed

Yokoo, Takashi; Fukui, Akira; Kobayashi, Eiji

2007-01-01

Following recent advancements of stem cell research, the potential for organ regeneration using somatic stem cells as an ultimate therapy for organ failure has increased. However, anatomically complicated organs such as the kidney and liver have proven more refractory to stem cell-based regenerative techniques. At present, kidney regeneration is considered to require one of two approaches depending on the type of renal failure, namely acute renal failure (ARF) and chronic renal failure (CRF).The kidney has the potential to regenerate itself provided that the damage is not too severe and the kidney's structure remains intact. Regenerative medicine for ARF should therefore aim to activate or support this potent. In cases of the irreversible damage to the kidney, which is most likely in patients with CRF undergoing long-term dialysis, self-renewal is totally lost. Thus, regenerative medicine for CRF will likely involve the establishment of a functional whole kidney de novo. This article reviews the challenges and recent advances in both approaches and discusses the potential approach of these novel strategies for clinical application.

Putting the past behind us: Social stress-induced urinary retention can be overcome.

PubMed

Weiss, Dana A; Butler, Stephan J; Fesi, Joanna; Long, Christopher J; Valentino, Rita J; Canning, Douglas A; Zderic, Stephen A

2015-08-01

To study the pathophysiology of dysfunctional voiding, we have previously developed a model of stress-induced voiding dysfunction. We have shown that cyclosporine A (CsA), an inhibitor of the Ca(2+)-calmodulin complex, can prevent social stress-induced urinary retention. However, treatment with cyclosporine has not had an effect on the increase in the stress peptide corticotrophin-releasing factor (CRF) in Barrington's nucleus, which is involved in the micturition pathway. We now investigate whether cyclosporine administered after stress can reverse the abnormal voiding phenotype, and whether it has effects on the bladder wall itself, or on the stress response within Barrington's nucleus. Six-week old Swiss-Webster mice were exposed to aggressor males for 1 h a day, followed by 23 h of barrier separation. In a long-term trial, 1 month of stress was followed by single-cage housing for 6 months. In a separate CsA reversal trial, mice either received CsA in drinking water or had plain drinking water during 1 month of single-cage housing during recovery. Bladder contractile function was examined on a Guth myograph. Nuclear translocation of myocyte enhancing factor (MEF)-2 and NFAT (nuclear factor of activated T cells) in the bladder was assessed using electrophoretic mobility shift assays (EMSAs). The expression of CRF was determined in Barrington's nucleus using in situ hybridization. Voiding dysfunction persisted for up to 6 months after stress exposure while mice recovered in single-cage housing. In the CsA reversal trial, voiding patterns improved when they received CsA in water during single-cage housing following stress, whereas those that underwent single-cage housing alone had persistent abnormal voiding (Fig. A). There was no difference between CRF levels in Barrington's nucleus between reversal groups (p = 0.42) (Fig. B), possibly indicating a direct effect on the bladder rather than a persistent stress effect. There were no differences in the contractility of bladder wall muscle. CsA decreased the nuclear translocation of MEF-2 and NFAT induced by stress (Fig. C,D). CsA reverses stress-induced urinary retention, but does not change the stress-induced CRF increase in Barrington's nucleus. Furthermore, bladder smooth muscle contractility is unchanged by CsA; however, there are changes in the levels of the downstream transcription factors MEF-2 and NFAT. We suspect that additional CsA responsive neural changes play a pivotal role in the abnormal voiding phenotype following social stress. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

The hypothalamic-pituitary-adrenal axis: what can it tell us about stressors?

PubMed

Armario, Antonio

2006-10-01

The hypothalamic-pituitary-adrenal (HPA) axis is an extremely sensitive physiological system whose activation, with the consequent release of ACTH and glucocorticoids, is triggered by a wide range of psychological experiences and physiological perturbations (stressors). The HPA axis is also activated by a high number of pharmacological agents that markedly differ in structure and function, although the precise mechanisms remain in most cases unknown. Activation of the HPA axis is the consequence of the convergence of stimulatory inputs from different brain regions into the paraventricular nucleus of the hypothalamus (PVN), where the most important ACTH secretagogues (corticotrophin releasing factor, CRF, and arginin-vasopressin, AVP) are formed. Plasma levels of ACTH and corticosterone (the latter under more restricted conditions), are considered as good markers of stress for three main reasons: (a) their plasma levels are proportional to the intensity of emotional and systemic stressors, (b) daily repeated exposure to a stressor usually resulted in reduced ACTH response to the same stressor, that is termed adaptation or habituation; and (c) chronic exposure to stressful situations results in tonic changes in the HPA axis that can be used as indices of the accumulative impact of these situations. These changes can be evaluated under resting conditions (i.e. adrenal weight, CRF and AVP gene expression in the PVN) or after some challenges (administration of CRF, ACTH or dexamethasone) that are classical endocrinological tests. There is also evidence that the activation of the HPA axis may also reflect subtle changes in the characteristics of the stressful situations (unpredictability, lack of control, omission of expected rewards, presence of conspecifics), although this is a topic that requires further studies.

Effect of Primary Preventive Examination with Cardiorespiratory Fitness Test.

PubMed

Kunzová, Šárka; Fiala, Jindřich; Řimák, Pavel; Kaňovský, Petr

2017-06-01

The aim of this study was to explore the potential of free comprehensive primary preventive examination (CPPE) combined with cardiorespiratory fitness (CRF) test in terms of its attractiveness for general population and moreover to evaluate the induced behavioural changes. The main focus was on physical activity behaviour (PA). In 2009-2013, 250 people (100 men, 150 women) aged 18-65 years were examined. CPPE included assessment of health status and lifestyle, CRF test and individualized counselling. Expectations, reasons and motivations for participating were recorded. The sample was evaluated in terms of age, gender, lifestyle, body mass index, body fat percentage, CRF, and health characteristics. Evaluation according to subjective benefits, perceived effects on health and lifestyle was performed after six months using electronic feedback questionnaires (FQ). Comparison was made within groups formed according to the reported increase in PA. People aged 18-39 years accounted for 72.8% of the sample; mean age 34.4±11.0 years; 40.0% were men. Behavioural and health risks were lower in comparison with the general Czech population, but at least 1 of 5 assessed risk factors was present in 88.8% (low fruit and vegetable consumption 74.8%, low physical activity level (PAL) 45.6%, smoking 19.6%, risky alcohol use 18.8%, and stress load 10.4%). The most represented category of CRF was "endurance-trained" (both genders). CPPE was perceived as a source of information concerning health, CRF and lifestyle. 40.0% of men and 30.7% of women were focused on improvement in CRF. The response rate of FQ was 75.6%. Individuals with low PAL and low CRF provided feedback less often (p<0.05). In terms of perceived effect, 84.1% of the respondents implemented some kind of behavioural change; 60.9% reported increase in PA, but only 38.1% reported maintaining improvement in PA after 6 months. A higher proportion of reported lasting changes in PA occurred in subjects who were overweight/obese and in those with low CRF. Participants with low PAL and higher number of lifestyle risks more likely increased their PA only temporarily. Improvement in PA was associated with reported changes in diet (p<0.001). In the group of respondents there was an increase in self-perceived PA (SPA) compared to the baseline (p=0.001). Moreover, individuals who reported increase in PA showed improvement in subjectively perceived health. The testing of CRF appears to be a promising motivating factor for going through the intervention, especially for younger people and men. CPPE is effective at the individual level in terms of providing information and initiating behavioural changes in PA. However, this type of intervention is less attractive and less effective for individuals with a higher behavioural risk profile. Copyright© by the National Institute of Public Health, Prague 2017

Associations of cardiorespiratory fitness, physical activity, and obesity with metabolic syndrome in Hong Kong Chinese midlife women

PubMed Central

2013-01-01

Background Several studies have simultaneously examined physical activity (PA) and cardiorespiratory fitness (CRF) with metabolic syndrome (MS). However, the independent roles of both PA and CRF with MS are less firmly established. The combined contributions of PA and CRF with MS are less studied, particularly among Chinese women. There is uncertainty over the extent to which metabolically healthy but overweight/obese individuals have a higher CRF level. Methods The sample included 184 Chinese women aged 55 to 69 years with available metabolic data and lifestyle factors. PA was assessed by self-reported questionnaire; CRF was assessed by maximal oxygen consumption (VO2max) during a symptom-limited maximal exercise test on a cycle ergometer. Metabolically healthy/abnormal was defined on the basis of absence or presence of MS. Overweight was defined as a body mass index (BMI) of ≥ 23 kg/m2 and obese was defined as a BMI of ≥ 25 kg/m2. Results The prevalence of MS was 21.7%. PA was inversely associated with the prevalence of MS after adjustment for age, BMI, and dietary total calories intake, but the association was eliminated after further adjustment for CRF. CRF was inversely associated with the prevalence of MS independent of age, BMI, and dietary total calories intake, and the association remained significant after further adjustment for PA. In the PA and CRF combined analysis, compared with those in the lowest tertile of PA (inactive) and lowest tertile of CRF (unfit), the OR (95%CI) of having MS was 0.31 (0.09–1.06) for subjects in the higher tertiles (2nd–3rd) of PA (active) but were unfit, 0.23 (0.06–0.88) for subjects who were inactive but in the higher tertiles (2nd–3rd) of CRF (fit), and 0.14 (0.04–0.45) for subjects who were active and fit. Metabolically healthy but overweight/obese subjects had a higher CRF level than their metabolically abnormal and overweight/obese peers. However, the difference did not reach statistically significance. Conclusions CRF has greater association with the prevalence of MS compared with PA in Chinese midlife women. The interrelationships between CRF, obesity, and MS needs further study. PMID:23805900

[Analysis on HIV-1 subtypes and transmission clusters in newly reported HIV/AIDS cases in Yiwu, Zhejiang Province, 2016].

PubMed

Zhang, J F; Yao, J M; Fan, Q; Chen, W J; Pan, X H; Ding, X B; Yang, J Z; Fu, T

2017-12-10

Objective: To understand the characteristics of distribution on HIV-1 subtypes and the transmission clusters in Yiwu in Zhejiang province. Methods: A cross-sectional study of molecular epidemiology was carried out on newly reported HIV/AIDS cases in Yiwu. RNA was extracted from 168 plasma samples, followed by RT-PCR and nest-PCR for pol gene amplification, sequencing, phylogenetic tree construction used for analyzing the subtypes and transmission clusters. Mutations on drug resistance was analyzed by CPR 6.0 online tool. Results: Subjects were mainly males (86.3%, 145/168), with average age as (39.1±13.4) years old and most of them were migrants (66.7%, 112/168). The major routes of transmission included homosexual (51.2%, 86/168) and heterosexual (48.8%, 82/168) contacts. The rate of success for sequence acquisition was 89.9% (151/168). The dominant subtypes showed as CRF01_AE (74, 49.0%) and CRF07_BC (64, 42.4%), followed by CRF08_BC (5, 3.3%), CRF55_01B (3, 2.0%), each case of subtype B, CRF45_cpx, CRF59_01B, CRF85_BC and URF (B/C). CRF45_cpx and CRF85_BC were discovered the first time in Zhejiang province. Twenty-six transmission clusters involving 65 cases were found, with the total clustered rate as 43.0% (65/151), in which the CRF01_AE clustered rate appeared as 54.1% (40/74), higher than that of CRF07_BC (21/64, 32.8%). The average size of cluster was 2.5 cases/cluster, with average size of cluster in CRF01_AE patients infected through heterosexual transmission as the largest (3.5 cases/cluster). The prevalence of transmitted drug resistance was 4.6% (7/151). Seven cases with surveillance drug resistant mutations (SDRM) were found, including 5 cases of M46L (3.3%), and one case of F77L or Y181C. Conclusion: HIV genetic diversity and a variety of transmission clusters had been noticed in this study area (Yiwu). Programs on monitoring the subtypes and transmission clusters should be continued and strengthened.

Anti-stress effects of transcutaneous electrical nerve stimulation (TENS) on colonic motility in rats.

PubMed

Yoshimoto, Sazu; Babygirija, Reji; Dobner, Anthony; Ludwig, Kirk; Takahashi, Toku

2012-05-01

Disorders of colonic motility may contribute to symptoms in patients with irritable bowel syndrome (IBS), and stress is widely believed to play a major role in developing IBS. Stress increases corticotropin releasing factor (CRF) of the hypothalamus, resulting in acceleration of colonic transit in rodents. In contrast, hypothalamic oxytocin (OXT) has an anti-stress effect via inhibiting CRF expression and hypothalamic-pituitary-adrenal axis activity. Although transcutaneous electrical nerve stimulation (TENS) and acupuncture have been shown to have anti-stress effects, the mechanism of the beneficial effects remains unknown. We tested the hypothesis that TENS upregulates hypothalamic OXT expression resulting in reduced CRF expression and restoration of colonic dysmotility in response to chronic stress. Male SD rats received different types of stressors for seven consecutive days (chronic heterotypic stress). TENS was applied to the bilateral hind limbs every other day before stress loading. Another group of rats did not receive TENS treatment. TENS significantly attenuated accelerated colonic transit induced by chronic heterotypic stress, which was antagonized by a central injection of an OXT antagonist. Immunohistochemical study showed that TENS increased OXT expression and decreased CRF expression at the paraventricular nucleus (PVN) following chronic heterotypic stress. It is suggested that TENS upregulates hypothalamic OXT expression which acts as an anti-stressor agent and mediates restored colonic dysmotility following chronic stress. TENS may be useful to treat gastrointestinal symptoms associated with stress.

The association of cardiorespiratory fitness and physical activity with incidence of hypertension in men.

PubMed

Chase, Nancy L; Sui, Xuemei; Lee, Duck-chul; Blair, Steven N

2009-04-01

Few prospective studies have simultaneously investigated the relationship between physical activity, cardiorespiratory fitness (CRF), and the development of hypertension in initially normotensive individuals. In the Aerobics Center Longitudinal Study (ACLS), we examined this association among initially healthy normotensive men. Participants were 16,601 men aged 20-82 years who completed a baseline examination during 1970-2002 and were followed for hypertension incidence. Physical activity was self-reported and CRF was quantified from the duration of a maximal treadmill test. A total of 2,346 men reported hypertension during a mean 18 years of follow-up. Event rates per 10,000 man-years adjusted for age and examination year were 86.2, 76.6, and 66.7 across physical activity groups of sedentary, walker/jogger/runner (WJR), and sport/fitness, respectively, and 89.8, 78.4, and 64.6 for low, middle, and high CRF, respectively (trend P < 0.0001). These associations persisted after further adjustment for body mass index (BMI), smoking, alcohol intake, resting systolic blood pressure, baseline health status, family history of diseases, and survey response patterns. Both physical activity and CRF are associated with lower risk of developing hypertension in a graded fashion. These findings provide a basis for health professionals to emphasize the importance of participating in regular physical activity to improve fitness for the primary prevention of hypertension in men.

Cyclotides Isolated from an Ipecac Root Extract Antagonize the Corticotropin Releasing Factor Type 1 Receptor

PubMed Central

Fahradpour, Mohsen; Keov, Peter; Tognola, Carlotta; Perez-Santamarina, Estela; McCormick, Peter J.; Ghassempour, Alireza; Gruber, Christian W.

2017-01-01

Cyclotides are plant derived, cystine-knot stabilized peptides characterized by their natural abundance, sequence variability and structural plasticity. They are abundantly expressed in Rubiaceae, Psychotrieae in particular. Previously the cyclotide kalata B7 was identified to modulate the human oxytocin and vasopressin G protein-coupled receptors (GPCRs), providing molecular validation of the plants’ uterotonic properties and further establishing cyclotides as valuable source for GPCR ligand design. In this study we screened a cyclotide extract derived from the root powder of the South American medicinal plant ipecac (Carapichea ipecacuanha) for its GPCR modulating activity of the corticotropin-releasing factor type 1 receptor (CRF1R). We identified and characterized seven novel cyclotides. One cyclotide, caripe 8, isolated from the most active fraction, was further analyzed and found to antagonize the CRF1R. A nanomolar concentration of this cyclotide (260 nM) reduced CRF potency by ∼4.5-fold. In contrast, caripe 8 did not inhibit forskolin-, or vasopressin-stimulated cAMP responses at the vasopressin V2 receptor, suggesting a CRF1R-specific mode-of-action. These results in conjunction with our previous findings establish cyclotides as modulators of both classes A and B GPCRs. Given the diversity of cyclotides, our data point to other cyclotide-GPCR interactions as potentially important sources of drug-like molecules. PMID:29033832

Physical activity enhances metabolic fitness independently of cardiorespiratory fitness in marathon runners.

PubMed

Laye, M J; Nielsen, M B; Hansen, L S; Knudsen, T; Pedersen, B K

2015-01-01

High levels of cardiovascular fitness (CRF) and physical activity (PA) are associated with decreased mortality and risk to develop metabolic diseases. The independent contributions of CRF and PA to metabolic disease risk factors are unknown. We tested the hypothesis that runners who run consistently >50 km/wk and/or >2 marathons/yr for the last 5 years have superior metabolic fitness compared to matched sedentary subjects (CRF, age, gender, and BMI). Case-control recruitment of 31 pairs of runner-sedentary subjects identified 10 matched pairs with similar VO2max (mL/min/kg) (similar-VO2max). The similar-VO2max group was compared with a group of age, gender, and BMI matched pairs who had the largest difference in VO2max (different-VO2max). Primary outcomes that defined metabolic fitness including insulin response to an oral glucose tolerance test, fasting lipids, and fasting insulin were superior in runners versus sedentary controls despite similar VO2max. Furthermore, performance (velocity at VO2max, running economy), improved exercise metabolism (lactate threshold), and skeletal muscle levels of mitochondrial proteins were superior in runners versus sedentary controls with similar VO2max. In conclusion subjects with a high amount of PA have more positive metabolic health parameters independent of CRF. PA is thus a good marker against metabolic diseases.

Physical Activity Enhances Metabolic Fitness Independently of Cardiorespiratory Fitness in Marathon Runners

PubMed Central

Laye, M. J.; Nielsen, M. B.; Hansen, L. S.; Knudsen, T.; Pedersen, B. K.

2015-01-01

High levels of cardiovascular fitness (CRF) and physical activity (PA) are associated with decreased mortality and risk to develop metabolic diseases. The independent contributions of CRF and PA to metabolic disease risk factors are unknown. We tested the hypothesis that runners who run consistently >50 km/wk and/or >2 marathons/yr for the last 5 years have superior metabolic fitness compared to matched sedentary subjects (CRF, age, gender, and BMI). Case-control recruitment of 31 pairs of runner-sedentary subjects identified 10 matched pairs with similar VO2max (mL/min/kg) (similar-VO2max). The similar-VO2max group was compared with a group of age, gender, and BMI matched pairs who had the largest difference in VO2max (different-VO2max). Primary outcomes that defined metabolic fitness including insulin response to an oral glucose tolerance test, fasting lipids, and fasting insulin were superior in runners versus sedentary controls despite similar VO2max. Furthermore, performance (velocity at VO2max, running economy), improved exercise metabolism (lactate threshold), and skeletal muscle levels of mitochondrial proteins were superior in runners versus sedentary controls with similar VO2max. In conclusion subjects with a high amount of PA have more positive metabolic health parameters independent of CRF. PA is thus a good marker against metabolic diseases. PMID:25821340

Demonstration of the need for cardiovascular and pulmonary normative data for cancer survivors.

PubMed

Schneider, C M; Repka, C P; Brown, J M; Lalonde, T L; Dallow, K T; Barlow, C E; Hayward, R

2014-12-01

Despite evidence that cancer and its treatments severely reduce cardiorespiratory fitness (CRF), normative data for cancer survivors do not exist. The present study identifies age and gender-specific CRF distributions in a cancer population. The use of cancer-specific normative CRF data may help stratify initial fitness status and assess improvements in response to exercise interventions in cancer survivors. Data from 703 cancer survivors were analyzed for this study. Quintiles were compiled for peak oxygen consumption (VO2peak), forced vital capacity (FVC), and forced expiratory volume (FEV1) for males and females in 5 age groups (19-39, 40-49, 50-59, 60-69, and ≥70 years of age). VO2peak values for the cancer population were significantly lower than the general US population. The cancer population average in each age group fell within the "very poor" classification of VO2peak values for the general population. FVC values in the cancer population were similar to the general population. Cancer survivors had very low age group-specific VO2peak values compared to the apparently healthy general US population. Previously, CRF values of cancer survivors were compared to normative values for the apparently healthy general population, which yielded imprecise classifications of initial fitness and changes in fitness, resulting in patient discouragement. © Georg Thieme Verlag KG Stuttgart · New York.

The Impact of Cardiorespiratory Fitness on Age-Related Lipids and Lipoproteins

PubMed Central

Park, Yong-Moon Mark; Sui, Xuemei; Liu, Junxiu; Zhou, Haiming; Kokkinos, Peter F.; Lavie, Carl J.; Hardin, James W.; Blair, Steven N.

2015-01-01

Background Evidence on the effect of cardiorespiratory fitness (CRF) on age-related longitudinal changes of lipids and lipoproteins is scarce. Objectives This study sought to assess the longitudinal, aging trajectory of lipids and lipoproteins for the life course in adults, and to determine whether CRF modifies the age-associated trajectory of lipids and lipoproteins. Methods Data came from 11,418 men, 20 to 90 years of age, without known high cholesterol, high triglycerides, cardiovascular disease, and cancer at baseline and during follow-up from the Aerobics Center Longitudinal Study. There were 43,821 observations spanning 2 to 25 (mean 3.5) health examinations between 1970 and 2006. CRF was quantified by a maximal treadmill exercise test. Marginal models using generalized estimating equations were applied. Results Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C) presented similar inverted U-shaped quadratic trajectories with aging: gradual increases were noted until the mid-40s to early 50s, with subsequent declines (all p < 0.0001). Compared to men with higher CRF, those with lower CRF developed abnormal values earlier in life: TC (≥200 mg/dl), LDL-C (≥130 mg/dl), non-HDL-C (≥160 mg/dl), and TG/HDL-C ratio (≥3.0). Notably, abnormal values for TC and LDL-C in men with low CRF were observed around 15 years earlier than in those with high CRF. After adjusting for time-varying covariates, a significant interaction was found between age and CRF in each trajectory, indicating that CRF was more strongly associated with the aging trajectories of lipids and lipoproteins in young to middle-aged men than in older men. Conclusions Our investigation reveals a differential trajectory of lipids and lipoproteins with aging according to CRF in healthy men, and suggests that promoting increased CRF levels may help delay the development of dyslipidemia. PMID:25975472

Escitalopram alters gene expression and HPA axis reactivity in rats following chronic overexpression of corticotropin-releasing factor from the central amygdala

PubMed Central

Flandreau, Elizabeth I.; Bourke, Chase H.; Ressler, Kerry J.; Vale, Wylie W.; Nemeroff, Charles B.; Owens, Michael J.

2013-01-01

Summary We have previously demonstrated that viral-mediated overexpression of corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) reproduces many of the behavioral and endocrine consequences of chronic stress. The present experiment sought to determine whether administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram reverses the adverse effects of CeA CRF overexpression. In a 2 × 2 design, adult male rats received bilateral infusions of a control lentivirus or a lentivirus in which a portion of the CRF promoter is used to drive increased expression of CRF peptide. Four weeks later, rats were then implanted with an Alzet minipump to deliver vehicle or 10 mg/kg/day escitalopram for a 4-week period of time. The defensive withdrawal (DW) test of anxiety and the sucrose-preference test (SPT) of anhedonia were performed both before and after pump implantation. Additional post-implant behavioral tests included the elevated plus maze (EPM) and social interaction (SI) test. Following completion of behavioral testing, the dexamethasone/CRF test was performed to assess HPA axis reactivity. Brains were collected and expression of HPA axis-relevant transcripts were measured using in situ hybridization. Amygdalar CRF overexpression increased anxiety-like behavior in the DW test at week eight, which was only partially prevented by escitalopram. In both CRF-overexpressing and control groups, escitalopram decreased hippocampal CRF expression while increasing hypothalamic and hippocampal expression of the glucocorticoid receptor (GR). These gene expression changes were associated with a significant decrease in HPA axis reactivity in rats treated with escitalopram. Interestingly, escitalopram increased the rate of weight gain only in rats overexpressing CRF. Overall these data support our hypothesis that amygdalar CRF is critical in anxiety-like behavior; because the antidepressant was unable to reverse behavioral manifestations of CeA CRF-OE. This may be a potential animal model to study treatment-resistant psychopathologies. PMID:23267723

Associations of fractalkine receptor (CX3CR1) and CCR5 gene variants with hypertension, diabetes and atherosclerosis in chronic renal failure patients undergoing hemodialysis.

PubMed

Bagci, Binnur; Bagci, Gokhan; Huzmeli, Can; Sezgin, Ilhan; Ozdemir, Ozturk

2016-07-01

We aimed to investigate the associations of fractalkine receptor (CX3CR1) V249I, T280M and CCR5-59029 A/G gene polymorphisms in chronic renal failure (CRF) subjects undergoing hemodialysis and to evaluate possible associations of these polymorphisms with hypertension (HT), diabetes mellitus (DM) and atherosclerosis (AS). A total of 225 CRF subjects undergoing hemodialysis and 201 healthy controls were enrolled in the study. CRF subjects were divided into three major subgroups according to comorbidities including HT (n = 127), DM (n = 65) and AS (n = 33). Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism method. The II genotype and I allele frequencies of CX3CR1 V249I polymorphism were found significantly more frequent in CRF subjects, CRF subjects with DM and CRF subjects with AS compared with controls (p < 0.05 for all comparisons). G allele frequency of CCR5 polymorphism was found significantly more prevalent in CRF subjects with DM than that of controls. Further, GG genotype and G allele frequencies of CCR5 polymorphism were significantly more prevalent in CRF subjects with AS compared with controls (p < 0.05). We also explored these polymorphisms among CRF subjects with and without following comorbidities: HT, DM, AS. We found significant association between CRF subjects with HT and without HT in terms of genotype and allele frequencies of V249I polymorphism (p < 0.05). CX3CR1 T280M polymorphism was not found significantly different in none of the comparisons. These data demonstrate possible associations between CX3CR1 V249I and CCR5-59029 A/G polymorphisms and/or HT, DM and AS in CRF subjects.

Laboratory Characterization of Cemented Rock Fill for Underhand Cut and Fill Method of Mining

NASA Astrophysics Data System (ADS)

Kumar, Dinesh; Singh, Upendra Kumar; Singh, Gauri Shankar Prasad

2016-10-01

Backfilling with controlled specifications is employed for improved ground support and pillar recovery in underground metalliferous mine workings. This paper reports the results of a laboratory study to characterise various mechanical properties of cemented rock fill (CRF) formulations for different compaction levels and cement content percentage for use in underhand cut and fill method of mining. Laboratory test set ups and procedures have been described for conducting compressive and bending tests of CRF block samples. A three dimensional numerical modelling study has also been carried out to overcome the limitations arising due to non-standard dimension of test blocks used in flexural loading test and the test setup devised for this purpose. Based on these studies, specific relations have been established between the compressive and the flexural properties of the CRF. The flexural strength of the wire mesh reinforced CRF is also correlated with its residual strength and the Young's modulus of elasticity under flexural loading condition. The test results of flexural strength, residual flexural strength and modulus show almost linear relations with cement content in CRF. The compressive strength of the CRF block samples is estimated as seven times the flexural strength whereas the compressive modulus is four times the flexural modulus. It has been found that the strengths of CRF of low compaction and no compaction are 75 and 60 % respectively to that of the medium compaction CRF. The relation between the strength and the unit weight of CRF as obtained in this study is significantly important for design and quality control of CRF during its large scale application in underhand cut and fill stopes.

Molecular epidemiological study of HIV-1 CRF01_AE transmission in Hong Kong.

PubMed

Chen, J H K; Wong, K H; Li, P; Chan, K C; Lee, M P; Lam, H Y; Cheng, V C C; Yuen, K Y; Yam, W C

2009-08-15

The objective of this study was to investigate the transmission history of the HIV-1 CRF01_AE epidemics in Hong Kong between 1994 and 2007. A total of 465 HIV-1 CRF01_AE pol sequences were derived from an in-house or a commercial HIV-1 genotyping system. Phylogenies of CRF01_AE sequences were analyzed by the Bayesian coalescent method. CRF01_AE patient population included 363 males (78.1%) and 102 females (21.9%), whereas 65% (314 of 465) were local Chinese. Major transmission routes were heterosexual contact (63%), followed by intravenous drug use (IDU) (19%) and men having sex with men (MSM) (17%). From phylogenetic analysis, local CRF01_AE strains were from multiple origins with 3 separate transmission clusters identified. Cluster 1 consisted mainly of Chinese male IDUs and heterosexuals. Clusters 2 and 3 included mainly local Chinese MSM and non-Chinese Asian IDUs, respectively. Chinese reference isolates available from China (Fujian, Guangxi, or Liaoning) were clonally related to our transmission clusters, demonstrating the epidemiological linkage of CRF01_AE infections between Hong Kong and China. The 3 individual local transmission clusters were estimated to have initiated since late 1980s and late 1990s, causing subsequent epidemics in the early 2000s. This is the first comprehensive molecular epidemiological study of HIV-1 CRF01_AE in Hong Kong. It revealed that MSM contact is becoming a major route of local CRF01_AE transmission in Hong Kong. Epidemiological linkage of CRF01_AE between Hong Kong and China observed in this study indicates the importance of regular molecular epidemiological surveillance for the HIV-1 epidemic in our region.

Escalated cocaine "binges" in rats: enduring effects of social defeat stress or intra-VTA CRF.

PubMed

Leonard, Michael Z; DeBold, Joseph F; Miczek, Klaus A

2017-09-01

Exposure to intermittent social defeat stress elicits corticotropin releasing factor (CRF) release into the VTA and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists. The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake. Male Long-Evans rats were microinjected into the VTA with CRF (50 or 500 ng/side), vehicle, or subjected to social defeat stress, intermittently over 10 days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-h extended access "binge." Rats that experienced social defeat or received intra-VTA CRF microinfusions (50 ng) both took significantly more cocaine than controls over the 24-h binge but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. α) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B. Repeated infusion of CRF into the VTA persistently alters cocaine valuation and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation.

Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: alcohol and CRF effects

PubMed Central

Herman, Melissa A.; Varodayan, Florence P.; Oleata, Christopher S.; Luu, George; Kirson, Dean; Heilig, Markus; Ciccocioppo, Roberto; Roberto, Marisa

2015-01-01

The CRF system of the central nucleus of the amygdala (CeA) is important for the processing of anxiety, stress, and effects of acute and chronic ethanol. We previously reported that ethanol decreases evoked glutamate transmission in the CeA of Sprague Dawley rats and that ethanol dependence alters glutamate release in the CeA. Here, we examined the effects of ethanol, CRF and a CRF1 receptor antagonist on spontaneous and evoked glutamatergic transmission in CeA neurons from Wistar and Marchigian Sardinian Preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and characterized by heightened activity of the CRF1 system. Basal spontaneous and evoked glutamate transmission in CeA neurons from msP rats was increased compared to Wistar rats. Ethanol had divergent effects, either increasing or decreasing spontaneous glutamate release in the CeA of Wistar rats. This bidirectional effect was retained in msP rats, but the magnitude of the ethanol-induced increase in glutamate release was significantly smaller. The inhibitory effect of ethanol on evoked glutamatergic transmission was similar in both strains. CRF also either increased or decreased spontaneous glutamate release in CeA neurons of Wistar rats, however, in msP rats CRF only increased glutamate release. The inhibitory effect of CRF on evoked glutamatergic transmission was also lost in neurons from msP rats. A CRF1 antagonist produced only minor effects on spontaneous glutamate transmission, which were consistent across strains, and no effects on evoked glutamate transmission. These results demonstrate that the genetically altered CRF system of msP rats results in alterations in spontaneous and stimulated glutamate signaling in the CeA that may contribute to both the anxiety and drinking behavioral phenotypes. PMID:26519902

Ozone Therapy on Rats Submitted to Subtotal Nephrectomy: Role of Antioxidant System

PubMed Central

Calunga, José Luis; Zamora, Zullyt B.; Borrego, Aluet; del Río, Sarahí; Barber, Ernesto; Menéndez, Silvia; Hernández, Frank; Montero, Teresita; Taboada, Dunia

2005-01-01

Chronic renal failure (CRF) represents a world health problem. Ozone increases the endogenous antioxidant defense system, preserving the cell redox state. The aim of this study is to evaluate the effect of ozone/oxygen mixture in the renal function, morphology, and biochemical parameters, in an experimental model of CRF (subtotal nephrectomy). Ozone/oxygen mixture was applied daily, by rectal insufflation (0.5 mg/kg) for 15 sessions after the nephrectomy. Renal function was evaluated, as well as different biochemical parameters, at the beginning and at the end of the study (10 weeks). Renal plasmatic flow (RPF), glomerular filtration rate (GFR), the urine excretion index, and the sodium and potassium excretions (as a measurement of tubular function) in the ozone group were similar to those in Sham group. Nevertheless, nephrectomized rats without ozone (positive control group) showed the lowest RPF, GFR, and urine excretion figures, as well as tubular function. Animals treated with ozone showed systolic arterial pressure (SAP) figures lower than those in the positive control group, but higher values compared to Sham group. Serum creatinine values and protein excretion in 24 hours in the ozone group were decreased compared with nephrectomized rats, but were still higher than normal values. Histological study demonstrated that animals treated with ozone showed less number of lesions in comparison with nephrectomized rats. Thiobarbituric acid reactive substances were significantly increased in nephrectomized and ozone-treated nephrectomized rats in comparison with Sham group. In the positive control group, superoxide dismutase (SOD) and catalase (CAT) showed the lowest figures in comparison with the other groups. However, ozone/oxygen mixture induced a significant stimulation in the enzymatic activity of CAT, SOD, and glutathione peroxidase, as well as reduced glutathione in relation with Sham and positive control groups. In this animal model of CRF, ozone rectal administrations produced a delay in the advance of the disease, protecting the kidneys against vascular, hemorheological, and oxidative mechanisms. This behavior suggests ozone therapy has a protective effect on renal tissue by downregulation of the oxidative stress shown in CRF. PMID:16192672

Inhibitory effect of ramosetron on corticotropin releasing factor- and soybean oil-induced delays in gastric emptying in rats.

PubMed

Hirata, Takuya; Keto, Yoshihiro; Yamano, Mayumi; Yokoyama, Toshihide; Sengoku, Takanori; Seki, Nobuo

2012-09-01

Symptoms of functional dyspepsia (FD) are highly prevalent in patients with irritable bowel syndrome (IBS). However, the effects of therapeutic agents for IBS on the pathophysiology of FD are unclear. In this study, therefore, we examined the effects of ramosetron, a serotonin 5-HT(3) receptor antagonist, on corticotropin releasing factor (CRF)- and soybean oil-induced delays in gastric emptying of rats, in comparison with anti-diarrheal agent and spasmolytics. The involvement of 5-HT and the 5-HT(3) receptor in delayed gastric emptying was also evaluated. Corticotropin releasing factor was administered intravenously to rats 10min before oral administration of 0.05% phenol red solution, and the amount remaining in the stomach was measured after 30min. Soybean oil was administered orally with glass beads, and the number of residual beads in the stomach was counted 1h later. Both CRF and soybean oil inhibited gastric emptying dose-dependently. Ramosetron and itopride, a gastro-prokinetic agent, significantly reduced both CRF- and soybean oil-induced delays in gastric emptying, while an anti-diarrheal agent and spasmolytics aggravated them. Pretreatment with p-chlorophenylalanine for 2days to reduced the synthesis of endogenous 5-HT diminished the effects of both CRF and soybean oil on gastric emptying. A 5-HT(3) receptor agonist m-chlorophenylbiguanide suppressed gastric emptying of both phenol red and glass beads, and those effects were reversed by ramosetron. These results suggest that CRF and soybean oil suppress gastric emptying in rats by activating 5-HT(3) receptors, and that by antagonizing these receptors, ramosetron may ameliorate symptoms of FD in clinical settings. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Effects of Corticotropin Releasing Factor (CRF) on Sleep and Body Temperature Following Controllable Footshock Stress in Mice

PubMed Central

Yang, L; Wellman, LL; Tang, X; Sanford, LD

2011-01-01

Rapid eye movement sleep (REM) is increased after controllable stress (modeled by escapable footshock, ES) and decreased after uncontrollable stress (modeled by inescapable footshock, IS). Decreases in REM after IS are exacerbated by corticotropin releasing factor (CRF) and attenuated by a CRF antagonist. In this study, we trained mice with ES following injections of CRF, astressin (AST), or saline (SAL) to determine whether CRF would alter REM after ES. Male BALB/cJ mice (n=7) were implanted for recording sleep, activity and body temperature via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery, sleep following exposure to a novel chamber was recorded as a handling control (HC). The mice received one day of training with ES without injection followed by weekly training sessions in which they received counterbalanced intracerebroventricular (ICV) microinjections of either SAL or CRF (days 7 & 14) or SAL or AST (days 21 & 28) prior to ES. On each experimental day, sleep was recorded for 20 hours. Compared to HC, the mice showed significantly increased REM when receiving either SAL or AST prior to ES whereas CRF prior to ES significantly reduced REM. Stress-induced hyperthermia had longer duration after ES compared to HC, and was not significantly altered by CRF or AST compared to SAL. The current results demonstrate that activity in the central CRF system is an important regulator of stress-induced alterations in REM. PMID:21651923

Systematic review of non-invasive positive pressure ventilation for chronic respiratory failure.

PubMed

Hannan, Liam M; Dominelli, Giulio S; Chen, Yi-Wen; Darlene Reid, W; Road, Jeremy

2014-02-01

This systematic review examined the effect of non-invasive positive pressure ventilation (NIPPV) on patient reported outcomes (PROs) and survival for individuals with or at risk of chronic respiratory failure (CRF). Randomised controlled trials (RCTs) and prospective non-randomised studies in those treated with NIPPV for CRF were identified from electronic databases, reference lists and grey literature. Diagnostic groups included in the review were amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), Duchenne muscular dystrophy (DMD), restrictive thoracic disease (RTD) and obesity hypoventilation syndrome (OHS). Eighteen studies were included and overall study quality was weak. Those with ALS/MND had improved somnolence and fatigue as well as prolonged survival with NIPPV. For OHS, improvements in somnolence and fatigue, dyspnoea and sleep quality were demonstrated, while for RTD, measures of dyspnoea, sleep quality, physical function and health, mental and emotional health and social function improved. There was insufficient evidence to form conclusions regarding the effect of NIPPV for those with DMD. This review has demonstrated that NIPPV influences PROs differently depending on the underlying cause of CRF. These findings may provide assistance to patients and clinicians to determine the relative costs and benefits of NIPPV therapy and also highlight areas in need of further research. Copyright © 2013 Elsevier Ltd. All rights reserved.

An integrated lipidomics and metabolomics reveal nephroprotective effect and biochemical mechanism of Rheum officinale in chronic renal failure

PubMed Central

Zhang, Zhi-Hao; Vaziri, Nosratola D.; Wei, Feng; Cheng, Xian-Long; Bai, Xu; Zhao, Ying-Yong

2016-01-01

Chronic renal failure (CRF) is a major public health problem worldwide. Earlier studies have revealed salutary effects of rhubarb extracts in CRF. In this study, we employed lipidomic and metabolomic approaches to identify the plasma biomarkers and to determine the effect of treatment with petroleum ether, ethyl acetate and n-butanol extracts of rhubarb in a rat model of CRF with adenine-induced chronic tubulointerstitial nephropathy. In addition, clinical biochemistry, histological evaluation and pro-fibrotic protein expression were analyzed. Significant changes were found between the CRF and control groups representing characteristic phenotypes of rats with CRF. Treatment with the three rhubarb extracts improved renal injury and dysfunction, either fully or partially reversed the plasma metabolites abnormalities and attenuated upregulation of pro-fibrotic proteins including TGF-β1, α-SMA, PAI-1, CTGF, FN and collagen-1. The nephroprotective effect of ethyl acetate extract was better than other extracts. The differential metabolites were closely associated with glycerophospholipid, fatty acid and amino acid metabolisms. The results revealed a strong link between renal tubulointerstitial fibrosis and glycerophospholipid metabolism and L-carnitine metabolism in the development of CRF. Amelioration of CRF with the three rhubarb extracts was associated with the delayed development and/or reversal the disorders in key metabolites associated with adenine-induced CRF. PMID:26903149

Identification of Two New HIV-1 Circulating Recombinant Forms (CRF87_cpx and CRF88_BC) from Reported Unique Recombinant Forms in Asia.

PubMed

Hu, Yihong; Wan, Zhenzhou; Zhou, Yan-Heng; Smith, Davey; Zheng, Yong-Tang; Zhang, Chiyu

2017-04-01

The on-going generation of HIV-1 intersubtype recombination has led to new circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in Asia. In this study, we evaluated whether previously reported URFs were actually CRFs. All available complete or near full-length HIV-1 URF sequences from Asia were retrieved from the HIV Los Alamos National Laboratory Sequence database, and phylogenetic, transmission cluster, and bootscan analyses were performed using MEGA 6.0, Cluster Picker 1.2.1, and SimPlot3.5.1. According to the criterion of new CRFs, two new HIV-1 CRFs (CRF87_cpx and CRF88_BC) were identified from these available URFs. CRF87_cpx comprised HIV-1 subtypes B, C, and CRF01_AE, and CRF88_BC comprised subtypes B and C. HIV Blast and bootscan analysis revealed that besides the three representative strains, there were two additional CRF87_cpx strains. Furthermore, we defined seven dominant URFs (dURF01-dURF07), each of which contained two strains sharing same recombination map and can be used as sequence references to facilitate the finding of new potential CRFs in future. These results will benefit the molecular epidemiological investigation of HIV-1 in Asia.

Predictors of Responses to Corticosteroids for Cancer-Related Fatigue in Advanced Cancer Patients: A Multicenter, Prospective, Observational Study.

PubMed

Matsuo, Naoki; Morita, Tatsuya; Matsuda, Yoshinobu; Okamoto, Kenichiro; Matsumoto, Yoshihisa; Kaneishi, Keisuke; Odagiri, Takuya; Sakurai, Hiroki; Katayama, Hideki; Mori, Ichiro; Yamada, Hirohide; Watanabe, Hiroaki; Yokoyama, Taro; Yamaguchi, Takashi; Nishi, Tomohiro; Shirado, Akemi; Hiramoto, Shuji; Watanabe, Toshio; Kohara, Hiroyuki; Shimoyama, Satofumi; Aruga, Etsuko; Baba, Mika; Sumita, Koki; Iwase, Satoru

2016-07-01

Although corticosteroids are widely used to relieve cancer-related fatigue (CRF), information regarding the factors predicting responses to corticosteroids remains limited. The aim of this study was to identify potential factors predicting responses to corticosteroids for CRF in advanced cancer patients. Inclusion criteria for this multicenter, prospective, observational study were patients who had metastatic or locally advanced cancer and had a fatigue intensity score of 4 or more on a 0-10 Numerical Rating Scale (NRS). Univariate and multivariate analyses were conducted to identify the factors predicting two-point reduction or more in NRS on day 3. Among 179 patients who received corticosteroids, 86 (48%; 95% CI 41%-56%) had a response with two-point reduction or more. Factors that significantly predicted responses were performance status score of 3 or more, Palliative Performance Scale score more than 40, absence of ascites, absence of drowsiness, absence of depression, serum albumin level greater than 3 mg/dL, serum sodium level greater than 135 mEq/L, and baseline NRS score greater than 5. A multivariate analysis showed that the independent factors predicting responses were baseline NRS score greater than 5 (odds ratio [OR] 6.6, 95% CI 2.8-15.4), Palliative Performance Scale score more than 40 (OR 4.4, 95% CI 2.1-9.3), absence of drowsiness (OR 3.4, 95% CI 1.7-6.9), absence of ascites (OR 2.3, 95% CI 1.1-4.7), and absence of pleural effusion (OR 2.2, 95% CI 1.0-5.0). Treatment responses to corticosteroids for CRF may be predicted by baseline symptom intensity, performance status, drowsiness, and severity of fluid retention symptoms. Larger prospective studies are needed to confirm these results. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Integrating Analysis Goals for EOP, CRF and TRF

NASA Technical Reports Server (NTRS)

Ma, Chopo; MacMillan, D.; Petrov, L.; Smith, David E. (Technical Monitor)

2001-01-01

In a simplified, idealized way the TRF can be considered a set of positions at epoch and corresponding linear rates of change while the CRF is a set of fixed directions in space. VLBI analysis can be optimized for CRF and TRF separately while handling some of the complexity of geodetic and astrometric reality. For EOP time series both CRF and TRF should be accurate at the epoch of interest and well defined over time. The optimal integral EOP, TRF and CRF in a single VLBI solution configuration requires a detailed consideration of the data set and the possibly conflicting nature of reference frames.

LSTM-CRF | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

LSTM-CRF uses Natural Language Processing methods for detecting Adverse Drug Events, Drugname, Indication and other medically relevant information from Electronic Health Records. It implements Recurrent Neural Networks using several CRF based inference methods.

Modulation of the adaptive response to stress by brain activation of selective somatostatin receptor subtypes.

PubMed

Stengel, Andreas; Rivier, Jean; Taché, Yvette

2013-04-01

Somatostatin-14 was discovered in 1973 in the hypothalamus as a peptide inhibiting growth hormone release. Somatostatin interacts with five receptor subtypes (sst(1-5)) which are widely distributed in the brain with a distinct, but overlapping, expression pattern. During the last few years, the development of highly selective peptide agonists and antagonists provided new insight to characterize the role of somatostatin receptor subtypes in the pleiotropic actions of somatostatin. Recent evidence in rodents indicates that the activation of selective somatostatin receptor subtypes in the brain blunts stress-corticotropin-releasing factor (CRF) related ACTH release (sst2/5), sympathetic-adrenal activaton (sst5), stimulation of colonic motility (sst1), delayed gastric emptying (sst5), suppression of food intake (sst2) and the anxiogenic-like (sst2) response. These findings suggest that brain somatostatin signaling pathways may play an important role in dampening CRF-mediated endocrine, sympathetic, behavioral and visceral responses to stress. Published by Elsevier Inc.

GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis

PubMed Central

Gafford, Georgette M.; Ressler, Kerry J.

2016-01-01

Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. PMID:25888455

Genotypic characterization of CRF01_AE env genes derived from human immunodeficiency virus type 1-infected patients residing in central Thailand.

PubMed

Utachee, Piraporn; Jinnopat, Piyamat; Isarangkura-Na-Ayuthaya, Panasda; de Silva, Udayanga Chandimal; Nakamura, Shota; Siripanyaphinyo, Uamporn; Wichukchinda, Nuanjun; Tokunaga, Kenzo; Yasunaga, Teruo; Sawanpanyalert, Pathom; Ikuta, Kazuyoshi; Auwanit, Wattana; Kameoka, Masanori

2009-02-01

CRF01_AE is a major subtype of human immunodeficiency virus type 1 (HIV-1) circulating in Southeast Asia, including Thailand. HIV-1 env genes were amplified by polymerase chain reaction from blood samples of HIV-1-infected patients residing in Thailand in 2006, and cloned into the pNL4-3-derived reporter viral construct. Generated envelope protein (Env)-recombinant virus was examined for its infectivity, and then 35 infectious CRF01_AE Env-recombinant viruses were selected. Sequencing analysis revealed that the interclone variation of the deduced amino acid sequences was higher in CRF01_AE env genes isolated in 2006 than in those isolated in the early 1990s, suggesting that env gene variation has been increasing gradually among CRF01_AE viruses prevalent in Thailand. We also examined the characteristics of the deduced amino acid sequences of 35 CRF01_AE env genes. Our results may provide useful information to help in better understanding the genotype of env genes of CRF01_AE viruses currently circulating in Thailand.

Antisocial and seizure susceptibility phenotypes in an animal model of epilepsy are normalized by impairment of brain corticotropin-releasing factor.

PubMed

Turner, Laura H; Lim, Chen E; Heinrichs, Stephen C

2007-02-01

Social interaction phenotyping is an unexplored niche in animal modeling of epilepsy despite the sensitivity of affiliative behaviors to emotionality and stress, which are known seizure triggers. Thus, the present studies examined the social phenotype of seizure-susceptible El and nonsusceptible ddY strains both in untreated animals and following preexposure to a handling stressor. The second aim of the present studies was to evaluate the dependence of sociability in El mice on the proconvulsive, stress neuropeptide corticotropin-releasing factor (CRF) using CRF-SAP, a conjugate of CRF and the toxin saporin, which selectively reduced CRF peptide levels in the basolateral amygdala of El mice. El mice exhibited lower social investigation times than ddY counterparts, whereas central administration of CRF-SAP normalized social investigation times relative to ddY controls. Moreover, handling-induced seizures in El mice were reduced by 50% following treatment with CRF-SAP relative to saporin alone-injected El controls. The results of this study suggest that tonically activated CRF systems in the El mouse brain suppress affiliative behavior and facilitate evoked seizures.

Polarization of T-helper lymphocytes toward the Th2 phenotype in uremic patients.

PubMed

Libetta, C; Rampino, T; Dal Canton, A

2001-08-01

T-helper (Th) lymphocytes consist of Th1 and Th2 subsets. Th1 cells are effectors of cell-mediated immunity and secrete interferon-gamma (IFN-gamma), which recruits new Th1 cells in cooperation with interleukin-12 (IL-12; produced by monocytes) and inhibits Th2 differentiation. Th2 cells produce IL-4 and IL-10, which inhibit IFN-gamma secretion and cell immunity. We investigated whether the impaired immune response in uremia is associated with an altered balance of Th1/Th2. Peripheral-blood mononuclear cells (PBMCs) were collected from patients with chronic renal failure (CRF) on conservative treatment (CRF patients), patients with end-stage renal disease (ESRD) on regular hemodialysis therapy (ESRD-HD patients), and healthy controls (CON). CD4(+) cells were isolated from PBMCs by negative selection using a magnetic labeling system. PBMCs and purified CD4(+) cells were cultured in Iscove's medium and Iscove's medium plus mitogens (phytohemagglutinin and lipopolysaccharide). IFN-gamma, IL-12, IL-4, and IL-10 were measured in supernatant. The constitutive release of IL-4 and IL-10 by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was increased by five to eight times in comparison with CON (P < 0.001). Constitutive IFN-gamma release by PBMCs of ESRD-HD patients was undetectable, although they secreted an increased amount of IL-12. Mitogen-stimulated release of IFN-gamma by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was blunted (average PBMCs: CON, 115.8 pg/2 x10(6) cells; CRF, 81.8 pg/2 x10(6) cells; ESRD-HD, 9.3 pg/2 x10(6) cells; CD4(+) cells: CON, 358.0 pg/5 x 10(5) cells; CRF, 165.4 pg/5 x 10(5) cells; ESRD-HD, 43.5 pg/5 x 10(5) cells). The ability of PBMCs of ESRD-HD patients to secrete IFN-gamma was recovered after IL-4 and IL-10 neutralization. Uremia is associated with a prevalence of Th1 over Th2 cells and a configuration of cytokine network that depresses cell-mediated immunity.

Analysis of normal and truncated holo- and apo-retinol-binding protein (RBP) in human serum: altered ratios in chronic renal failure.

PubMed

Jaconi, S; Saurat, J H; Siegenthaler, G

1996-05-01

Retinol, the precursor of the retinoic acid hormone, is transported in the serum by a specific carrier, the retinol-binding protein (RBP). Compared to serum of healthy controls, the serum of patients with chronic renal failure (CRF) contains markedly increased levels of the RBP form truncated at the C terminal, des(182Leu-183Leu), (RBP2), which suggests that RBP2 is cleared by the kidney in healthy people but accumulates in serum of CRF patients (Jaconi S, et al. J Lipid Res 1995:36:1247-53). To understand better the mechanism of retinol transport, we have developed a new analytical strategy to analyze the various forms of RBP that circulate in the blood: RBP with and without retinol (holo- and apo-RBP, respectively), RBP bound or not to transthyretin (TTR) and to determine in which of these forms RBP2 circulates. We confirm, but now by direct measurement, that holo-RBP and, to a larger extent, apo-RBP are increased in CRF serum compared to normal serum. We also show that almost all apo-RBP and about 50% of total holo-RBP, corresponding to RBP excess in CRF serum, circulate free and are not complexed to TTR, the remaining 50% being complexed to TTR. This observation suggests that the high levels of free holo-RBP, not bound to TTR, which correspond to the increase in total RBPs measured in CRF serum, may alter the tissue uptake of retinol and be responsible for the signs of hypervitaminosis A observed in these patients. Secondly, we found that the truncation resulting in RBP2 does not alter its binding properties for retinol nor those of holo-RBP2 for TTR. We observed that the high amounts of free holo-RBP2 and holo-RBP in sera of CRF patients were low in normal serum, suggesting that these forms are cleared by the kidney in normal conditions. The possible role of free holo-RBPs is discussed in the context of retinol recycling.

Integrating copper toxicity and climate change to understand extinction risk to two species of pond-breeding anurans.

PubMed

Weir, Scott M; Scott, David E; Salice, Christopher J; Lance, Stacey L

2016-09-01

Chemical contamination is often suggested as an important contributing factor to amphibian population declines, but direct links are rarely reported. Population modeling provides a quantitative method to integrate toxicity data with demographic data to understand the long-term effects of contaminants on population persistence. In this study we use laboratory-derived embryo and larval toxicity data for two anuran species to investigate the potential for toxicity to contribute to population declines. We use the southern toad (Anaxyrus terrestris) and the southern leopard frog (Lithobates sphenocephalus) as model species to investigate copper (Cu) toxicity. We use matrix models to project populations through time and quantify extinction risk (the probability of quasi-extinction in 35 yr). Life-history parameters for toads and frogs were obtained from previously published literature or unpublished data from a long-term (>35 yr) data set. In addition to Cu toxicity, we investigate the role of climate change on amphibian populations by including the probability of early pond drying that results in catastrophic reproductive failure (CRF, i.e., complete mortality of all larval individuals). Our models indicate that CRF is an important parameter for both species as both were unable to persist when CRF probability was >50% for toads or 40% for frogs. Copper toxicity alone did not result in significant effects on extinction risk unless toxicity was very high (>50% reduction in survival parameters). For toads, Cu toxicity and high probability of CRF both resulted in high extinction risk but no synergistic (or greater than additive) effects between the two stressors occurred. For leopard frogs, in the absence of CRF survival was high even under Cu toxicity, but with CRF Cu toxicity increased extinction risk. Our analyses highlight the importance of considering multiple stressors as well as species differences in response to those stressors. Our models were consistently most sensitive to juvenile and adult survival, further suggesting the importance of terrestrial stages to population persistence. Future models will incorporate multiple wetlands with different combinations of stressors to understand if our results for a single wetland result in a population sink within the landscape. © 2016 by the Ecological Society of America.

Cancer and Cancer-Related Fatigue and the Interrelationships With Depression, Stress, and Inflammation

PubMed Central

Weber, Daniel; O’Brien, Kylie

2016-01-01

Cancer-related fatigue (CRF) is a common symptom experienced in cancer patients. Depression, anxiety, and stress are associated with cancer. Depression and anxiety are also associated with CRF. At the cellular level, much is known about the impact of stress on the body generally, and its potential role in cancer. Stress, anxiety, and depression have been found to depress the immune system. Depression and stress have also been found to create inflammatory changes in the body and there is emerging evidence that inflammation is involved in cancer pathogenesis and in CRF. This article examines the relationships between stress, anxiety, depression, and cancer; relationships between anxiety and depression and CRF; and what happens at the cellular level, including impact on the immune system and emerging evidence of the role of inflammation in CRF. It also reports on research in relation to some Chinese herbal medicines that may be used to treat CRF.

Four Closely Related HIV-1 CRF01_AE/CRF07_BC Recombinant Forms Identified in East China.

PubMed

Li, Fan; Li, Yuxueyun; Feng, Yi; Hu, Jing; Ruan, Yuhua; Xing, Hui; Shao, Yiming

2017-07-01

Five near full-length genomes of novel second-generation HIV-1 recombinant virus (JS150021, JS150029, JS150129, JS150132, and AH150183) were identified from five HIV-positive people in Jiangsu and Anhui province, east China. Phylogenic analyses showed that these five sequences are all composed of two well-established circulating recombinant forms (CRFs) CRF07_BC and CRF01_AE, grouped into four new discovered recombinant forms, which show several very similar but not identical recombinant breakpoints. The four recombinant forms are also identified to be a sort of family or related viruses, seems to be the results of different recombination events. The emergence of a serious new closely related CRF07_BC/CRF01_AE recombinant strain indicates the increasing complexity of sexual transmission of the HIV-1 epidemic in China.

Cancer-related fatigue in palliative care: a global perspective.

PubMed

Vilchynska, Tetyana; Beard, Barbara

2016-05-01

Cancer-related fatigue (CRF) in a palliative care setting is a distressing symptom that can have a negative impact on a patient's quality of life. A range of setting- and disease-specific factors, unknown aetiology and absence of unilateral guidelines make CRF treatment a challenge for clinicians. In the absence of high-quality evidence in favour of any pharmacological and nonpharmacological measures, except exercise, cognitive behavioural therapy and psychosocial interventions, a personalised integrative oncology approach can lead to effective management. Findings suggest adoption of a severity-based symptom-stage adjusted CRF management care pathway, highlighting best practices to illustrate the lived experience of this symptom. Overcoming barriers by staff training, patient education, facilitating communication and patients' self-care, will increase CRF management effectiveness. Future CRF multisymptom or multidimensional nature investigation trials of its underlying mechanisms and new pharmacological and nonpharmacological strategies applied separately or in combination, will help reveal the best approach to CRF diagnosis, assessment and management.

Identification of a new HIV-1 circulating recombinant form CRF65_cpx strain in Jilin, China.

PubMed

Wang, Jia-Ye; Chen, Xiao-Hong; Shao, Bing; Huo, Qing-Qing; Liu, Si-Yu; Li, Jin; Wang, Fu-Xiang

2018-05-04

This study reported a new HIV-1 circulating recombinant form CRF65_cpx virus isolated from a man who had sex with men (MSM) in Jilin, China. The near full-length genome of this virus was composed of fourteen mosaic gene fragments derived from CRF01_AE, subtype B' (Thai B) and subtype C, highly similar to the CRF65_cpx viruses recently identified in Yunnan and Anhui of China. Phylogenetic tree analysis suggested that this CRF65_cpx strain was not generated among MSM in Jilin, but originated in southern regions of China and spread to Jilin by MSM population. The emergence of CRF65_cpx in Jilin indicated HIV-1 epidemic in this area was more and more complicated and the MSM population has become the important source for generation of new recombinant viruses. Real-time surveillance of new HIV-1 infections among MSM population is quite required.

Effects of Paternal Predation Risk and Rearing Environment on Maternal Investment and Development of Defensive Responses in the Offspring

PubMed Central

Bauer, Jessica

2016-01-01

Abstract Detecting past experiences with predators of a potential mate informs a female about prevailing ecological threats, in addition to stress-induced phenotypes that may be disseminated to offspring. We examined whether prior exposure of a male rat to a predator (cat) odor influences the attraction of a female toward a male, subsequent mother–infant interactions and the development of defensive (emotional) responses in the offspring. Females displayed less interest in males that had experienced predator odor. Mothers that reared young in larger, seminaturalistic housing provided more licking and grooming and active arched back-nursing behavior toward their offspring compared with dams housed in standard housing, although some effects interacted with paternal experience. Paternal predation risk and maternal rearing environment revealed sex-dependent differences in offspring wean weight, juvenile social interactions, and anxiety-like behavior in adolescence. Additionally, paternal predator experience and maternal housing independently affected variations in crf gene promoter acetylation and crf gene expression in response to an acute stressor in offspring. Our results show for the first time in mammals that variation among males in their predator encounters may contribute to stable behavioral variation among females in preference for mates and maternal care, even when the females are not directly exposed to predator threat. Furthermore, when offspring were exposed to the same threat experienced by the father, hypothalamic crf gene regulation was influenced by paternal olfactory experience and early housing. These results, together with our previous findings, suggest that paternal stress exposure and maternal rearing conditions can influence maternal behavior and the development of defensive responses in offspring. PMID:27896313

Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome.

PubMed

Beene, Lauren C; Traboulsi, Elias I; Seven, Ibrahim; Ford, Matthew R; Sinha Roy, Abhijit; Butler, Robert S; Dupps, William J

2016-01-01

To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. Prospective observational clinical study. Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses. Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 ± 20, control 69 ± 14, P = .003; AUROC = 0.80). Corneal hysteresis (CH) and corneal resistance factor (CRF) were decreased (Marfan syndrome CH 9.45 ± 1.62, control CH 11.24 ± 1.21, P = .01; Marfan syndrome CRF 9.77 ± 1.65, control CRF 11.03 ± 1.72, P = .01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 ± 2.09 diopter, control Kmean 42.70 ± 1.81 diopter, P = .046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for noninvasive clinical diagnosis of Marfan syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of the CRF1 receptor influences the activity of antidepressant drugs in the forced swim test in rats.

PubMed

Wróbel, Andrzej; Serefko, Anna; Szopa, Aleksandra; Rojek, Karol; Poleszak, Ewa; Skalicka-Woźniak, Krystyna; Dudka, Jarosław

2017-08-01

Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and impairment of the central corticotropin-releasing factor (CRF) system are factors in the pathogenesis of depression. Though several antagonists of the CRF 1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between CRF 1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of SN003, a CRF 1 receptor blocker, on the activity of imipramine and fluoxetine in the forced swim test (FST) in rats which presented some signs of depression. The experiments were carried out on female Wistar rats subjected to 14-day subcutaneous corticosterone (CORT) administration (20 mg/kg/day). The antidepressant-like effect was determined by the FST and the CRF levels in the hypothalamus, amygdala, and peripheral blood were measured by a high-sensitivity immunoenzymatic test. SN003 (0.5 mg/kg) potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (7.5 mg/kg). Moreover, the co-administration of the tested agents abolished CORT-induced increase in CRF levels in the examined biological material more profoundly than monotherapy. Our present findings give further evidence that the blockage of CRF action may be useful in the treatment of mood disorders. The concurrent use of well-known antidepressants with CRF 1 receptor antagonists could be beneficial in terms of safety, since it requires lower doses of the applied agents.

Cardiorespiratory fitness not sedentary time or physical activity is associated with cardiometabolic risk in active older adults.

PubMed

Pollock, R D; Duggal, N A; Lazarus, N R; Lord, J M; Harridge, S D R

2018-02-10

Sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) are associated with cardiometabolic health. Cardiorespiratory fitness (CRF) is also implicated but often overlooked in health recommendations. This study assessed the relationships between ST, MVPA, CRF, and cardiometabolic health in highly active older individuals. 125 healthy amateur cyclists aged 55 to 79 years had their ST and MVPA levels assessed by actigraphy over a 7-day period. CRF was assessed using a maximal effort cycle ergometry test to determine VO 2max with results normalized to both body mass and fat-free mass measured by DXA. Markers of cardiometabolic risk (blood glucose, triglycerides, cholesterol, HDL, LDL, Insulin, HOMA IR, blood pressure, and body fat) were assessed and used to determine cumulative cardiometabolic risk. Multiple linear regression was used to assess ST, MVPA, and CRF associations with cardiometabolic health with the relationship between activity levels and CRF determined. CRF was associated with training volume (P = .003), but not ST or MVPA. A high CRF was associated with lower cumulative cardiometabolic risk, body fat percentage, triglyceride, and HDL levels (P < .05 in all cases). MVPA was negatively associated with body fat percentage, while ST was not associated with any marker of cardiometabolic risk when adjusting for activity levels. An association between CRF and cardiometabolic risk even in a group of older individuals with high fitness levels highlights the importance that CRF may have in maintaining health. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Independent Associations between Sedentary Time, Moderate-To-Vigorous Physical Activity, Cardiorespiratory Fitness and Cardio-Metabolic Health: A Cross-Sectional Study

PubMed Central

Lefevre, Johan; Wijtzes, Anne; Charlier, Ruben; Mertens, Evelien; Bourgois, Jan G.

2016-01-01

We aimed to study the independent associations of sedentary time (ST), moderate-to-vigorous physical activity (MVPA), and objectively measured cardiorespiratory fitness (CRF) with clustered cardio-metabolic risk and its individual components (waist circumference, fasting glucose, HDL-cholesterol, triglycerides and blood pressure). We also investigated whether any associations between MVPA or ST and clustered cardio-metabolic risk were mediated by CRF. MVPA, ST, CRF and individual cardio-metabolic components were measured in a population-based sample of 341 adults (age 53.8 ± 8.9 years; 61% men) between 2012 and 2014. MVPA and ST were measured with the SenseWear pro 3 Armband and CRF was measured with a maximal exercise test. Multiple linear regression models and the product of coefficients method were used to examine independent associations and mediation effects, respectively. Results showed that low MVPA and low CRF were associated with a higher clustered cardio-metabolic risk (β = -0.26 and β = -0.43, both p<0.001, respectively). CRF explained 73% of the variance in the association between MVPA and clustered cardio-metabolic risk and attenuated this association to non-significance. After mutual adjustment for MVPA and ST, CRF was the most important risk factor for a higher clustered cardio-metabolic risk (β = -0.39, p<0.001). In conclusion, because of the mediating role of CRF, lifestyle-interventions need to be feasible yet challenging enough to lead to increases in CRF to improve someone’s cardio-metabolic health. PMID:27463377

Cancer-related fatigue and depression in breast cancer patients postchemotherapy: Different associations with optimism and stress appraisals.

PubMed

Levkovich, Inbar; Cohen, Miri; Pollack, Shimon; Drumea, Karen; Fried, Georgeta

2015-10-01

Symptoms of depression and cancer-related fatigue (CRF) are common among breast cancer patients postchemotherapy and may seriously impair quality of life (QoL). This study aimed to assess the relationship between depression and CRF in breast cancer patients postchemotherapy and to examine their relationships to optimism and to threat and challenge appraisals. Participants included 95 breast cancer patients (stages 1-3) 1 to 6 months after completion of chemotherapy. Patients submitted personal and medical details and completed the following: physical symptom questionnaires (EORTC QLQ-C30, and QLQ-BR23), a symptoms of depression questionnaire (CES-D), the Fatigue Symptom Inventory (FSI), the Life Orientation Test (LOT-R), and a stress appraisals questionnaire. We found levels of depression, CRF, and appraisals of cancer as a threat to bemoderate and levels of optimism and appraisals of cancer as a challenge to be high. Depression and CRF were positively associated. A multivariate regression analysis revealed that 51% of the CRF variancewas explained; physical symptoms and threat appraisal were significantly associated with CRF. A 67% of the CRF variance of depression was explained; challenge and threat appraisals were significantly associated with depression [corrected]. Although CRF and depression were often experienced simultaneously and both were found to be higher among individuals who gave higher appraisals of cancer as a threat, only depression was related to optimism and challenge appraisals, while CRF was related mainly to intensity of physical symptoms. The different pattern of associations between optimism and appraisals warrants further clinical attention as well as future study.

Interplay between HIV-1 and Host Genetic Variation: A Snapshot into Its Impact on AIDS and Therapy Response

PubMed Central

Sampathkumar, Raghavan; Shadabi, Elnaz; Luo, Ma

2012-01-01

As of February 2012, 50 circulating recombinant forms (CRFs) have been reported for HIV-1 while one CRF for HIV-2. Also according to HIV sequence compendium 2011, the HIV sequence database is replete with 414,398 sequences. The fact that there are CRFs, which are an amalgamation of sequences derived from six or more subtypes (CRF27_cpx (cpx refers to complex) is a mosaic with sequences from 6 different subtypes besides an unclassified fragment), serves as a testimony to the continual divergent evolution of the virus with its approximate 1% per year rate of evolution, and this phenomena per se poses tremendous challenge for vaccine development against HIV/AIDS, a devastating disease that has killed 1.8 million patients in 2010. Here, we explore the interaction between HIV-1 and host genetic variation in the context of HIV/AIDS and antiretroviral therapy response. PMID:22666249

Physical Activity is Related to Fatty Liver Marker in Obese Youth, Independently of Central Obesity or Cardiorespiratory Fitness

PubMed Central

Martins, Clarice; Aires, Luisa; Júnior, Ismael Freitas; Silva, Gustavo; Silva, Alexandre; Lemos, Luís; Mota, Jorge

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent complications associated with excess adiposity and has been identified as the leading cause of liver disease in pediatric populations worldwide. Because cardiorespiratory fitness (CRF) is related to physical activity (PA) levels, and increased PA plays a protective role against NAFLD risk factors, the aim of this study was to analyze the association between PA and a fatty liver marker (alanine aminotransferase - ALT) in obese children and adolescents, independently of central adiposity or CRF. 131 obese children (83 girls, 7-15 year-olds) involved in a PA promotion program comprised the sample. Measurements included anthropometric and body composition evaluations (DEXA), biological measurements (venipuncture), CRF (progressive treadmill test), PA (accelerometry), and maturational stage (Tanner criteria). The associations between ALT with PA intensities, central obesity, and CRF were calculated by three different models of linear regression, adjusted for potential confounders. Level of significance was set at 95%. RESULTS: ALT was negatively associated with MVPA (β = -0.305), and CRF (β = -0.426), and positively associated with central obesity (β=.468). After adjustment for central obesity the negative and statistically significant association between ALT with MVPA (β = -0.364) and CRF (β = -0.550) still persists while a positive and significantly correlation was shown between ALT and SB (β = 0.382). Additional adjustment for CRF (Model 3) showed significant associations for all the PA intensities analyzed including light activity. PA at different intensities is associated to a fatty liver marker in obese children and adolescents, independently of central adiposity or CRF. Key points In a previous study our group observed that there might be a potential protective effect of cardiorespiratory fitness (CRF) against abnormal ALT values; Considering that CRF is related to physical activity (PA), and increased PA plays a protective role against fatty liver, we hypothesized that it might be an association between PA and fatty liver in obese youth, independently of central adiposity or CRF; No other study has investigated these associations in obese youth; Our findings stresses the fact that moderate-to-vigorous and light physical activities, as well as lower sedentary behavior, is associated with lower fatty liver marker, independent of the effect of potential mediators, such as central obesity or CRF. PMID:25729297

[Biomechanical condition of the cornea as a new indicator for pathological and structural changes].

PubMed

Spörl, E; Terai, N; Haustein, M; Böhm, A G; Raiskup-Wolf, F; Pillunat, L E

2009-06-01

Several methods permit the measurement of geometric parameters of the cornea, but until now biomechanical conditions of the cornea have been ignored (e.g. in refractive corneal surgery). Besides the geometric condition, biomechanical properties of the cornea have been shown to influence applanation measurement of intra-ocular pressure (IOP) and epidemiological studies have identified corneal thickness as an independent risk factor for the development and progression of glaucoma. The aim of this investigation was to characterize the biomechanical properties of the cornea using the ocular response analyzer (ORA). The ocular response analyzer (ORA) is a new method available for non-contact measurement of the biomechanical properties of the cornea. We evaluated the reproducibility of measurements, the difference between static and dynamic factors and the impact of independent factors (e.g. IOP, age, CCT, swelling of the cornea) on 2,500 measurements of corneal hysteresis (CH) and corneal resistance factor (CRF). In a large sample size we observed changes in CH and CRF after refractive surgery procedures (LASIK, UV-A cross-linking, keratoplasty) and in other corneal disorders (keratoconus, corneal dystrophies). CRF and CH changes may reflect structural changes of the cornea. Thus, the ORA provides valuable information for a better understanding and characterization of the biomechanical condition of the cornea, especially with regard to diseases such as keratoconus and glaucoma.

Exercise and the Cardiovascular System: Clinical Science and Cardiovascular Outcomes

PubMed Central

Lavie, Carl J.; Arena, Ross; Swift, Damon L.; Johannsen, Neil M.; Sui, Xuemei; Lee, Duck-chul; Earnest, Conrad P.; Church, Timothy S.; O’Keefe, James H.; Milani, Richard V.; Blair, Steven N.

2015-01-01

Substantial evidence has established the value of high levels of physical activity (PA), exercise training (ET), and overall cardiorespiratory fitness (CRF) in the prevention and treatment of cardiovascular diseases (CVD). This paper reviews some basics of exercise physiology and the acute and chronic responses of ET, as well as the impact of PA and CRF on CVD. This review also surveys data from epidemiologic and ET studies in the primary and secondary prevention of CVD, particularly coronary heart disease (CHD) and heart failure (HF). These data strongly support the routine prescription of ET to all patients and referrals for patients with CVD, especially CHD and HF, to specific cardiac rehabilitation and ET programs. PMID:26139859

Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors.

PubMed

Garcia-Lavandeira, Montserrat; Saez, Carmen; Diaz-Rodriguez, Esther; Perez-Romero, Sihara; Senra, Ana; Dieguez, Carlos; Japon, Miguel A; Alvarez, Clara V

2012-01-01

Adult stem cells maintain some markers expressed by embryonic stem cells and express other specific markers depending on the organ where they reside. Recently, stem/progenitor cells in the rodent and human pituitary have been characterized as expressing GFRA2/RET, PROP1, and stem cell markers such as SOX2 and OCT4 (GPS cells). Our objective was to detect other specific markers of the pituitary stem cells and to investigate whether craniopharyngiomas (CRF), a tumor potentially derived from Rathke's pouch remnants, express similar markers as normal pituitary stem cells. We conducted mRNA and Western blot studies in pituitary extracts, and immunohistochemistry and immunofluorescence on sections from normal rat and human pituitaries and 20 CRF (18 adamantinomatous and two papillary). Normal pituitary GPS stem cells localized in the marginal zone (MZ) express three key embryonic stem cell markers, SOX2, OCT4, and KLF4, in addition to SOX9 and PROP1 and β-catenin overexpression. They express the RET receptor and its GFRA2 coreceptor but also express the coreceptor GFRA3 that could be detected in the MZ of paraffin pituitary sections. CRF maintain the expression of SOX2, OCT4, KLF4, SOX9, and β-catenin. However, RET and GFRA3 expression was altered in CRF. In 25% (five of 20), both RET and GFRA3 were detected but not colocalized in the same cells. The other 75% (15 of 20) lose the expression of RET, GFRA3, or both proteins simultaneously. Human pituitary adult stem/progenitor cells (GPS) located in the MZ are characterized by expression of embryonic stem cell markers SOX2, OCT4, and KLF4 plus the specific pituitary embryonic factor PROP1 and the RET system. Redundancy in RET coreceptor expression (GFRA2 and GFRA3) suggest an important systematic function in their physiological behavior. CRF share the stem cell markers suggesting a common origin with GPS. However, the lack of expression of the RET/GFRA system could be related to the cell mislocation and deregulated growth of CRF.

Geographic Distribution and Temporal Trends of HIV-1 Subtypes through Heterosexual Transmission in China: A Systematic Review and Meta-Analysis

PubMed Central

Xiao, Peipei; Li, Jianjun; Fu, Gengfeng; Zhou, Ying; Huan, Xiping; Yang, Haitao

2017-01-01

Background: Heterosexual transmission (HST) has become the current predominant transmission pathways of the HIV-1 epidemic in China. The aim of this study was to explore the geographic and dynamic change of HIV-1 subtypes through HST in China from published studies. Methods: Several electronic databases were searched to identify the studies, and the overall prevalence of HIV-1 subtypes was estimated by a meta-analysis method. Subgroup analysis was conducted by study region and time period. Publication bias was evaluated using Egger’s test. The χ2 test was used to evaluate the proportion differences among subgroups. Sensitivity analysis was carried out to assess the stability of the overall prevalence estimates. Results: 42 studies were included in our final analysis. The overall prevalence of CRF01_AE was 46.34% (95% CI: 40.56–52.17%), CRF07_BC was 19.16% (95% CI: 15.02–23.66%), B/B’ was 13.25% (95% CI: 9.68–17.25%), CRF08_BC was 10.61% (95% CI: 7.08–14.70%), and C was 4.29% (95% CI: 1.85–7.48%). In subgroup analysis, the prevalence of CRF01_AE and CRF07_BC increased, while the prevalence of B/B’ decreased over time, whereby the prevalence of CRF07_BC and CRF08_BC have exceeded that of B/B’ since 2010. A significant higher prevalence of CRF01_AE was found in the South provinces, CRF07_BC in East provinces, CRF08_BC and C in Southwest provinces, and B/B’ in North provinces. Conclusions: The HIV-1 prevalent strains have evolved into complicated and diverse subtypes, and the proportion of HIV-1 subtypes through HST has changed constantly in different regions and periods in China. This highlights the urgent need to vigorously strengthen the prevention and control of the HIV-1 epidemic. PMID:28737729

GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis.

PubMed

Gafford, Georgette M; Ressler, Kerry J

2015-11-01

This article is part of a Special Issue "SBN 2014". Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. Copyright © 2015. Published by Elsevier Inc.

[Effects of controlled-release fertilizers on summer maize grain yield, field ammonia volatilization, and fertilizer nitrogen use efficiency].

PubMed

Zhao, Bin; Dong, Shu-Ting; Wang, Kong-Jun; Zhang, Ji-Wang; Liu, Peng

2009-11-01

A field experiment with colophony-coated fertilizer (CRF) and sulfur-coated fertilizer (SCF) showed that under the same application rates of N, P and K, applying CRF and SCF increased the summer maize grain yield by 13.15% and 14.15%, respectively, compared to the application of common compound fertilizer CCF. When the applied amount of CRF and SCF was decreased by 25%, the yield increment was 9.69% and 10.04%, respectively; and when the applied amount of CRF and SCF was decreased by 50%, the yield had less difference with that under CCF application. The field ammonia volatilization rate in treatments CRF and SCF increased slowly, with a peak appeared 7 days later than that in treatment CCF, and the total amount of ammonia volatilization in treatments CRF and SCF was ranged from 0.78 kg N x hm(-2) to 4.43 kg N x hm(-2), with a decrement of 51.34%-91.34% compared to that in treatment CCF. The fertilizer nitrogen use efficiency and agronomic nitrogen use efficiency of CRF and SCF were also significantly higher than those of CCF.

The oral health status of dentate patients with chronic renal failure undergoing dialysis therapy.

PubMed

Bots, C P; Poorterman, J H G; Brand, H S; Kalsbeek, H; van Amerongen, B M; Veerman, E C I; Nieuw Amerongen, A V

2006-03-01

The aim of this study was to compare the oral health status of chronic renal failure (CRF) patients on renal replacement therapy with a matched reference population. Cross-sectional study. Forty-two dentate CRF patients--aged 25-52 years old--were matched with a reference group of 808 dentate subjects. The oral health was assessed using decayed missing filled (DMF) indices, simplified oral hygiene index and periodontal status. An oral health questionnaire was used to assess self-reported dental problems. Student t-tests and chi-square tests were performed to compare the CRF patients with the controls. All index-scores in the CRF patients were comparable with the controls except for number of teeth covered with calculus that was significantly higher (P < 0.05) in CRF patients (4.1 +/- 2.6) than in controls (3.0 +/- 2.9). The self-reported oral health questionnaire revealed a trend for increased temporomandibular complaints in CRF patients (16.7%vs 5.7% in controls; P = 0.06) as well as bad taste (31.0%vs 6.8% in controls, P = 0.08). For most dental aspects, the oral health of CRF patients is comparable with controls.

Independent association of clustered metabolic risk factors with cardiorespiratory fitness in youth aged 11-17 years.

PubMed

Machado-Rodrigues, Aristides M; Leite, Neiva; Coelho-e-Silva, Manuel J; Martins, Raul A; Valente-dos-Santos, João; Mascarenhas, Luís P G; Boguszewski, Margaret C S; Padez, Cristina; Malina, Robert M

2014-01-01

Although the prevalence of metabolic syndrome (MetS) has increased in youth, the potential independent contribution of cardiorespiratory fitness (CRF) to the clustering of metabolic risk factors has received relatively little attention. This study evaluated associations between the clustering of metabolic risk factors and CRF in a sample of youth. Height, weight, BMI, fasting glucose, insulin, HDL-cholesterol, triglycerides and blood pressures were measured in a cross-sectional sample of 924 youth (402 males, 522 females) of 11-17 years. CRF was assessed using the 20-metre shuttle run test. Physical activity (PA) was measured with a 3-day diary. Outcome variables were statistically normalized and expressed as Z-scores. A MetS risk score was computed as the mean of the Z-scores. Multiple linear regression was used to test associations between CRF and metabolic risk, adjusted for age, sex, BMI, PA and parental education. CRF was inversely associated with MetS after adjustment for potential confounders. After adjusting for BMI, the relationship between CRF and metabolic risk has substantially improved. CRF was independently associated with the clustering of metabolic risk factors in youth of 11-17 years of age.

Effect of topical corneal anaesthesia on ocular response analyzer parameters: pilot study.

PubMed

Ehongo, A; De Maertelaer, V; Pourjavan, S

2009-10-01

The effect of topical corneal anaesthesia on corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg), and corneal compensated IOP (IOPcc) was measured by ocular response analyzer (ORA). Observational, cross-sectional study. We examined both eyes of 23 healthy volunteers. Patients with external eye disease, previous refractive surgery, contact lenses or topical medication were excluded. ORA parameters were first measured in both eyes. Oxybuprocaïne 0.4% eye drop was instilled in the right eyes (RE) and physiologic saline in the left eyes (LE) as a control to rule out the lubrication effect. After 2 min, the ORA measurements were performed again. Goldmann applanation tonometry (GAT) was finally done. Data are expressed as mean +/- standard deviation (SD). The medians of the four CH, CRF, IOPg, and IOPcc values measured before and after instillation were compared by using Wilcoxon signed ranks tests for RE and LE. The mean age was 39.5 +/- 11.6 years. The mean GAT was 13.1 +/- 2.5 mmHg for RE and 12.8 +/- 2.5 mmHg for LE. In the RE, the respective values for the two sequences were IOPcc = 15.6 +/- 2.6 mmHg and 15 +/- 2.8 mmHg (P = 0.036); IOPg = 15.3 +/- 3.3 mmHg and 15.4 +/- 3.5 mmHg (P = 0.806); CH = 11 +/- 1.3 mmHg and 11.1 +/- 1.4 mmHg (P = 0.563); CRF = 11.1 +/- 1.8 mmHg and 10.9 +/- 1.9 mmHg (P = 0.053). In the LE, the respective values for the two sequences were IOPcc = 15.4 +/- 2.6 mmHg and 15.6 +/- 2.8 mmHg (P = 0.903); IOPg = 15.5 +/- 3.5 mmHg and 15.4 +/- 3.4 mmHg (P = 0.208); CH = 10.8 +/- 1.4 mmHg and 10.7 +/- 1.7 mmHg (P = 0.494); CRF = 10.7 +/- 1.8 mmHg and 10.7 +/- 2.2 mmHg (P = 0.626). Two minutes after instillation, topical corneal anaesthetic slightly decreases IOPcc and also-but not statistically significantly-CRF. We did not find any statistical significant difference in CH or IOPg before and after topical corneal anaesthesia. Further investigation with more patients should be advised.

Enduring sensorimotor gating abnormalities following predator exposure or corticotropin-releasing factor in rats: a model for PTSD-like information-processing deficits?

PubMed

Bakshi, Vaishali P; Alsene, Karen M; Roseboom, Patrick H; Connors, Elenora E

2012-02-01

A deficit in prepulse inhibition (PPI) can be one of the clinically observed features of post-traumatic stress disorder (PTSD) that is seen long after the acute traumatic episode has terminated. Thus, reduced PPI may represent an enduring psychophysiological marker of this illness in some patients. PPI is an operational measure of sensorimotor gating and refers to the phenomenon in which a weak stimulus presented immediately before an intense startling stimulus inhibits the magnitude of the subsequent startle response. The effects of stress on PPI have been relatively understudied, and in particular, there is very little information on PPI effects of ethologically relevant psychological stressors. We aimed to develop a paradigm for evaluating stress-induced sensorimotor gating abnormalities by comparing the effects of a purely psychological stressor (predator exposure) to those of a nociceptive physical stressor (footshock) on PPI and baseline startle responses in rats over an extended period of time following stressor presentation. Male Sprague-Dawley rats were exposed (within a protective cage) to ferrets for 5 min or left in their homecage and then tested for PPI immediately, 24 h, 48 h, and 9 days after the exposure. The effects of footshock were evaluated in a separate set of rats. The effects seen with stressor presentation were compared to those elicited by corticotropin-releasing factor (CRF; 0.5 and 3 μg/6 μl, intracerebroventricularly). Finally, the effects of these stressors and CRF administration on plasma corticosterone were measured. PPI was disrupted 24 h after ferret exposure; in contrast, footshock failed to affect PPI at any time. CRF mimicked the predator stress profile, with the lowdose producing a PPI deficit 24 h after infusion. Interestingly, the high dose also produced a PPI deficit 24 h after infusion, but with this dose, the PPI deficit was evident even 9d later. Plasma corticosterone levels were elevated acutely (before PPI deficits emerged) by both stressors and CRF, but returned to normal control levels 24 h later, when PPI deficits were present. Thus, predator exposure produces a delayed disruption of PPI, and stimulation of CRF receptors recapitulates these effects. Contemporaneous HPA axis activation is neither necessary nor sufficient for these PPI deficits. These results indicate that predator exposure, perhaps acting through CRF, may model the delayed-onset and persistent sensorimotor gating abnormalities that have been observed clinically in PTSD, and that further studies using this model may shed insight on the mechanisms of information-processing deficits in this disorder. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Evaluating immunologic response and clinical deterioration in treatment-naïve patients initiating first-line therapies infected with HIV-1 CRF01_AE and subtype B

PubMed Central

Oyomopito, Rebecca A.; Li, Patrick CK.; Sungkanuparph, Somnuek; Phanuphak, Praphan; Tee, Kok Keng; Sirisanthana, Thira; Kantipong, Pacharee; Oka, Shinichi; Lee, Chris KC.; Kamarulzaman, Adeeba; Choi, Jun Yong; Sohn, Annette H.; Law, Matthew; Chen, Yi-Ming A.

2012-01-01

Background HIV-1 group M viruses diverge 25%–35% in envelope, important for viral attachment during infection, and 10–15% in the pol region, under selection pressure from common antiretrovirals. In Asia, subtypes B and CRF01_AE are common genotypes. Our objectives were to determine whether clinical, immunologic or virologic treatment responses differed by genotype in treatment-naïve patients initiating first-line therapy. Methods Prospectively collected, longitudinal data from patients in Thailand, Hong Kong, Malaysia, Japan, Taiwan and South Korea were provided for analysis. Covariates included demographics, hepatitis B and C coinfections, baseline CD4 T lymphocyte count and plasma HIV-1 RNA levels. Clinical deterioration (a new diagnosis of CDC category B/AIDS-defining illness or death) was assessed by proportional hazards models. Surrogate endpoints were 12-month change in CD4 cell count and virologic suppression post-therapy, evaluated by linear and logistic regression, respectively. Results Of 1105 patients, 1036 (93.8%) infected with CRF01_AE or subtype B were eligible for inclusion in clinical deterioration analyses and contributed 1546.7 person-years of follow-up (median:413 days, IQR:169–672 days). Patients >40 years demonstrated smaller immunological increases (p=0.002) and higher risk of clinical deterioration (HR=2.17; p=0.008). Patients with baseline CD4 cell counts >200 cells/μL had lower risk of clinical deterioration (HR=0.373; p=0.003). A total of 532 patients (48.1% of eligible) had CD4 counts available at baseline and 12 months post-therapy for inclusion in immunolgic analyses. Patients infected with subtype B had larger increases in CD4 counts at 12 months (p=0.024). A total of 530 patients (48.0% of eligible) were included in virologic analyses with no differences in response found between genotypes. Conclusions Results suggest that patients infected with CRF01_AE have reduced immunologic response to therapy at 12 months, compared to subtype-B-infected counterparts. Clinical deterioration was associated with low baseline CD4 counts and older age. The lack of differences in virologic outcomes suggests that all patients have opportunities for virologic suppression. PMID:23138836

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

PubMed Central

Prévost, Jérémie; Zoubchenok, Daria; Richard, Jonathan; Veillette, Maxime; Pacheco, Beatriz; Coutu, Mathieu; Brassard, Nathalie; Parsons, Matthew S.; Ruxrungtham, Kiat; Bunupuradah, Torsak; Tovanabutra, Sodsai; Hwang, Kwan-Ki; Moody, M. Anthony; Haynes, Barton F.; Bonsignori, Mattia; Sodroski, Joseph; Kaufmann, Daniel E.; Shaw, George M.; Chenine, Agnès L.

2017-01-01

ABSTRACT HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy. IMPORTANCE HIV-1-infected cells presenting Env in the CD4-bound conformation on their surface are preferentially targeted by ADCC mediated by HIV-positive (HIV+) sera. Here we show that the gp120 Phe 43 cavity modulates the propensity of Env to sample this conformation and therefore affects the susceptibility of infected cells to ADCC. CRF01_AE HIV-1 strains have an unusual Phe 43 cavity-filling His 375 residue, which increases the propensity of Env to sample the CD4-bound conformation, thereby increasing susceptibility to ADCC. PMID:28100618

Corneal Biomechanical Changes Following Toric Soft Contact Lens Wear.

PubMed

Radaie-Moghadam, Somayeh; Hashemi, Hassan; Jafarzadehpur, Ebrahim; Yekta, Abbas Ali; Khabazkhoob, Mehdi

2016-01-01

To determine the effect of using toric soft contact lenses on corneal biomechanical properties. We enrolled 33 healthy patients with mean age of 23.18 ± 4.06 and minimal cylinder power of 1 D (-1.98 ± 0.808 SD) and negative history of contact lens use; keratoconic patients were excluded from the study. Toric soft contact lenses (BIOFINITY, Comfilcon A, Coopervision, Southampton, UK) were fitted in all participants. The Ocular Response Analyzer (Reichert Ophthalmic Instruments, Depew, New York, USA) was used to measure corneal hysteresis (CH), corneal resistance factor (CRF), and the Pentacam HR (Oculus, Inc., Lynnwood, WA, USA) was used to measure central corneal thickness (CCT) and mean keratometry (K mean) before and one week, one month, and three months after using the toric soft contact lenses. CH and CRF were decreased significantly one month after using the contact lens; mean CH decreased from 9.99 ± 1.44 to 9.59 ± 1.54 mmHg, and mean CRF decreased from 9.96 ± 1.71 to 9.63 ± 1.73 mmHg (P = 0.013 and P = 0.017, respectively). Mean CCT and K mean did not show a significant change during the period of toric soft contact lens use. CH and CRF decreased significantly one month after fitting toric soft contact lenses while CCT and Kmean did not change significantly. Corneal biomechanical parameters may alter with toric soft contact lens use and such changes may have implications with long-term use such lenses.

Social instigation and repeated aggressive confrontations in male Swiss mice: analysis of plasma corticosterone, CRF and BDNF levels in limbic brain areas.

PubMed

Fortes, Paula Madeira; Albrechet-Souza, Lucas; Vasconcelos, Mailton; Ascoli, Bruna Maria; Menegolla, Ana Paula; de Almeida, Rosa Maria M

2017-01-01

Agonistic behaviors help to ensure survival, provide advantage in competition, and communicate social status. The resident-intruder paradigm, an animal model based on male intraspecific confrontations, can be an ethologically relevant tool to investigate the neurobiology of aggressive behavior. To examine behavioral and neurobiological mechanisms of aggressive behavior in male Swiss mice exposed to repeated confrontations in the resident intruder paradigm. Behavioral analysis was performed in association with measurements of plasma corticosterone of mice repeatedly exposed to a potential rival nearby, but inaccessible (social instigation), or to 10 sessions of social instigation followed by direct aggressive encounters. Moreover, corticotropin-releasing factor (CRF) and brain-derived neurotrophic factor (BNDF) were measured in the brain of these animals. Control mice were exposed to neither social instigation nor aggressive confrontations. Mice exposed to aggressive confrontations exhibited a similar pattern of species-typical aggressive and non-aggressive behaviors on the first and the last session. Moreover, in contrast to social instigation only, repeated aggressive confrontations promoted an increase in plasma corticosterone. After 10 aggressive confrontation sessions, mice presented a non-significant trend toward reducing hippocampal levels of CRF, which inversely correlated with plasma corticosterone levels. Conversely, repeated sessions of social instigation or aggressive confrontation did not alter BDNF concentrations at the prefrontal cortex and hippocampus. Exposure to repeated episodes of aggressive encounters did not promote habituation over time. Additionally, CRF seems to be involved in physiological responses to social stressors.

Fast Dissemination of New HIV-1 CRF02/A1 Recombinants in Pakistan

PubMed Central

Chen, Yue; Hora, Bhavna; DeMarco, Todd; Shah, Sharaf Ali; Ahmed, Manzoor; Sanchez, Ana M.; Su, Chang; Carter, Meredith; Stone, Mars; Hasan, Rumina; Hasan, Zahra; Busch, Michael P.; Denny, Thomas N.; Gao, Feng

2016-01-01

A number of HIV-1 subtypes are identified in Pakistan by characterization of partial viral gene sequences. Little is known whether new recombinants are generated and how they disseminate since whole genome sequences for these viruses have not been characterized. Near full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes or next generation sequencing from 34 HIV-1-infected individuals in Pakistan. Phylogenetic tree analysis showed that the newly characterized sequences were 16 subtype As, one subtype C, and 17 A/G recombinants. Further analysis showed that all 16 subtype A1 sequences (47%), together with the vast majority of sequences from Pakistan from other studies, formed a tight subcluster (A1a) within the subtype A1 clade, suggesting that they were derived from a single introduction. More in-depth analysis of 17 A/G NFLG sequences showed that five shared similar recombination breakpoints as in CRF02 (15%) but were phylogenetically distinct from the prototype CRF02 by forming a tight subcluster (CRF02a) while 12 (38%) were new recombinants between CRF02a and A1a or a divergent A1b viruses. Unique recombination patterns among the majority of the newly characterized recombinants indicated ongoing recombination. Interestingly, recombination breakpoints in these CRF02/A1 recombinants were similar to those in prototype CRF02 viruses, indicating that recombination at these sites more likely generate variable recombinant viruses. The dominance and fast dissemination of new CRF02a/A1 recombinants over prototype CRF02 suggest that these recombinant have more adapted and may become major epidemic strains in Pakistan. PMID:27973597

CRF antagonism within the ventral tegmental area but not the extended amygdala attenuates the anxiogenic effects of cocaine in rats.

PubMed

Ettenberg, Aaron; Cotten, Samuel W; Brito, Michael A; Klein, Adam K; Ohana, Tatum A; Margolin, Benjamin; Wei, Alex; Wenzel, Jennifer M

2015-11-01

In addition to its initial rewarding effects, cocaine has been shown to produce profound negative/anxiogenic actions. Recent work on the anxiogenic effects of cocaine has examined the role of corticotropin releasing factor (CRF), with particular attention paid to the CRF cell bodies resident to the extended amygdala (i.e., the central nucleus of the amygdala [CeA] and the bed nucleus of the stria terminalis [BNST]) and the interconnections within and projections outside the region (e.g., to the ventral tegmental area [VTA]). In the current study, localized CRF receptor antagonism was produced by intra-BNST, intra-CeA or intra-VTA application of the CRF antagonists, D-Phe CRF(12-41) or astressin-B. The effect of these treatments were examined in a runway model of i.v. cocaine self-administration that has been shown to be sensitive to both the initial rewarding and delayed anxiogenic effects of the drug in the same animal on the same trial. These dual actions of cocaine are reflected in the development of an approach-avoidance conflict ("retreat behaviors") about goal box entry that stems from the mixed associations that subjects form about the goal. CRF antagonism within the VTA, but not the CeA or BNST, significantly reduced the frequency of approach-avoidance retreat behaviors while leaving start latencies (an index of the positive incentive properties of cocaine) unaffected. These results suggest that the critical CRF receptors contributing to the anxiogenic state associated with acute cocaine administration may lie outside the extended amygdala, and likely involve CRF projections to the VTA. Copyright © 2015 Elsevier Inc. All rights reserved.

Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review.

PubMed

Al-Mamgani, Abrahim; van Werkhoven, Erik; Navran, Arash; Karakullukcu, Baris; Hamming-Vrieze, Olga; Machiels, Melanie; van der Velden, Lilly-Ann; Vogel, Wouter V; Klop, W Martin

2017-09-01

The head and neck region has rich regional lymphatic network, with a theoretical risk on contralateral metastasis from oropharyngeal cancer (OPC). There is a long-standing convention to irradiate the great majority of these tumors electively to both sides of the neck to reduce the risk of contralateral regional failure (cRF), but this can induce significant toxicity. We aimed to identify patient groups where elective contralateral irradiation may safely be omitted. PubMed and EMBASE were searched for original full-text articles in English with a combination of search terms related to the end points: cRF in OPC primarily treated by radiotherapy only to the ipsilateral neck and identifying predictive factors for increased incidence of cRF. The data from the identified studies were pooled, the incidence of cRF was calculated and the correlation with different predictive factors was investigated. Eleven full-text articles met the inclusion criteria. In these studies, 1116 patients were treated to the ipsilateral neck alone. The mean incidence of cRF was 2.42% (range 0-5.9%, 95% CI 1.6-3.5%). The incidence of cRF correlated only with T-stage (p=0.008), and involvement of midline (p=0.001). However, the significant correlation with T-stage can be explained by the very low incidence of cRF among T1 (0.77%), and disappeared when the incidence of cRF was compared between T2, T3,and T4 (p=0.344). The incidence of cRF in patients with OPC is very low, with involvement of midline providing the most significant prognosticator. These results call for trials on unilateral elective irradiation in selected groups. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cardiorespiratory Fitness, Waist Circumference and Alanine Aminotransferase in Youth

PubMed Central

Trilk, Jennifer L.; Ortaglia, Andrew; Blair, Steven N.; Bottai, Matteo; Church, Timothy S.; Pate, Russell R.

2012-01-01

Non-alcoholic fatty liver disease (NAFLD) is considered the liver component of the metabolic syndrome and is strongly associated with cardiometabolic diseases. In adults, cardiorespiratory fitness (CRF) is inversely associated with alanine aminotransferase (ALT), a blood biomarker for NAFLD. However, information regarding these associations is scarce for youth. Purpose To examine associations between CRF, waist circumference (WC) and ALT in youth. Methods Data were obtained from youth (n=2844, 12-19 years) in the National Health and Nutrition Examination Survey (NHANES) 2001-2004. CRF was dichotomized into youth FITNESSGRAM® categories of “low” and “adequate” CRF. Logistic and quantile regression were used for a comprehensive analysis of associations, and variables with previously-reported associations with ALT were a priori included in the models. Results Results from logistic regression suggested that youth with low CRF had 1.5 times the odds of having an ALT>30 than youth with adequate CRF, although the association was not statistically significant (P=0.09). However, quantile regression demonstrated that youth with low CRF had statistically significantly higher ALT (+1.04, +1.05, and +2.57 U/L) at the upper end of the ALT distribution (80th, 85th, and 90th percentiles, respectively) than youth with adequate CRF. For every 1-cm increase in WC, the odds of having an ALT>30 increased by 1.06 (P<0.001), and the strength of this association increased across the ALT distribution. Conclusions Future studies should examine whether interventions to improve CRF can decrease hepatic fat and liver enzyme concentrations in youth with ALT ≥80th percentile or in youth diagnosed with NAFLD. PMID:23190589

Less contribution of mast cells to the progression of renal fibrosis in Rat kidneys with chronic renal failure.

PubMed

Baba, Asuka; Tachi, Masahiro; Ejima, Yutaka; Endo, Yasuhiro; Toyama, Hiroaki; Saito, Kazutomo; Abe, Nozomu; Yamauchi, Masanori; Miura, Chieko; Kazama, Itsuro

2017-02-01

Chronic renal failure (CRF) is histopathologically characterized by tubulointerstitial fibrosis in addition to glomerulosclerosis. Although mast cells are known to infiltrate into the kidneys with chronic inflammation, we know little about their contribution to the pathogenesis of renal fibrosis associated with CRF. The aim of this study was to reveal the involvement of mast cells in the progression of renal fibrosis in CRF. Using a rat model with CRF resulting from 5/6 nephrectomy, we examined the histopathological features of the kidneys and the infiltration of mast cells into the renal interstitium. By treating the rats with a potent mast cell stabilizer, tranilast, we also examined the involvement of mast cells in the progression of renal fibrosis associated with CRF. The CRF rat kidneys were characterized by the wide staining of collagen III and increased number of myofibroblasts, indicating the progression of renal fibrosis. Compared to T-lymphocytes or macrophages, the number of tryptase-positive mast cells was much smaller within the fibrotic kidneys and they did not proliferate in situ. The mRNA expression of mast cell-derived fibroblast-activating factors was not increased in the renal cortex isolated from CRF rat kidneys. Treatment with tranilast did not suppress the progression of renal fibrosis, nor did it ameliorate the progression of glomerulosclerosis and the interstitial proliferation of inflammatory leukocytes. This study demonstrated for the first time that mast cells are neither increased nor activated in the fibrotic kidneys of CRF rats. Compared to T-lymphocytes or macrophages that proliferate in situ within the fibrotic kidneys, mast cells were less likely to contribute to the progression of renal fibrosis associated with CRF. © 2016 Asian Pacific Society of Nephrology.

Acute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition.

PubMed

Gibelin, Aude; Parrot, Antoine; Maitre, Bernard; Brun-Buisson, Christian; Mekontso Dessap, Armand; Fartoukh, Muriel; de Prost, Nicolas

2016-02-01

Some patients presenting with acute respiratory failure and meeting the Berlin criteria for acute respiratory distress syndrome (ARDS) lack exposure to common risk factors (CRF). These so-called ARDS mimickers often lack histological diffuse alveolar damage. We aimed to describe such ARDS mimickers lacking CRF (ARDS CRF-) in comparison with others (ARDS CRF+). Retrospective study including all patients receiving invasive mechanical ventilation for ARDS admitted to the intensive care units (ICUs) of two tertiary care centers from January 2003 to December 2012. The prevalence of ARDS CRF- was 7.5 % (95 % CI [5.5-9.5]; n = 50/665). On the basis of medical history, bronchoalveolar lavage fluid cytology, and chest CT scan patterns, four etiological categories were identified: immune (n = 18; 36 %), drug-induced (n = 13; 26 %), malignant (n = 7; 14 %), and idiopathic (n = 12; 24 %). Although the ARDS CRF- patients had a lower logistic organ dysfunction score (4 [3-8] vs. 10 [6-13]; p < 0.0001) and less often shock upon ICU admission (44 vs. 80 %; p < 0.0001) than their counterparts, their overall ICU mortality rate was very high (66 % [46-74]), and the absence of CRF remained associated with ICU mortality by multivariable logistic regression analysis (adjusted OR = 2.06; 95 % CI [1.02-4.18]; p = 0.044). Among ARDS CRF- patients, the presence of potentially reversible lung lesions with corticosteroids (aOR = 0.14; 95 % CI [0.03-0.62]) was associated with ICU survival. The absence of CRF among patients with ARDS is common and associated with a higher risk of mortality. For such atypical ARDS, a complete diagnostic workup, including bronchoalveolar lavage fluid cytology and chest CT scan patterns, should be performed to identify those patients who might benefit from specific therapies, including corticosteroids.

Overview of HIV molecular epidemiology among people who inject drugs in Europe and Asia.

PubMed

Nikolopoulos, Georgios K; Kostaki, Evangelia-Georgia; Paraskevis, Dimitrios

2016-12-01

HIV strains continuously evolve, tend to recombine, and new circulating variants are being discovered. Novel strains complicate efforts to develop a vaccine against HIV and may exhibit higher transmission efficiency and virulence, and elevated resistance to antiretroviral agents. The United Nations Joint Programme on HIV/AIDS (UNAIDS) set an ambitious goal to end HIV as a public health threat by 2030 through comprehensive strategies that include epidemiological input as the first step of the process. In this context, molecular epidemiology becomes invaluable as it captures trends in HIV evolution rates that shape epidemiological pictures across several geographical areas. This review briefly summarizes the molecular epidemiology of HIV among people who inject drugs (PWID) in Europe and Asia. Following high transmission rates of subtype G and CRF14_BG among PWID in Portugal and Spain, two European countries, Greece and Romania, experienced recent HIV outbreaks in PWID that consisted of multiple transmission clusters including subtypes B, A, F1, and recombinants CRF14_BG and CRF35_AD. The latter was first identified in Afghanistan. Russia, Ukraine, and other Former Soviet Union (FSU) states are still facing the devastating effects of epidemics in PWID produced by A FSU (also known as IDU-A), B FSU (known as IDU-B), and CRF03_AB. In Asia, CRF01_AE and subtype B (Western B and Thai B) travelled from PWID in Thailand to neighboring countries. Recombination hotspots in South China, Northern Myanmar, and Malaysia have been generating several intersubtype and inter-CRF recombinants (e.g. CRF07_BC, CRF08_BC, CRF33_01B etc.), increasing the complexity of HIV molecular patterns. Copyright © 2016 Elsevier B.V. All rights reserved.

Overview of HIV molecular epidemiology among People who Inject Drugs in Europe and Asia

PubMed Central

Nikolopoulos, Georgios K.; Kostaki, Evangelia-Georgia; Paraskevis, Dimitrios

2016-01-01

HIV strains continuously evolve, tend to recombine and new circulating variants are being discovered. Novel strains complicate efforts to develop a vaccine against HIV and may exhibit higher transmission efficiency and virulence, and elevated resistance to antiretroviral agents. The United Nations Joint Programme on HIV/AIDS (UNAIDS) set an ambitious goal to end HIV as a public health threat by 2030 through comprehensive strategies that include epidemiological input as the first step of the process. In this context, molecular epidemiology becomes invaluable as it captures trends in HIV evolution rates that shape epidemiological pictures across several geographical areas. This review briefly summarizes the molecular epidemiology of HIV among people who inject drugs (PWID) in Europe and Asia. Following high transmission rates of subtype G and CRF14_BG among PWID in Portugal and Spain, two European countries, Greece and Romania, experienced recent HIV outbreaks in PWID that consisted of multiple transmission clusters including subtypes B, A, F1 and recombinants CRF14_BG and CRF35_AD. The latter was first identified in Afghanistan. Russia, Ukraine and other Former Soviet Union (FSU) states are still facing the devastating effects of epidemics in PWID produced by AFSU (also known as IDU-A), BFSU (known as IDU-B), and CRF03_AB. In Asia, CRF01_AE and subtype B (Western B and Thai B) travelled from PWID in Thailand to neighboring countries. Recombination hotspots in South China, Northern Myanmar, and Malaysia have been generating several intersubtype and inter-CRF recombinants (e.g. CRF07_BC, CRF08_BC, CRF33_01B etc.) increasing the complexity of HIV molecular patterns. PMID:27287560

Association of triglyceride-to-high density lipoprotein cholesterol ratio to cardiorespiratory fitness in men.

PubMed

Vega, Gloria Lena; Grundy, Scott M; Barlow, Carolyn E; Leonard, David; Willis, Benjamin L; DeFina, Laura F; Farrell, Stephen W

Both triglyceride-to-high density lipoprotein cholesterol (TG/HDL-C) and cardiorespiratory fitness (CRF) impart risk for all-cause morbidity and mortality independently of conventional risk factors. To determine prevalence and/or incidence of high TG/HDL-C ratio in men with low CRF. Clinical characteristics and CRF were used to determine prevalence of a TG/HDL-C ratio ≥ 3.5 (high ratio) in 13,954 men of the Cooper Center Longitudinal Study. High-ratio conversion was determined in 10,424 men with normal baseline TG/HDL-C ratio. Hazard ratio (HR) of incident high TG/HDL-C was adjusted for age and waist girth. Men with low CRF had the highest prevalence of a high TG/HDL-C ratio. In the population with normal TG/HDL-C, age-adjusted HR of incident high TG/HDL-C ratio was 2.77 times higher in men with lowest CRF than in those with highest CRF. Incidence of conversion of normal to high ratio was 5.5% per year in low CRF population, compared with 1.7% in high CRF subjects. Incidence HR was independent of waist girth. Men who converted from normal to high TG/HDL-C ratio during the follow-up period had increased number of metabolic risk factors and a higher prevalence of metabolic syndrome. Men who did not convert to a high TG/HDL-C ratio retained a low prevalence of metabolic syndrome risk factors. A high TG/HDL-C ratio is common in men with low CRF. Metabolic syndrome also is common among those with a high ratio. Copyright © 2016 National Lipid Association. All rights reserved.

The Effects of Chronic Aerobic Exercise on Cardiovascular Risk Factors in Persons with Diabetes Mellitus.

PubMed

Miele, Emily M; Headley, Samuel A E

2017-09-12

Aerobic exercise training is a component of diabetes mellitus (DM) care guidelines due to its favorable effects on glycemic control and cardiovascular disease (CVD) risk factors. The purpose of this review is to outline the recent evidence regarding the clinical effects of chronic aerobic exercise on CVD risk factors in persons with DM and to compare the effects of varying intensities and types of exercise. Among individuals with DM, all types of aerobic exercise training can impact positively on some traditional and non-traditional risk factors for CVD. Training programs with a higher volume or intensity induce greater improvements in vascular function, cardiorespiratory fitness (CRF), and lipid profiles. The beneficial outcomes of aerobic training include improvements in glycemic control, endothelial function, oxidative stress, dyslipidemia, myocardial function, adiposity, and CRF. Findings regarding markers of inflammation are discrepant and further research should focus on the role of exercise to impact upon the chronic inflammation associated with DM.

Integrating Analysis Goals for EOP, CRF and TRF

NASA Technical Reports Server (NTRS)

Ma, Chopo; MacMillan, Daniel; Petrov, Leonid

2002-01-01

In a simplified, idealized way the TRF (Terrestrial Reference Frame) can be considered a set of positions at epoch and corresponding linear rates of change while the CRF (Celestial Reference Frame) is a set of fixed directions in space. VLBI analysis can be optimized for CRF and TRF separately while handling some of the complexity of geodetic and astrometric reality. For EOP (Earth Orientation Parameter) time series both CRF and TRF should be accurate at the epoch of interest and well defined over time. The optimal integration of EOP, TRF and CRF in a single VLBI solution configuration requires a detailed consideration of the data set and the possibly conflicting nature of the reference frames. A possible approach for an integrated analysis is described.

Impact of preoperative chronic renal failure on liver transplantation: a population-based cohort study

PubMed Central

Chung, Peter Chi-Ho; Chen, Hsiu-Pin; Lin, Jr-Rung; Liu, Fu-Chao; Yu, Huang-Ping

2016-01-01

Purpose The purpose of this study was to assess whether preoperative chronic renal failure (CRF) affects the rates of postoperative complications and survival after liver transplantation. Methods This population-based retrospective cohort study included 2,931 recipients of liver transplantation performed between 1998 and 2012, enrolled from the Taiwan National Health Insurance Research Database. Patients were divided into two groups, based on the presence or absence of preoperative CRF. Results The overall estimated survival rate of liver transplantation recipients (LTRs) with preoperative CRF was significantly lower than that of patients without preoperative CRF (P=0.0085). There was no significant difference between the groups in terms of duration of intensive care unit stay, total hospital stay, bacteremia, postoperative bleeding, and pneumonia during hospitalization. Long-term adverse effects, including cerebrovascular disease and coronary heart disease, were not different between patients with versus without CRF. Conclusion These findings suggest that LTRs with preoperative CRF have a higher rate of mortality. PMID:28008264

Electrochemical characterization of monoclinic and orthorhombic Li3CrF6 as positive electrodes in lithium-ion batteries synthesized by a sol-gel process with environmentally benign chemicals

NASA Astrophysics Data System (ADS)

Lieser, Georg; Winkler, Volker; Geßwein, Holger; de Biasi, Lea; Glatthaar, Sven; Hoffmann, M. J.; Ehrenberg, Helmut; Binder, Joachim R.

2015-10-01

Lithium transition metal fluorides (Li3MF6; M = Fe, V) with cryolite structure are investigated as positive electrode materials for lithium-ion batteries. A novel sol-gel process with trifluoroacetic acid as fluorine source was used to synthesize monoclinic and orthorhombic Li3CrF6. A ball milling process with Li3CrF6, binder, and conductive agent was applied to form a Li3CrF6 composite, which was electrochemically characterized against lithium metal for the first time. The electrochemical properties of two different modifications are quite similar, with a reversible specific capacity of 111 mAhg-1 for monoclinic Li3CrF6 and 106 mAhg-1 for orthorhombic Li3CrF6 (1 eq. Li ≙ 143 mAhg-1). The electrochemically active redox couple CrIII/CrII was confirmed by X-ray photoelectron spectroscopy.

HIV genetic diversity in Cameroon: possible public health importance.

PubMed

Ndongmo, Clement B; Pieniazek, Danuta; Holberg-Petersen, Mona; Holm-Hansen, Carol; Zekeng, Leopold; Jeansson, Stig L; Kaptue, Lazare; Kalish, Marcia L

2006-08-01

To monitor the evolving molecular epidemiology and genetic diversity of HIV in a country where many distinct strains cocirculate, we performed genetic analyses on sequences from 75 HIV-1-infected Cameroonians: 74 were group M and 1 was group O. Of the group M sequences, 74 were classified into the following env gp41 subtypes or recombinant forms: CRF02 (n = 54), CRF09 (n = 2), CRF13 (n = 2), A (n = 5), CRF11 (n = 4), CRF06 (n = 1), G (n = 2), F2 (n = 2), and E (n = 1, CRF01), and 1 was a JG recombinant. Comparison of phylogenies for 70 matched gp41 and protease sequences showed inconsistent classifications for 18 (26%) strains. Our data show that recombination is rampant in Cameroon with recombinant viruses continuing to recombine, adding to the complexity of circulating HIV strains. This expanding genetic diversity raises public health concerns for the ability of diagnostic assays to detect these unique HIV mosaic variants and for the development of broadly effective HIV vaccines.

Low Cardiorespiratory Fitness in African Americans: A Health Disparity Risk Factor?

PubMed Central

Swift, Damon L.; Staiano, Amanda E.; Johannsen, Neil M.; Lavie, Carl J.; Earnest, Conrad P.; Katzmarzyk, Peter T.; Blair, Steven N.; Newton, Robert L.; Church, Timothy S.

2013-01-01

Low cardiorespiratory fitness (CRF) is a well-established risk factor for all-cause and cardiovascular disease mortality. African Americans have higher rates of cardiovascular disease compared to their Caucasian counterparts. However, the extent to which lower CRF levels contribute to the excess risk in African Americans has not been fully explored. The purpose of this review is to: 1) explore the literature evaluating the relationship between CRF and mortality specifically in African American populations; and 2) critically evaluate the studies which have compared CRF between African American and Caucasians in epidemiological studies and clinical trials. We have further discussed several potential mechanisms that may contribute to the observation of lower CRF levels in African American compared to Caucasian adults including potential racial differences in physical activity levels, muscle fiber type distribution, and hemoglobin levels. If lower CRF is generally present in African Americans compared to Caucasians, and is of a clinically meaningful difference, this may represent an important public health concern. PMID:23982718

Characterization of a New HIV-1 CRF01_AE/ CRF07_BC recombinant virus in Tianjin, China.

PubMed

Zhou, Zhehua; Ma, Ping; Feng, Yi; Ou, Weidong; Qian, Jing; Gao, Liying; Zhang, Defa; Shao, Yiming; Wei, Min

2018-05-04

Human immunodeficiency virus (HIV) is notorious for its rapid evolving since its transmissions from money to human. Currently, HIV contains multiple subtypes, circulating recombinant forms (CRFs) and unique recombinant forms (URFs). Here, from an HIV-positive mother and her child in Tianjin, China, we identified a novel HIV-1 second-generation recombinant virus (TJ20170316 and TJ20170317) between CRF01_AE and CRF07_BC. Near full-length genomes were obtained from both samples, and they shared very close sequences, except some point mutations. Phylogenetic analyses of the near full-length genomes showed that they consist of CRF01_AE backbone and part CRF07_BC sequences. Recombinant Identification Program (RIP) and Simplot software identified four breakpoints in gag, pol, vif, tat genes in TJ20170316, totally different from other reported CRFs and URFs. The emergence of such URF in Tianjin, China, highlights the complexity of HIV-1 epidemic and more measures should be taken to prevent HIV transmissions.

Chronic social stress in pigs impairs intestinal barrier and nutrient transporter function, and alters neuro-immune mediator and receptor expression

PubMed Central

Li, Yihang; Song, Zehe; Kerr, Katelyn A.; Moeser, Adam J.

2017-01-01

Psychosocial stress is a major factor driving gastrointestinal (GI) pathophysiology and disease susceptibility in humans and animals. The mechanisms governing susceptibility to stress-induced GI disease remain poorly understood. In the present study, we investigated the influence of chronic social stress (CSS) in pigs, induced by 7 d of chronic mixing/crowding stress, on intestinal barrier and nutrient transport function, corticotropin releasing factor (CRF) signaling and immunological responses. Results from this study showed that CSS resulted in a significant impairment of ileal and colonic barrier function indicated by reduced transepithelial electrical resistance (TER) in the ileum and increased FD4 flux in the ileum (by 0.8 fold) and colon (by 0.7 fold). Ileal sodium glucose linked transporter 1 (SGLT-1) function, measured as glucose-induced changes in short-circuit current (Isc), was diminished (by 52%) in CSS pigs, associated with reduced body weight gain and feed efficiency. Although reductions in SGLT-1 function were observed in CSS pigs, mRNA expression for SGLT-1, villus heights were increased in CSS pigs. Corticotropin releasing factor (CRF) mRNA was upregulated (by 0.9 fold) in the ileum of CSS pigs but not in the colon. Urocortin 2 (Ucn2) mRNA was upregulated (by 1.5 fold) in the colon of CSS pigs, but not in the ileum. In CSS pigs, a downregulation of pro-inflammatory cytokines mRNA (IL1B, TNFA, IL8, and IL6) was observed in both ileum and colon, compared with controls. In contrast CSS induced a marked upregulation of mRNA for IL10 and mast cell chymase gene (CMA1) in the ileum and colon. Together, these data demonstrate that chronic stress in pigs results in significant alterations in intestinal barrier and nutrient transport function and neuro-immune mediator and receptor expression. PMID:28170426

Effect of the Capsicoside G-rich Fraction from Pepper (Capsicum annuum L.) Seeds on High-fat Diet-induced Obesity in Mice.

PubMed

Sung, Jeehye; Jeong, Heon Sang; Lee, Junsoo

2016-11-01

Obesity is one of the most common metabolic syndromes and is a major threat to human health worldwide. Given the size of this problem, there is growing interest in natural agents that may decrease obesity. In this study, we investigated the anti-obesity effect of a capsicoside G-rich fraction (CRF; 13.35% capsicoside G) isolated from pepper seeds in diet-induced obese mice. C57BL/6J mice were fed either a normal diet or a high-fat diet (HFD), with or without CRF (HFD + CRF; 10 and 100 mg/kg body weight). The body weight and food efficiency ratio of mice fed HFD + CRF were lower in comparison to that of mice fed only an HFD. Epididymal adipose tissue weight and adipocyte hypertrophy were significantly lower in HFD + CRF mice than in HFD mice. The fat deposition in the liver of mice fed HFD + CRF was lower compared to that of mice fed only an HFD. CRF significantly reversed the HFD-induced elevation of the expression of key adipocyte differentiation regulators, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, sterol regulatory element binding protein 1c, and their target genes. These results suggest that CRF could be used as dietary therapy for the prevention of obesity and obesity-related metabolic diseases. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of a Physical Activity Program on Cardiorespiratory Fitness and Pulmonary Function in Obese Women after Bariatric Surgery: a Pilot Study.

PubMed

Onofre, Tatiana; Carlos, Renata; Oliver, Nicole; Felismino, Amanda; Fialho, Davi; Corte, Renata; da Silva, Eliane Pereira; Godoy, Eudes; Bruno, Selma

2017-08-01

In severely obese individuals, reducing body weight induced by bariatric surgery is able to promote a reduction in comorbidities and improve respiratory symptoms. However, cardiorespiratory fitness (CRF) reflected by peak oxygen uptake (VO 2peak ) may not improve in individuals who remain sedentary post-surgery. The objective of this study was to evaluate the effects of a physical training program on CRF and pulmonary function in obese women after bariatric surgery, and to compare them to a control group. Twelve obese female candidates for bariatric surgery were evaluated in the preoperative, 3 months postoperative (3MPO), and 6 months postoperative (6MPO) periods through anthropometry, spirometry, and cardiopulmonary exercise testing (CPX). In the 3MPO period, patients were divided into control group (CG, n = 6) and intervention group (IG, n = 6). CG received only general guidelines while IG underwent a structured and supervised physical training program involving aerobic and resistance exercises, lasting 12 weeks. All patients had a significant reduction in anthropometric measurements and an increase in lung function after surgery, with no difference between groups. However, only IG presented a significant increase (p < 0.05) in VO 2peak and total CPX duration of 5.9 mL/kg/min (23.8%) and 4.9 min (42.9%), respectively. Applying a physical training program to a group of obese women after 3 months of bariatric surgery could promote a significant increase in CRF only in the trained group, yet also showing that bariatric surgery alone caused an improvement in the lung function of both groups.

Stress-Induced Transcriptional Regulation in the Developing Rat Brain Involves Increased Cyclic Adenosine 3′,5′-Monophosphate-Regulatory Element Binding Activity

PubMed Central

Hatalski, Carolyn G.; Baram, Tallie Z.

2012-01-01

The cAMP-regulatory element (CRE) binding protein (CREB) functions as a trans-acting regulator of genes containing the CRE sequence in their promoter. These include a number of critical genes, such as CRF, involved in the hypothalamic response to stressful stimuli in the adult. The ability of the developing rat (during the first 2 postnatal weeks) to mount the full complement of this stress response has been questioned. We have previously demonstrated the stress-induced up-regulation of the transcription of hypothalamic CRF during the second postnatal week in the rat. The focus of the current study was to explore the mechanism of transcriptional regulation in response to stress through the physiological induction of transcriptional trans-activators that bind to the CRE in the developing rat brain. CRE-binding activity was detected via gel shift analysis in extracts from both the hypothalamus and the cerebral cortex of the developing rat. CREB was identified in these extracts by Western blot analysis and was shown to be the major contributor to the CRE-binding activity by gel shift analysis with two specific antibodies directed against CREB. After acute hypothermic stress, the abundance of CRE-binding activity (but not of total immunoreactive CREB), increased in hypothalamic extracts. This enhanced CRE-binding activity was blocked by an antiserum directed against CREB and was accompanied by an apparent increase in CREB phosphorylation. These results indicate that posttranslational enhancement of CRE-binding activity is likely to constitute an important mechanism for up-regulation of genes possessing the CRE sequence in the developing rat hypothalamus by adverse external signals. PMID:9415405

Stress-induced suppression of neuropeptide Y-induced hunger in anorexic chicks involves corticotrophin-releasing factor signalling and the paraventricular nucleus of the hypothalamus.

PubMed

Wang, J; Yi, J; Siegel, P B; Cline, M A; Gilbert, E R

2017-12-01

The Virginia lines of chickens have been selected for low (LWS) or high (HWS) juvenile body weight and have different severities of anorexia and obesity, respectively. The LWS that are exposed to stressors at hatch are refractory to neuropeptide Y (NPY)-induced food intake and the objective of the present study was to determine the underlying mechanisms. Chicks were exposed to a stressor (-20°C for 6 minutes and 22°C and delayed access to food for 24 hours) after hatching and the hypothalamic nuclei, including the lateral hypothalamus (LH), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and arcuate nucleus (ARC), were collected 5 days later. In LWS but not HWS, stress exposure up-regulated corticotrophin-releasing factor (CRF), CRF receptor subtypes 1 and 2 (CRFR1 and CRFR2, respectively), melanocortin receptor 4 and urocortin 3 in the PVN, as well as CRFR2 mRNA in the VMH and ARC. In LWS, stress exposure was also associated with greater NPY and NPY receptor subtype 5 mRNA in the ARC and PVN, respectively, as well as decreased agouti-related peptide mRNA in the ARC. In HWS, stress exposure was associated with increased CRFR1 and decreased cocaine- and amphetamine-regulated transcript in the ARC and PVN, respectively. Refractoriness of the food intake response to NPY in LWS may thus result from the over-riding anorexigenic tone in the PVN associated with CRF signalling. Indeed, the orexigenic effect of NPY was restored when LWS were injected with a CRF receptor antagonist, astressin, before stress exposure. The results of the present study provide insights into the molecular basis of eating disorders and suggest that CRF signalling in the PVN may exacerbate the anorexic phenotype in the presence of environmental stressors. © 2017 British Society for Neuroendocrinology.

Advanced glycation end products in children with chronic renal failure and type 1 diabetes.

PubMed

Misselwitz, Joachim; Franke, Sybille; Kauf, Eberhard; John, Ulrike; Stein, Günter

2002-05-01

Serum levels of advanced glycation end products (AGEs) are markedly elevated in adults with chronic renal failure (CRF) and diabetes mellitus. Accumulation of AGEs in tissues contributes to the development of long-term complications. Up to now little has been known about the formation of AGEs in childhood. We determined serum levels of the well known AGEs pentosidine and Nvarepsilon-carboxymethyllysine (CML) in children with CRF (n=12), end-stage renal disease (ESRD) (n=9), renal transplantation (n=12), and type 1 diabetes mellitus (n=42) and in healthy children (n=20). Pentosidine was measured by high-performance liquid chromatography (HPLC), CML by a competitive enzyme-linked immunosorbent assay (ELISA) system. Serum levels of pentosidine and CML were significantly higher in the children with CRF and ESRD than in controls (P< 0.001), but nearly within the normal range after transplantation. Both AGEs showed a significant negative correlation with creatinine clearance (P< 0.001). During a single session of low-flux hemodialysis, total pentosidine and CML levels did not change. Free pentosidine, however, was reduced by 78% (P=0.04). Diabetic children showed significantly elevated pentosidine levels (P< 0.001) despite normal renal function. We conclude that, similar to adults, increased formation and accumulation of AGEs also exist in children with CRF and type 1 diabetes mellitus. At present the best prevention of AGE-related complications is an early renal transplantation in children with ESRD, as well as a careful metabolic monitoring of diabetics.

Appearance of Drug Resistance-Associated Mutations in Human Immunodeficiency Virus Type 1 CRF01_AE Integrase Derived from Drug-Naive Thai Patients.

PubMed

Isarangkura-Na-Ayuthaya, Panasda; Kaewnoo, Wiyada; Auwanit, Wattana; de Silva, U Chandimal; Ikuta, Kazuyoshi; Sawanpanyalert, Pathom; Kameoka, Masanori

2010-12-01

CRF01_AE is a major subtype of human immunodeficiency virus type 1 (HIV-1) circulating in Southeast Asia, including Thailand. We performed genotypic studies on HIV-1 CRF01_AE integrase derived from plasma samples from drug-naive Thai patients. Direct sequencing of amplified CRF01_AE integrase genes revealed that although no primary mutations associated with drug resistance to integrase inhibitors were detected, at least one secondary mutation was found in 96% of samples. Our results indicate that the impact of these mutations on the baseline drug susceptibility of CRF01_AE viruses to integrase inhibitors may need to be addressed prior to the introduction of these drugs in Southeast Asian countries, including Thailand.

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

PubMed

Marcinkiewcz, Catherine A; Mazzone, Christopher M; D'Agostino, Giuseppe; Halladay, Lindsay R; Hardaway, J Andrew; DiBerto, Jeffrey F; Navarro, Montserrat; Burnham, Nathan; Cristiano, Claudia; Dorrier, Cayce E; Tipton, Gregory J; Ramakrishnan, Charu; Kozicz, Tamas; Deisseroth, Karl; Thiele, Todd E; McElligott, Zoe A; Holmes, Andrew; Heisler, Lora K; Kash, Thomas L

2016-09-01

Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT DRN ) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF BNST ) in mice. Specifically, 5-HT DRN projections to the BNST, via actions at 5-HT 2C receptors (5-HT 2C Rs), engage a CRF BNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF BNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF 1 R, also known as CRHR1), given that CRF 1 R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT DRN →CRF BNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.

Trends of HIV-1 Subtypes Among Young People in Hangzhou, China.

PubMed

Zhang, Wenjun; Chen, Junfang; Pan, Xiaohong; Zhang, Jiafeng; Guo, Zhihong; Luo, Yan; Yang, Jiezhe; Xia, Yan; He, Lin; Xu, Yun; Xu, Ke; Ding, Xiaobei

2017-03-01

To investigate the HIV-1 molecular epidemiology among young people (18 to 25 years old) in Hangzhou. Plasma samples from 262 newly diagnosed HIV-1-infected patients were collected between 2009 and 2013 from Hangzhou of Zhejiang province. HIV-1 nucleotide sequences of pol gene regions were amplified using a nested polymerase chain reaction method and sequenced. Phylogenetic and recombination analyses were used to determine the HIV-1 genotypes. Based on all sequences generated, the subtype/circulating recombinant forms (CRFs) distribution was as follows: CRF01_AE (68.70%), CRF07_BC (21.54%), subtype B (3.66%), CRF08_BC (2.44%), 01B (2.03%), BC (0.81%), and C (0.41%). We found that the percentage of CRF07_BC was increasing year by year among young people in Hangzhou. Novel CRFs such as CRF67_01B (HZ2011-15 CD4-4516) and CRF68_01B (HZ2011-20 CD4-4530 and HZ2011-29 CD4-4087) were first discovered in the area in this study. Our study presents a molecular epidemiology investigation describing the structure of HIV-1 strains cocirculating in young people in Hangzhou. Increasing CRF07_BC and new CRFs popular in young people are a challenge for future prevention in Hangzhou.

Evaluation of nasal mucociliary activity in patients with chronic renal failure.

PubMed

Kucur, Cuneyt; Ozbay, Isa; Gulcan, Erim; Kulekci, Semra; Aksoy, Sinan; Oghan, Fatih

2016-05-01

The ability of respiratory mucosal surfaces to eliminate foreign particles and pathogens and to keep mucosal surfaces moist and fresh depends on mucociliary activity. Chronic renal failure (CRF) is an irreversible medical condition that may result in important extrarenal systemic consequences, such as cardiovascular, metabolic, and respiratory system abnormalities. Although there are studies describing nasal manifestations of CRF, data are lacking concerning the effects of the condition on nasal mucosa. The goal of the current study was to evaluate nasal mucociliary clearance (NMC) time in patients with CRF. This prospective cohort study conducted in a tertiary referral center included 32 non-diabetic end-stage CRF patients and 30 control individuals. The control group consisted of voluntary participants who had been referred to our clinic for symptoms other than rhinological diseases. The mean NMC times in CRF patients and control individuals were 12.51 ± 3.74 min (range 7-22 min) and 8.97 ± 1.83 min (range 6-13 min), respectively. The mean NMC time in patients with CRF was significantly longer than that in control individuals (p < 0.001). Clinicians must keep in mind that NMC time in CRF patients is prolonged and must follow-up these patients more closely for sinonasal and middle ear infections.

Why are some people more fit than others? Correlates and determinants of cardiorespiratory fitness in adults: protocol for a systematic review.

PubMed

Perumal, Nita; Mensink, Gert B M; Keil, Thomas; Finger, Jonas David

2017-05-18

Cardiorespiratory fitness (CRF) is a physical condition that is now well established as a predictor of numerous adverse health outcomes, independent of physical activity levels. In order to be able to improve CRF at the population level and to develop effective interventions and public health programmes, it is important to understand why some people are more fit than others. Therefore, the primary aim of the systematic review described in this protocol is to examine individual and interpersonal factors that are correlated with or determine CRF among adults. The review will focus on quantitative studies that investigate any personal and interpersonal correlates and/or determinants of objectively measured CRF among the general, non-symptomatic, non-institutionalized adult population (aged 18-65 years) worldwide. The databases MEDLINE, Embase, and Cochrane Library will be searched to identify all relevant published journal articles, and Google Scholar and Scopus will be searched for grey literature. Studies where CRF is not an outcome variable and experimental studies where participants specifically receive a fitness intervention that increases CRF will be excluded. For each study, data extracted will include, among other variables, study characteristics, methodology for selecting participants into the study as well as the participants' demographic characteristics, types of correlates and determinants of CRF investigated and their measurement methods, the objective measure of CRF used and its measurement method and validity, and the main reported results on the association between the correlates or determinants and CRF. In addition, observational studies will be assessed for methodological quality and risk of bias using a customized version of the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies by the National Heart, Lung, and Blood Institute. Experimental studies will be assessed using the 27-item Downs and Black "Checklist for Measuring Study Quality". The final results will be presented as a narrative synthesis of the main findings of all included studies. By consolidating and synthesizing the current research on possible individual and interpersonal correlates and determinants of CRF among adults worldwide, we aim to aid future public health actions, as well as identify gaps in our full understanding of what influences CRF. PROSPERO CRD42017055456 .

Role of 11beta-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure.

PubMed

Yeyati, N L; Altuna, M E; Damasco, M C; Mac Laughlin, M A

2010-01-01

Aldosterone concentrations vary in advanced chronic renal failure (CRF). The isozyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), which confers aldosterone specificity for mineralocorticoid receptors in distal tubules and collecting ducts, has been reported to be decreased or normal in patients with renal diseases. Our objective was to determine the role of aldosterone and 11beta-HSD2 renal microsome activity, normalized for glomerular filtration rate (GFR), in maintaining K+ homeostasis in 5/6 nephrectomized rats. Male Wistar rats weighing 180-220 g at the beginning of the study were used. Rats with experimental CRF obtained by 5/6 nephrectomy (N = 9) and sham rats (N = 10) were maintained for 4 months. Systolic blood pressure and plasma creatinine (Pcr) concentration were measured at the end of the experiment. Sodium and potassium excretion and GFR were evaluated before and after spironolactone administration (10 mg.kg-1.day-1 for 7 days) and 11beta-HSD2 activity on renal microsomes was determined. Systolic blood pressure (means +/- SEM; Sham = 105 +/- 8 and CRF = 149 +/- 10 mmHg) and Pcr (Sham = 0.42 +/- 0.03 and CRF = 2.53 +/- 0.26 mg/dL) were higher (P < 0.05) while GFR (Sham = 1.46 +/- 0.26 and CRF = 0.61 +/- 0.06 mL/min) was lower (P < 0.05) in CRF, and plasma aldosterone (Pald) was the same in the two groups. Urinary sodium and potassium excretion was similar in the two groups under basal conditions but, after spironolactone treatment, only potassium excretion was decreased in CRF rats (sham = 0.95 +/- 0.090 (before) vs 0.89 +/- 0.09 microEq/min (after) and CRF = 1.05 +/- 0.05 (before) vs 0.37 +/- 0.07 microEq/min (after); P < 0.05). 11beta-HSD2 activity on renal microsomes was lower in CRF rats (sham = 0.807 +/- 0.09 and CRF = 0.217 +/- 0.07 nmol.min-1.mg protein-1; P < 0.05), although when normalized for mL GFR it was similar in both groups. We conclude that K+ homeostasis is maintained during CRF development despite normal Pald levels. This adaptation may be mediated by renal 11beta-HSD2 activity, which, when normalized for GFR, became similar to that of control rats, suggesting that mineralocorticoid receptors maintain their aldosterone selectivity.

Early diagnosis of diabetic vascular complications: impairment of red blood cell deformability

NASA Astrophysics Data System (ADS)

Shin, Sehyun; Ku, Yunhee; Park, Cheol-Woo; Suh, Jang-Soo

2006-02-01

Reduced deformability of red blood cells (RBCs) may play an important role on the pathogenesis of chronic vascular complications of diabetes mellitus. However, available techniques for measuring RBC deformability often require washing process after each measurement, which is not optimal for day-to-day clinical use at point of care. The objectives of the present study are to develop a device and to delineate the correlation of impaired RBC deformability with diabetic nephropathy. We developed a disposable ektacytometry to measure RBC deformability, which adopted a laser diffraction technique and slit rheometry. The essential features of this design are its simplicity (ease of operation and no moving parts) and a disposable element which is in contact with the blood sample. We studied adult diabetic patients divided into three groups according to diabetic complications. Group I comprised 57 diabetic patients with normal renal function. Group II comprised 26 diabetic patients with chronic renal failure (CRF). Group III consisted of 30 diabetic subjects with end-stage renal disease (ESRD) on hemodialysis. According to the renal function for the diabetic groups, matched non-diabetic groups were served as control. We found substantially impaired red blood cell deformability in those with normal renal function (group I) compared to non-diabetic control (P = 0.0005). As renal function decreases, an increased impairment in RBC deformability was found. Diabetic patients with chronic renal failure (group II) when compared to non-diabetic controls (CRF) had an apparently greater impairment in RBC deformability (P = 0.07). The non-diabetic cohort (CRF), on the other hand, manifested significant impairment in red blood cell deformability compared to healthy control (P = 0.0001). The newly developed slit ektacytometer can measure the RBC deformability with ease and accuracy. In addition, progressive impairment in cell deformability is associated with renal function loss in all patients regardless of the presence or absence of diabetes. In diabetic patients, early impairment in RBC deformability appears in patients with normal renal function.

Spatio-Temporal History of HIV-1 CRF35_AD in Afghanistan and Iran.

PubMed

Eybpoosh, Sana; Bahrampour, Abbas; Karamouzian, Mohammad; Azadmanesh, Kayhan; Jahanbakhsh, Fatemeh; Mostafavi, Ehsan; Zolala, Farzaneh; Haghdoost, Ali Akbar

2016-01-01

HIV-1 Circulating Recombinant Form 35_AD (CRF35_AD) has an important position in the epidemiological profile of Afghanistan and Iran. Despite the presence of this clade in Afghanistan and Iran for over a decade, our understanding of its origin and dissemination patterns is limited. In this study, we performed a Bayesian phylogeographic analysis to reconstruct the spatio-temporal dispersion pattern of this clade using eligible CRF35_AD gag and pol sequences available in the Los Alamos HIV database (432 sequences available from Iran, 16 sequences available from Afghanistan, and a single CRF35_AD-like pol sequence available from USA). Bayesian Markov Chain Monte Carlo algorithm was implemented in BEAST v1.8.1. Between-country dispersion rates were tested with Bayesian stochastic search variable selection method and were considered significant where Bayes factor values were greater than three. The findings suggested that CRF35_AD sequences were genetically similar to parental sequences from Kenya and Uganda, and to a set of subtype A1 sequences available from Afghan refugees living in Pakistan. Our results also showed that across all phylogenies, Afghan and Iranian CRF35_AD sequences formed a monophyletic cluster (posterior clade credibility> 0.7). The divergence date of this cluster was estimated to be between 1990 and 1992. Within this cluster, a bidirectional dispersion of the virus was observed across Afghanistan and Iran. We could not clearly identify if Afghanistan or Iran first established or received this epidemic, as the root location of this cluster could not be robustly estimated. Three CRF35_AD sequences from Afghan refugees living in Pakistan nested among Afghan and Iranian CRF35_AD branches. However, the CRF35_AD-like sequence available from USA diverged independently from Kenyan subtype A1 sequences, suggesting it not to be a true CRF35_AD lineage. Potential factors contributing to viral exchange between Afghanistan and Iran could be injection drug networks and mass migration of Afghan refugees and labours to Iran, which calls for extensive preventive efforts.

Cross-Border Sexual Transmission of the Newly Emerging HIV-1 Clade CRF51_01B

PubMed Central

Cheong, Hui Ting; Ng, Kim Tien; Ong, Lai Yee; Chook, Jack Bee; Chan, Kok Gan; Takebe, Yutaka; Kamarulzaman, Adeeba; Tee, Kok Keng

2014-01-01

A novel HIV-1 recombinant clade (CRF51_01B) was recently identified among men who have sex with men (MSM) in Singapore. As cases of sexually transmitted HIV-1 infection increase concurrently in two socioeconomically intimate countries such as Malaysia and Singapore, cross transmission of HIV-1 between said countries is highly probable. In order to investigate the timeline for the emergence of HIV-1 CRF51_01B in Singapore and its possible introduction into Malaysia, 595 HIV-positive subjects recruited in Kuala Lumpur from 2008 to 2012 were screened. Phylogenetic relationship of 485 amplified polymerase gene sequences was determined through neighbour-joining method. Next, near-full length sequences were amplified for genomic sequences inferred to be CRF51_01B and subjected to further analysis implemented through Bayesian Markov chain Monte Carlo (MCMC) sampling and maximum likelihood methods. Based on the near full length genomes, two isolates formed a phylogenetic cluster with CRF51_01B sequences of Singapore origin, sharing identical recombination structure. Spatial and temporal information from Bayesian MCMC coalescent and maximum likelihood analysis of the protease, gp120 and gp41 genes suggest that Singapore is probably the country of origin of CRF51_01B (as early as in the mid-1990s) and featured a Malaysian who acquired the infection through heterosexual contact as host for its ancestral lineages. CRF51_01B then spread rapidly among the MSM in Singapore and Malaysia. Although the importation of CRF51_01B from Singapore to Malaysia is supported by coalescence analysis, the narrow timeframe of the transmission event indicates a closely linked epidemic. Discrepancies in the estimated divergence times suggest that CRF51_01B may have arisen through multiple recombination events from more than one parental lineage. We report the cross transmission of a novel CRF51_01B lineage between countries that involved different sexual risk groups. Understanding the cross-border transmission of HIV-1 involving sexual networks is crucial for effective intervention strategies in the region. PMID:25340817

Spatio-Temporal History of HIV-1 CRF35_AD in Afghanistan and Iran

PubMed Central

Eybpoosh, Sana; Bahrampour, Abbas; Karamouzian, Mohammad; Azadmanesh, Kayhan; Jahanbakhsh, Fatemeh; Mostafavi, Ehsan; Zolala, Farzaneh; Haghdoost, Ali Akbar

2016-01-01

HIV-1 Circulating Recombinant Form 35_AD (CRF35_AD) has an important position in the epidemiological profile of Afghanistan and Iran. Despite the presence of this clade in Afghanistan and Iran for over a decade, our understanding of its origin and dissemination patterns is limited. In this study, we performed a Bayesian phylogeographic analysis to reconstruct the spatio-temporal dispersion pattern of this clade using eligible CRF35_AD gag and pol sequences available in the Los Alamos HIV database (432 sequences available from Iran, 16 sequences available from Afghanistan, and a single CRF35_AD-like pol sequence available from USA). Bayesian Markov Chain Monte Carlo algorithm was implemented in BEAST v1.8.1. Between-country dispersion rates were tested with Bayesian stochastic search variable selection method and were considered significant where Bayes factor values were greater than three. The findings suggested that CRF35_AD sequences were genetically similar to parental sequences from Kenya and Uganda, and to a set of subtype A1 sequences available from Afghan refugees living in Pakistan. Our results also showed that across all phylogenies, Afghan and Iranian CRF35_AD sequences formed a monophyletic cluster (posterior clade credibility> 0.7). The divergence date of this cluster was estimated to be between 1990 and 1992. Within this cluster, a bidirectional dispersion of the virus was observed across Afghanistan and Iran. We could not clearly identify if Afghanistan or Iran first established or received this epidemic, as the root location of this cluster could not be robustly estimated. Three CRF35_AD sequences from Afghan refugees living in Pakistan nested among Afghan and Iranian CRF35_AD branches. However, the CRF35_AD-like sequence available from USA diverged independently from Kenyan subtype A1 sequences, suggesting it not to be a true CRF35_AD lineage. Potential factors contributing to viral exchange between Afghanistan and Iran could be injection drug networks and mass migration of Afghan refugees and labours to Iran, which calls for extensive preventive efforts. PMID:27280293

Physical fitness and performance. Cardiorespiratory fitness in girls-change from middle to high school.

PubMed

Pfeiffer, Karin A; Dowda, Marsha; Dishman, Rod K; Sirard, John R; Pate, Russell R

2007-12-01

To determine how factors are related to change in cardiorespiratory fitness (CRF) across time in middle school girls followed through high school. Adolescent girls (N = 274, 59% African American, baseline age = 13.6 +/- 0.6 yr) performed a submaximal fitness test (PWC170) in 8th, 9th, and 12th grades. Height, weight, sports participation, and physical activity were also measured. Moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA) were determined by the number of blocks reported on the 3-Day Physical Activity Recall (3DPAR). Individual differences and developmental change in CRF were assessed simultaneously by calculating individual growth curves for each participant, using growth curve modeling. Both weight-relative and absolute CRF increased from 8th to 9th grade and decreased from 9th to 12th grade. On average, girls lost 0.16 kg.m.min.kg.yr in weight-relative PWC170 scores (P < 0.01) and gained 10.3 kg.m.min.yr in absolute PWC170 scores. Girls reporting two or more blocks of MVPA or one or more blocks of VPA at baseline showed an average increase in PWC170 scores of 0.40-0.52 kg.m.min.kg.yr (weight relative) and 22-28 kg.m.min.yr (absolute) in CRF. In weight-relative models, girls with higher BMI showed lower CRF (approximately 0.37 g.m.min.kg.yr), but this was not shown in absolute models. In absolute models, white girls (approximately 40 kg.m.min.yr) and sport participants (approximately 28 kg.m.min.yr) showed an increase in CRF over time. Although there were fluctuations in PWC170 scores across time, average scores decreased during 4 yr. Physical activity was related to change in CRF over time; BMI, race, and sport participation were also important factors related to change over time in CRF (depending on expression of CRF-weight-relative vs absolute). Subsequent research should focus on explaining the complex longitudinal interactions between CRF, physical activity, race, BMI, and sports participation.

The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice.

PubMed

Valero, E; Gómez-Milanés, I; Almela, P; Ribeiro Do Couto, B; Laorden, M L; Milanés, M V; Núñez, C

2018-06-08

Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories. Copyright © 2018 Elsevier Inc. All rights reserved.

Cross-border sexual transmission of the newly emerging HIV-1 clade CRF51_01B.

PubMed

Cheong, Hui Ting; Ng, Kim Tien; Ong, Lai Yee; Chook, Jack Bee; Chan, Kok Gan; Takebe, Yutaka; Kamarulzaman, Adeeba; Tee, Kok Keng

2014-01-01

A novel HIV-1 recombinant clade (CRF51_01B) was recently identified among men who have sex with men (MSM) in Singapore. As cases of sexually transmitted HIV-1 infection increase concurrently in two socioeconomically intimate countries such as Malaysia and Singapore, cross transmission of HIV-1 between said countries is highly probable. In order to investigate the timeline for the emergence of HIV-1 CRF51_01B in Singapore and its possible introduction into Malaysia, 595 HIV-positive subjects recruited in Kuala Lumpur from 2008 to 2012 were screened. Phylogenetic relationship of 485 amplified polymerase gene sequences was determined through neighbour-joining method. Next, near-full length sequences were amplified for genomic sequences inferred to be CRF51_01B and subjected to further analysis implemented through Bayesian Markov chain Monte Carlo (MCMC) sampling and maximum likelihood methods. Based on the near full length genomes, two isolates formed a phylogenetic cluster with CRF51_01B sequences of Singapore origin, sharing identical recombination structure. Spatial and temporal information from Bayesian MCMC coalescent and maximum likelihood analysis of the protease, gp120 and gp41 genes suggest that Singapore is probably the country of origin of CRF51_01B (as early as in the mid-1990s) and featured a Malaysian who acquired the infection through heterosexual contact as host for its ancestral lineages. CRF51_01B then spread rapidly among the MSM in Singapore and Malaysia. Although the importation of CRF51_01B from Singapore to Malaysia is supported by coalescence analysis, the narrow timeframe of the transmission event indicates a closely linked epidemic. Discrepancies in the estimated divergence times suggest that CRF51_01B may have arisen through multiple recombination events from more than one parental lineage. We report the cross transmission of a novel CRF51_01B lineage between countries that involved different sexual risk groups. Understanding the cross-border transmission of HIV-1 involving sexual networks is crucial for effective intervention strategies in the region.

Molecular Epidemiology of HIV-1 in Jilin Province, Northeastern China: Emergence of a New CRF07_BC Transmission Cluster and Intersubtype Recombinants

PubMed Central

Ning, Chuanyi; Feng, Yi; Xie, Cunxin; He, Xiang; Takebe, Yutaka; Sun, Liuyan; Guo, Qi; Xing, Hui; Kalish, Marcia L.; Shao, Yiming

2014-01-01

Objective To investigate the HIV-1 molecular epidemiology among newly diagnosed HIV-1 infected persons living in the Jilin province of northeastern China. Methods Plasma samples from 189 newly diagnosed HIV-1 infected patients were collected between June 2010 and August 2011 from all nine cities of Jilin province. HIV-1 nucleotide sequences of gag P17–P24 and env C2–C4 gene regions were amplified using a multiplex RT-PCR method and sequenced. Phylogenetic and recombination analyses were used to determine the HIV-1 genotypes. Results Based on all sequences generated, the subtype/CFR distribution was as follows: CRF01_AE (58.1%), CRF07_BC (13.2%), subtype B’ (13.2%), recombinant viruses (8.1%), subtype B (3.7%), CRF02_AG (2.9%), subtype C (0.7%). In addition to finding CRF01_AE strains from previously reported transmission clusters 1, 4 and 5, a new transmission cluster was described within the CRF07_BC radiation. Among 11 different recombinants identified, 10 contained portions of gene regions from the CRF01_AE lineage. CRF02_AG was found to form a transmission cluster of 4 in local Jilin residents. Conclusions Our study presents a molecular epidemiologic investigation describing the complex structure of HIV-1 strains co-circulating in Jilin province. The results highlight the critical importance of continuous monitoring of HIV-infections, along with detailed socio-demographic data, in order to design appropriate prevention measures to limit the spread of new HIV infections. PMID:25356726

The biology of cancer-related fatigue: a review of the literature.

PubMed

Saligan, Leorey N; Olson, Karin; Filler, Kristin; Larkin, David; Cramp, Fiona; Yennurajalingam, Sriram; Sriram, Yennu; Escalante, Carmen P; del Giglio, Auro; Kober, Kord M; Kamath, Jayesh; Palesh, Oxana; Mustian, Karen

2015-08-01

Understanding the etiology of cancer-related fatigue (CRF) is critical to identify targets to develop therapies to reduce CRF burden. The goal of this systematic review was to expand on the initial work by the National Cancer Institute CRF Working Group to understand the state of the science related to the biology of CRF and, specifically, to evaluate studies that examined the relationships between biomarkers and CRF and to develop an etiologic model of CRF to guide researchers on pathways to explore or therapeutic targets to investigate. This review was completed by the Multinational Association of Supportive Care in Cancer Fatigue Study Group-Biomarker Working Group. The initial search used three terms (biomarkers, fatigue, cancer), which yielded 11,129 articles. After removing duplicates, 9145 articles remained. Titles were assessed for the keywords "cancer" and "fatigue" resulting in 3811 articles. Articles published before 2010 and those with samples <50 were excluded, leaving 75 articles for full-text review. Of the 75 articles, 28 were further excluded for not investigating the associations of biomarkers and CRF. Of the 47 articles reviewed, 25 were cross-sectional and 22 were longitudinal studies. More than half (about 70 %) were published recently (2010-2013). Almost half (45 %) enrolled breast cancer participants. The majority of studies assessed fatigue using self-report questionnaires, and only two studies used clinical parameters to measure fatigue. The findings from this review suggest that CRF is linked to immune/inflammatory, metabolic, neuroendocrine, and genetic biomarkers. We also identified gaps in knowledge and made recommendations for future research.

Reference Values for Cardiorespiratory Fitness and Incidence of Type 2 Diabetes

PubMed Central

Kawakami, Ryoko; Sawada, Susumu S.; Matsushita, Munehiro; Okamoto, Takashi; Tsukamoto, Koji; Higuchi, Mitsuru; Miyachi, Motohiko

2014-01-01

Background In “Physical Activity Reference for Health Promotion 2013” the Japan Ministry of Health, Labour and Welfare publication gives reference values for cardiorespiratory fitness (CRF) required for good health. We examined the associations between the CRF reference values and incidence of type 2 diabetes. Methods This prospective cohort study enrolled 4633 nondiabetic Japanese men aged 20 to 39 years at baseline. CRF was measured using the cycle ergometer test, and maximal oxygen uptake was estimated. On the basis of the CRF reference value, participants were classified into 2 groups: those with values less than the reference value (under-RV) and those with values equal to or greater than reference value (over-RV). Hazard ratios (HRs) and 95% CIs for incident type 2 diabetes were estimated using a Cox proportional hazards model. Results A total of 266 participants developed type 2 diabetes during the 14 years of follow-up. As compared with the under-RV group, the over-RV group had a significantly lower multivariable-adjusted HR for type 2 diabetes (HR 0.67; 95% CI, 0.51–0.89). In receiver operating characteristic analysis, the optimal CRF cut-off value for predicting incident type 2 diabetes was 10.8 metabolic equivalents (sensitivity, 0.64; specificity, 0.64), which was close to the CRF reference value of 11.0 metabolic equivalents. Conclusions The reference CRF value appears to be reasonably valid for prevention of type 2 diabetes, especially among Japanese men younger than 40 years. Development of type 2 diabetes can be prevented by maintaining a CRF level above the reference value. PMID:24240630

ACTH releasing activity of KP-102 (GHRP-2) in rats is mediated mainly by release of CRF.

PubMed

Hirotani, Chiharu; Oki, Yutaka; Ukai, Kiyoharu; Okuno, Tadashi; Kurasaki, Shigeru; Ohyama, Tadashi; Doi, Naomi; Sasaki, Ken; Ase, Katsuhiko

2005-01-01

KP-102 (GHRP-2: pralmorelin) is a synthetic growth hormone releasing peptide (GHRP) that powerfully stimulates the release of GH by acting (i.v.) at both hypothalamic and pituitary sites. Intravenous (i.v.) administration of KP-102 also elicits slight but significant release of adrenocorticotropic hormone (ACTH) in both animals and humans, as is seen with other GHRPs. GHRPs are thought to stimulate the hypothalamic-pituitary-adrenal axis by releasing endogenous ACTH secretagogues such as arginine vasopressin (AVP) and/or corticotropin releasing factor (CRF), though neither AVP nor CRF has been shown clearly to be involved significantly in GHRP-evoked ACTH release. In the present study, we investigated the effects of KP-102 on ACTH release in conscious rats under improved experimental conditions that minimized the influence of stress. Administration of KP-102 i.v. increased plasma ACTH significantly, but did not stimulate ACTH release from rat primary pituitary cells. Administration of KP-102 together with either AVP or CRF elicited significantly greater increases in plasma ACTH levels than any of the agonists alone. Notably, the combination of KP-102 and AVP produced a much greater increase in ACTH than KP-102 plus CRF, indicating that KP-102 augments the effect of exogenous CRF only weakly. Conversely, a CRF antagonist markedly inhibited KP-102-induced ACTH release in conscious rats, whereas an AVP antagonist or anti-AVP antiserum did not. Taken together, these findings suggest that KP-102 acts via the hypothalamus to stimulate ACTH release in rats, and that these effects are mediated mainly by the release of CRF.

Substance use modulates stress reactivity: Behavioral and physiological outcomes.

PubMed

Fosnocht, Anne Q; Briand, Lisa A

2016-11-01

Drug addiction is a major public health concern in the United States costing taxpayers billions in health care costs, lost productivity and law enforcement. However, the availability of effective treatment options remains limited. The development of novel therapeutics will not be possible without a better understanding of the addicted brain. Studies in both clinical and preclinical models indicate that chronic drug use leads to alterations in the body and brain's response to stress. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may shed light on the ability of stress to increase vulnerability to relapse. Further, within both the HPA axis and limbic brain regions, corticotropin-releasing factor (CRF) is critically involved in the brain's response to stress. Alterations in both central and peripheral CRF activity seen following chronic drug use provide a mechanism by which substance use can alter stress reactivity, thus mediating addictive phenotypes. While many reviews have focused on how stress alters drug-mediated changes in physiology and behavior, the goal of this review is to focus on how substance use alters responses to stress. Copyright © 2016 Elsevier Inc. All rights reserved.

FMRI activity during associative encoding is correlated with cardiorespiratory fitness and source memory performance in older adults

PubMed Central

Hayes, Scott M.; Hayes, Jasmeet P.; Williams, Victoria J.; Liu, Huiting; Verfaellie, Mieke

2017-01-01

Older adults (OA), relative to young adults (YA), exhibit age-related alterations in functional Magnetic Resonance Imaging (fMRI) activity during associative encoding, which contributes to deficits in source memory. Yet, there are remarkable individual differences in brain health and memory performance among OA. Cardiorespiratory fitness (CRF) is one individual difference factor that may attenuate brain aging, and thereby contribute to enhanced source memory in OA. To examine this possibility, 26 OA and 31 YA completed a treadmill-based exercise test to evaluate CRF (peak VO2) and fMRI to examine brain activation during a face-name associative encoding task. Our results indicated that in OA, peak VO2 was positively associated with fMRI activity during associative encoding in multiple regions including bilateral prefrontal cortex, medial frontal cortex, bilateral thalamus and left hippocampus. Next, a conjunction analysis was conducted to assess whether CRF influenced age-related differences in fMRI activation. We classified OA as high or low CRF and compared their activation to YA. High fit OA (HFOA) showed fMRI activation more similar to YA than low fit OA (LFOA) (i.e., reduced age-related differences) in multiple regions including thalamus, posterior and prefrontal cortex. Conversely, in other regions, primarily in prefrontal cortex, HFOA, but not LFOA, demonstrated greater activation than YA (i.e., increased age-related differences). Further, fMRI activity in these brain regions was positively associated with source memory among OA, with a mediation model demonstrating that associative encoding activation in medial frontal cortex indirectly influenced the relationship between peak VO2 and subsequent source memory performance. These results indicate that CRF may contribute to neuroplasticity among OA, reducing age-related differences in some brain regions, consistent with the brain maintenance hypothesis, but accentuating age-differences in other regions, consistent with the brain compensation hypothesis. PMID:28161031

Differential Patterns of Impaired Cardiorespiratory Fitness and Cardiac Autonomic Dysfunction in Recently Diagnosed Type 1 and Type 2 Diabetes.

PubMed

Röhling, Martin; Strom, Alexander; Bönhof, Gidon; Püttgen, Sonja; Bódis, Kálmán; Müssig, Karsten; Szendrödi, Julia; Markgraf, Daniel; Lehr, Stefan; Roden, Michael; Ziegler, Dan

2017-02-01

Both impaired cardiorespiratory fitness (CRF) and heart rate variability (HRV) are predictors of mortality, but their relative roles in recent-onset diabetes are unknown. We determined to which extent CRF and HRV are reduced and interrelated in recent-onset diabetes. Participants from the German Diabetes Study with type 1 (n = 163) or type 2 (n = 188) diabetes with known diabetes duration <1 year and two age-matched glucose-tolerant control groups (n = 40 each) underwent spiroergometry and HRV assessment during a hyperinsulinemic-euglycemic clamp. Compared with control subjects, patients with type 2 diabetes showed reduced VO 2max (median [1st-3rd quartiles] 19.3 [16.5-22.9] vs. 25.6 [20.7-29.9] mL/kg body weight/min; P < 0.05), diminished VCO 2max (23.0 [19.1-26.8] vs. 30.9 [24.5-34.4] mL/kg body weight/min; P < 0.05), blunted heart rate recovery after 2 min (-29.0 [-35.0 to -23.0] vs. -36.0 [-42.8 to -28.0] beats/min; P < 0.05), and reduced HRV in four of nine indices, whereas patients with type 1 diabetes had unaltered CRF but reduced HRV in three of nine indices (P < 0.05), indicating diminished vagal and sympathetic HRV modulation. HRV measures correlated with VO 2max in patients with type 1 diabetes (r >0.34; P < 0.05) but not in those with type 2 diabetes. CRF is reduced in recently diagnosed type 2 diabetes but preserved in type 1 diabetes, whereas cardiac autonomic function is reduced in both diabetes types but is strongly associated with CRF only in type 1 diabetes. These results support the therapeutic concept of promoting physical fitness in the early course of diabetes. © 2017 by the American Diabetes Association.

FMRI activity during associative encoding is correlated with cardiorespiratory fitness and source memory performance in older adults.

PubMed

Hayes, Scott M; Hayes, Jasmeet P; Williams, Victoria J; Liu, Huiting; Verfaellie, Mieke

2017-06-01

Older adults (OA), relative to young adults (YA), exhibit age-related alterations in functional Magnetic Resonance Imaging (fMRI) activity during associative encoding, which contributes to deficits in source memory. Yet, there are remarkable individual differences in brain health and memory performance among OA. Cardiorespiratory fitness (CRF) is one individual difference factor that may attenuate brain aging, and thereby contribute to enhanced source memory in OA. To examine this possibility, 26 OA and 31 YA completed a treadmill-based exercise test to evaluate CRF (peak VO 2 ) and fMRI to examine brain activation during a face-name associative encoding task. Our results indicated that in OA, peak VO 2 was positively associated with fMRI activity during associative encoding in multiple regions including bilateral prefrontal cortex, medial frontal cortex, bilateral thalamus and left hippocampus. Next, a conjunction analysis was conducted to assess whether CRF influenced age-related differences in fMRI activation. We classified OA as high or low CRF and compared their activation to YA. High fit OA (HFOA) showed fMRI activation more similar to YA than low fit OA (LFOA) (i.e., reduced age-related differences) in multiple regions including thalamus, posterior and prefrontal cortex. Conversely, in other regions, primarily in prefrontal cortex, HFOA, but not LFOA, demonstrated greater activation than YA (i.e., increased age-related differences). Further, fMRI activity in these brain regions was positively associated with source memory among OA, with a mediation model demonstrating that associative encoding activation in medial frontal cortex indirectly influenced the relationship between peak VO 2 and subsequent source memory performance. These results indicate that CRF may contribute to neuroplasticity among OA, reducing age-related differences in some brain regions, consistent with the brain maintenance hypothesis, but accentuating age-differences in other regions, consistent with the brain compensation hypothesis. Published by Elsevier Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Jiansen; Xue, Hailing; Ma, Jing

HIV CRF07 B′/C is a strain circulating mainly in northwest region of China. The gp41 region of CRF07 is derived from a clade C virus. In order to compare the difference of CRF07 gp41 with that of typical clade B virus, we solved the crystal structure of the core region of CRF07 gp41. Compared with clade B gp41, CRF07 gp41 evolved more basic and hydrophilic residues on its helix bundle surface. Based on sequence alignment, a hyper-mutant cluster located in the middle of HR2 heptads repeat was identified. The mutational study of these residues revealed that this site is importantmore » in HIV mediated cell–cell fusion and plays critical roles in conformational changes during viral invasion. - Highlights: • We solved the crystal structure of HIV CRF07 gp41 core region. • A hyper-mutant cluster in the middle of HR2 heptads repeat was identified. • The hyper-mutant site is important in HIV-cell fusion. • The model will help to understand the HIV fusion process.« less

Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.

PubMed

Hartz, Richard A; Ahuja, Vijay T; Arvanitis, Argyrios G; Rafalski, Maria; Yue, Eddy W; Denhart, Derek J; Schmitz, William D; Ditta, Jonathan L; Deskus, Jeffrey A; Brenner, Allison B; Hobbs, Frank W; Payne, Joseph; Lelas, Snjezana; Li, Yu-Wen; Molski, Thaddeus F; Mattson, Gail K; Peng, Yong; Wong, Harvey; Grace, James E; Lentz, Kimberley A; Qian-Cutrone, Jingfang; Zhuo, Xiaoliang; Shu, Yue-Zhong; Lodge, Nicholas J; Zaczek, Robert; Combs, Andrew P; Olson, Richard E; Bronson, Joanne J; Mattson, Ronald J; Macor, John E

2009-07-23

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.

Prediction of Cardiorespiratory Fitness by the Six-Minute Step Test and Its Association with Muscle Strength and Power in Sedentary Obese and Lean Young Women: A Cross-Sectional Study

PubMed Central

Bonjorno Junior, José Carlos; de Oliveira, Cláudio Ricardo; Luporini, Rafael Luís; Mendes, Renata Gonçalves; Zangrando, Katiany Thais Lopes; Trimer, Renata; Arena, Ross

2015-01-01

Impaired cardiorespiratory fitness (CRF) is a hallmark characteristic in obese and lean sedentary young women. Peak oxygen consumption (VO2peak) prediction from the six-minute step test (6MST) has not been established for sedentary females. It is recognized that lower-limb muscle strength and power play a key role during functional activities. The aim of this study was to investigate cardiorespiratory responses during the 6MST and CPX and to develop a predictive equation to estimate VO2peak in both lean and obese subjects. Additionally we aim to investigate how muscle function impacts functional performance. Lean (LN = 13) and obese (OB = 18) women, aged 20–45, underwent a CPX, two 6MSTs, and isokinetic and isometric knee extensor strength and power evaluations. Regression analysis assessed the ability to predict VO2peak from the 6MST, age and body mass index (BMI). CPX and 6MST main outcomes were compared between LN and OB and correlated with strength and power variables. CRF, functional capacity, and muscle strength and power were lower in the OB compared to LN (<0.05). During the 6MST, LN and OB reached ~90% of predicted maximal heart rate and ~80% of the VO2peak obtained during CPX. BMI, age and number of step cycles (NSC) explained 83% of the total variance in VO2peak. Moderate to strong correlations between VO2peak at CPX and VO2peak at 6MST (r = 0.86), VO2peak at CPX and NSC (r = 0.80), as well as between VO2peak, NSC and muscle strength and power variables were found (p<0.05). These findings indicate the 6MST, BMI and age accurately predict VO2peak in both lean and obese young sedentary women. Muscle strength and power were related to measures of aerobic and functional performance. PMID:26717568

Presynaptic Inhibition of Diverse Afferents to the Locus Coeruleus by Kappa Opiate Receptors: a Novel Mechanism for Regulating the Central Norepinephrine System

PubMed Central

Kreibich, Arati S.; Reyes, Beverly A. S.; Curtis, Andre L.; Ecke, Laurel; Chavkin, Charles; Van Bockstaele, Elisabeth J.; Valentino, Rita J.

2008-01-01

The norepinephrine nucleus, locus coeruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAA), corticotropin-releasing factor (CRF) and endogenous opioids acting at μ-opiate receptors. As the LC is also innervated by the endogenous κ-opiate receptor (κ-OR) ligand, dynorphin, and expresses κ-ORs, this study investigated κ-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of κ-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the κ-OR agonist, U50488, into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the κ-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that κ-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC-NE system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate κ-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders or disorders characterized by abnormal sensory responses, such as autism. PMID:18562623

Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for regulating the central norepinephrine system.

PubMed

Kreibich, Arati; Reyes, Beverly A S; Curtis, Andre L; Ecke, Laurel; Chavkin, Charles; Van Bockstaele, Elisabeth J; Valentino, Rita J

2008-06-18

The norepinephrine nucleus, locus ceruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAAs), corticotropin-releasing factor (CRF), and endogenous opioids acting at mu-opiate receptors. Because the LC is also innervated by the endogenous kappa-opiate receptor (kappa-OR) ligand dynorphin and expresses kappa-ORs, this study investigated kappa-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of kappa-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the kappa-OR agonist (trans)-3,4-dichloro-N-methyl-N-[2-1-pyrrolidinyl)-cyclo-hexyl] benzeneacetamide (U50488) into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the kappa-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that kappa-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC-norepinephrine system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate kappa-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders, or disorders characterized by abnormal sensory responses, such as autism.

HIV-1 molecular epidemiology among newly diagnosed HIV-1 individuals in Hebei, a low HIV prevalence province in China.

PubMed

Lu, Xinli; Kang, Xianjiang; Liu, Yongjian; Cui, Ze; Guo, Wei; Zhao, Cuiying; Li, Yan; Chen, Suliang; Li, Jingyun; Zhang, Yuqi; Zhao, Hongru

2017-01-01

New human immunodeficiency virus type 1 (HIV-1) diagnoses are increasing rapidly in Hebei. The aim of this study presents the most extensive HIV-1 molecular epidemiology investigation in Hebei province in China thus far. We have carried out the most extensive systematic cross-sectional study based on newly diagnosed HIV-1 positive individuals in 2013, and characterized the molecular epidemiology of HIV-1 based on full length gag-partial pol gene sequences in the whole of Hebei. Nine HIV-1 genotypes based on full length gag-partial pol gene sequence were identified among 610 newly diagnosed naïve individuals. The four main genotypes were circulating recombinant form (CRF)01_AE (53.4%), CRF07_BC (23.4%), subtype B (15.9%), and unique recombinant forms URFs (4.9%). Within 1 year, three new genotypes (subtype A1, CRF55_01B, CRF65_cpx), unknown before in Hebei, were first found among men who have sex with men (MSM). All nine genotypes were identified in the sexually contracted HIV-1 population. Among 30 URFs, six recombinant patterns were revealed, including CRF01_AE/BC (40.0%), CRF01_AE/B (23.3%), B/C (16.7%), CRF01_AE/C (13.3%), CRF01_AE/B/A2 (3.3%) and CRF01_AE/BC/A2 (3.3%), plus two potential CRFs. This study elucidated the complicated characteristics of HIV-1 molecular epidemiology in a low HIV-1 prevalence northern province of China and revealed the high level of HIV-1 genetic diversity. All nine HIV-1 genotypes circulating in Hebei have spread out of their initial risk groups into the general population through sexual contact, especially through MSM. This highlights the urgency of HIV prevention and control in China.

HIV-1 molecular epidemiology among newly diagnosed HIV-1 individuals in Hebei, a low HIV prevalence province in China

PubMed Central

Lu, Xinli; Kang, Xianjiang; Liu, Yongjian; Cui, Ze; Guo, Wei; Zhao, Cuiying; Li, Yan; Chen, Suliang; Li, Jingyun; Zhang, Yuqi; Zhao, Hongru

2017-01-01

New human immunodeficiency virus type 1 (HIV-1) diagnoses are increasing rapidly in Hebei. The aim of this study presents the most extensive HIV-1 molecular epidemiology investigation in Hebei province in China thus far. We have carried out the most extensive systematic cross-sectional study based on newly diagnosed HIV-1 positive individuals in 2013, and characterized the molecular epidemiology of HIV-1 based on full length gag-partial pol gene sequences in the whole of Hebei. Nine HIV-1 genotypes based on full length gag-partial pol gene sequence were identified among 610 newly diagnosed naïve individuals. The four main genotypes were circulating recombinant form (CRF)01_AE (53.4%), CRF07_BC (23.4%), subtype B (15.9%), and unique recombinant forms URFs (4.9%). Within 1 year, three new genotypes (subtype A1, CRF55_01B, CRF65_cpx), unknown before in Hebei, were first found among men who have sex with men (MSM). All nine genotypes were identified in the sexually contracted HIV-1 population. Among 30 URFs, six recombinant patterns were revealed, including CRF01_AE/BC (40.0%), CRF01_AE/B (23.3%), B/C (16.7%), CRF01_AE/C (13.3%), CRF01_AE/B/A2 (3.3%) and CRF01_AE/BC/A2 (3.3%), plus two potential CRFs. This study elucidated the complicated characteristics of HIV-1 molecular epidemiology in a low HIV-1 prevalence northern province of China and revealed the high level of HIV-1 genetic diversity. All nine HIV-1 genotypes circulating in Hebei have spread out of their initial risk groups into the general population through sexual contact, especially through MSM. This highlights the urgency of HIV prevention and control in China. PMID:28178737

Consistent realization of Celestial and Terrestrial Reference Frames

NASA Astrophysics Data System (ADS)

Kwak, Younghee; Bloßfeld, Mathis; Schmid, Ralf; Angermann, Detlef; Gerstl, Michael; Seitz, Manuela

2018-03-01

The Celestial Reference System (CRS) is currently realized only by Very Long Baseline Interferometry (VLBI) because it is the space geodetic technique that enables observations in that frame. In contrast, the Terrestrial Reference System (TRS) is realized by means of the combination of four space geodetic techniques: Global Navigation Satellite System (GNSS), VLBI, Satellite Laser Ranging (SLR), and Doppler Orbitography and Radiopositioning Integrated by Satellite. The Earth orientation parameters (EOP) are the link between the two types of systems, CRS and TRS. The EOP series of the International Earth Rotation and Reference Systems Service were combined of specifically selected series from various analysis centers. Other EOP series were generated by a simultaneous estimation together with the TRF while the CRF was fixed. Those computation approaches entail inherent inconsistencies between TRF, EOP, and CRF, also because the input data sets are different. A combined normal equation (NEQ) system, which consists of all the parameters, i.e., TRF, EOP, and CRF, would overcome such an inconsistency. In this paper, we simultaneously estimate TRF, EOP, and CRF from an inter-technique combined NEQ using the latest GNSS, VLBI, and SLR data (2005-2015). The results show that the selection of local ties is most critical to the TRF. The combination of pole coordinates is beneficial for the CRF, whereas the combination of Δ UT1 results in clear rotations of the estimated CRF. However, the standard deviations of the EOP and the CRF improve by the inter-technique combination which indicates the benefits of a common estimation of all parameters. It became evident that the common determination of TRF, EOP, and CRF systematically influences future ICRF computations at the level of several μas. Moreover, the CRF is influenced by up to 50 μas if the station coordinates and EOP are dominated by the satellite techniques.

Significant contribution of subtype G to HIV-1 genetic complexity in Nigeria identified by a newly developed subtyping assay specific for subtype G and CRF02_AG

PubMed Central

Heipertz, Richard A.; Ayemoba, Ojor; Sanders-Buell, Eric; Poltavee, Kultida; Pham, Phuc; Kijak, Gustavo H.; Lei, Esther; Bose, Meera; Howell, Shana; O'Sullivan, Anne Marie; Bates, Adam; Cervenka, Taylor; Kuroiwa, Janelle; Akintunde, Akindiran; Ibezim, Onyekachukwu; Alabi, Abraham; Okoye, Obumneke; Manak, Mark; Malia, Jennifer; Peel, Sheila; Maisaka, Mohammed; Singer, Darrell; O’Connell, Robert J.; Robb, Merlin L.; Kim, Jerome H.; Michael, Nelson L.; Njoku, Ogbonnaya; Tovanabutra, Sodsai

2016-01-01

Abstract While abundant sequence information is available from human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C and CRF01_AE for HIV-1 vaccine design, sequences from West Africa are less represented. We sought to augment our understanding of HIV-1 variants circulating in 6 Nigerian cities as a step to subsequent HIV-1 vaccine development. The G/CRF02_AG multi-region hybridization assay (MHA) was developed to differentiate subtype G, CRF02_AG and their recombinants from other subtypes based on 7 HIV-1 segments. Plasma from 224 HIV-1 infected volunteers enrolled in a cohort examining HIV-1 prevalence, risk factor, and subtype from Makurdi (30), Abuja (18), Enugu (11), Kaduna (12), Tafa (95), and Ojo/Lagos (58) was analyzed using MHA. HIV-1 genomes from 42 samples were sequenced to validate the MHA and fully explore the recombinant structure of G and CRF02_AG variants. The sensitivity and specificity of MHA varied between 73–100% and 90–100%, respectively. The subtype distribution as identified by MHA among 224 samples revealed 38% CRF02_AG, 28% G, and 26% G/CRF02_AG recombinants while 8% remained nontypeable strains. In envelope (env) gp120, 38.84% of the samples reacted to a G probe while 31.25% reacted to a CRF02 (subtype A) probe. Full genome characterization of 42 sequences revealed the complexity of Nigerian HIV-1 variants. CRF02_AG, subtype G, and their recombinants were the major circulating HIV-1 variants in 6 Nigerian cities. High proportions of samples reacted to a G probe in env gp120 confirms that subtype G infections are abundant and should be considered in strategies for global HIV-1 vaccine development. PMID:27512845

Simulation of seasonal cloud forcing anomalies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Randall, D.A.

1990-08-01

One useful way to classify clouds is according to the processes that generate them. There are three main cloud-formation agencies: deep convection; surface evaporation; large-scale lifting in the absence of conditional instability. Although traditionally clouds have been viewed as influencing the atmospheric general circulation primarily through the release of latent heat, the atmospheric science literature contains abundant evidence that, in reality, clouds influence the general circulation through four more or less equally important effects: interactions with the solar and terrestrial radiation fields; condensation and evaporation; precipitation; small-scale circulations within the atmosphere. The most advanced of the current generation of GCMsmore » include parameterizations of all four effects. Until recently there has been lingering skepticism, in the general circulation modeling community, that the radiative effects of clouds significantly influence the atmospheric general circulation. GCMs have provided the proof that the radiative effects of clouds are important for the general circulation of the atmosphere. An important concept in analysis of the effects of clouds on climate is the cloud radiative forcing (CRF), which is defined as the difference between the radiative flux which actually occurs in the presence of clouds, and that which would occur if the clouds were removed but the atmospheric state were otherwise unchanged. We also use the term CRF to denote warming or cooling tendencies due to cloud-radiation interactions. Cloud feedback is the change in CRF that accompanies a climate change. The present study concentrates on the planetary CRF and its response to external forcing, i.e. seasonal change.« less

Urea-induced ROS cause endothelial dysfunction in chronic renal failure.

PubMed

D'Apolito, Maria; Du, Xueliang; Pisanelli, Daniela; Pettoello-Mantovani, Massimo; Campanozzi, Angelo; Giacco, Ferdinando; Maffione, Angela Bruna; Colia, Anna Laura; Brownlee, Michael; Giardino, Ida

2015-04-01

The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia. Primary cultures of human aortic endothelial cells (HAEC) were exposed to 20mM urea for 48 h. C57BL/6J wild-type mice underwent 5/6 nephrectomy or a sham operation. Randomized groups of 5/6 nephrectomized mice and their controls were also injected i.p. with a SOD/catalase mimetic (MnTBAP) for 15 days starting immediately after the final surgical procedure. Urea at concentrations seen in CRF induced mitochondrial ROS production in cultured HAEC. Urea-induced ROS caused the activation of endothelial pro-inflammatory pathways through the inhibition of GAPDH, including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular AGEs (advanced glycation end products). Urea-induced ROS directly inactivated the anti-atherosclerosis enzyme PGI2 synthase and also caused ER stress. Normalization of mitochondrial ROS production prevented each of these effects of urea. In uremic mice, treatment with MnTBAP prevented aortic oxidative stress, PGI2 synthase activity reduction and increased expression of the pro-inflammatory proteins TNFα, IL-6, VCAM1, Endoglin, and MCP-1. Taken together, these data show that urea itself, at levels common in patients with CRF, causes endothelial dysfunction and activation of proatherogenic pathways. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Relationship of cardiac structure and function to cardiorespiratory fitness and lean body mass in adolescents and young adults with Type 2 Diabetes

USDA-ARS?s Scientific Manuscript database

To investigate the relationships of cardiac structure and function with body composition and cardiorespiratory fitness (CRF) among adolescents with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Cross-sectional evaluation of 233 participant...

The Influence of Prior Choices on Current Choice

PubMed Central

de la Piedad, Xochitl; Field, Douglas; Rachlin, Howard

2006-01-01

Three pigeons chose between random-interval (RI) and tandem, continuous-reinforcement, fixed-interval (crf-FI) reinforcement schedules by pecking either of two keys. As long as a pigeon pecked on the RI key, both keys remained available. If a pigeon pecked on the crf-FI key, then the RI key became unavailable and the crf-FI timer began to time out. With this procedure, once the RI key was initially pecked, the prospective value of both alternatives remained constant regardless of time spent pecking on the RI key without reinforcement (RI waiting time). Despite this constancy, the rate at which pigeons switched from the RI to the crf-FI decreased sharply as RI waiting time increased. That is, prior choices influenced current choice—an exercise effect. It is argued that such influence (independent of reinforcement contingencies) may serve as a sunk-cost commitment device in self-control situations. In a second experiment, extinction was programmed if RI waiting time exceeded a certain value. Rate of switching to the crf-FI first decreased and then increased as the extinction point approached, showing sensitivity to both prior choices and reinforcement contingencies. In a third experiment, crf-FI availability was limited to a brief window during the RI waiting time. When constrained in this way, switching occurred at a high rate regardless of when, during the RI waiting time, the crf-FI became available. PMID:16602373

Diversity and abundance of human-pathogenic fungi associated with pigeon faeces in urban environments.

PubMed

Lee, Won Dong; Fong, Jonathan J; Eimes, John A; Lim, Young Woon

2017-09-01

Pathogenic fungi are a growing health concern worldwide, particularly in large, densely populated cities. The dramatic upsurge of pigeon populations in cities has been implicated in the increased incidence of invasive fungal infections. In this study, we used a culture-independent, high-throughput sequencing approach to describe the diversity of clinically relevant fungi (CRF) associated with pigeon faeces and map the relative abundance of CRF across Seoul, Korea. In addition, we tested whether certain geographical, sociological and meteorological factors were significantly associated with the diversity and relative abundance of CRF. Finally, we compared the CRF diversity of fresh and old pigeon faeces to identify the source of the fungi and the role of pigeons in dispersal. Our results demonstrated that both the composition and relative abundance of CRF are unevenly distributed across Seoul. The green area ratio and the number of multiplex houses were positively correlated with species diversity, whereas wind speed and number of households were negatively correlated. The number of workers and green area ratio were positively correlated with the relative abundance of CRF, whereas wind speed was negatively correlated. Because many CRF were absent in fresh faeces, we inferred that most species cannot survive the gastrointestinal tract of pigeons and instead are likely transmitted through soil or air and use pigeon faeces as a substrate for proliferation. © 2017 John Wiley & Sons Ltd.

Genetic characterization and antiretroviral resistance mutations among treatment-naive HIV-infected individuals in Jiaxing, China.

PubMed

Guo, Jinlei; Yan, Yong; Zhang, Jiafeng; Ji, Jimei; Ge, Zhijian; Ge, Rui; Zhang, Xiaofei; Wang, Henghui; Chen, Zhongwen; Luo, Jianyong

2017-03-14

The aim of this study was to characterize HIV-1 genotypes and antiretroviral resistance mutations among treatment-naive HIV-infected individuals in Jiaxing, China. The HIV-1 partial polymerase (pol) genes in 93 of the 99 plasma samples were successfully amplified and analyzed. Phylogenetic analysis revealed the existence of five HIV-1 genotypes, of which the most prevalent genotype was CRF01_AE (38.7%), followed by CRF07_BC (34.4%), CRF08_BC (16.1%), subtype B/B' (5.4%), and CRF55_01B (2.1%). Besides, three types of unique recombination forms (URFs) were also observed, including C/F2/A1, CRF01_AE/B, and CRF08_BC/CRF07_BC. Among 93 amplicons, 46.2% had drug resistance-associated mutations, including 23.7% for protease inhibitors (PIs) mutations, 1.1% for nucleoside reverse transcriptase inhibitors (NRTIs) mutations, and 20.4% for non-nucleoside reverse transcriptase inhibitors (NNRTIs) mutations. Six (6.5%) out of 93 treatment-naive subjects were identified to be resistant to one or more NNRTIs, while resistance to NRTIs or PIs was not observed. Our study showed the genetic diversity of HIV-1 strains circulating in Jiaxing and a relative high proportion of antiretroviral resistance mutations among treatment-naive patients, indicating a serious challenge for HIV prevention and treatment program.

Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors.

PubMed

Adams, Scott C; DeLorey, Darren S; Davenport, Margie H; Fairey, Adrian S; North, Scott; Courneya, Kerry S

2018-05-08

Testicular cancer survivors (TCS) are at increased risk of cancer-related fatigue (CRF), psychosocial impairment, and poor mental health-related quality of life (HRQoL). Here, we examine the effects of high-intensity interval training (HIIT) on patient-reported outcomes (PROs) in TCS. Secondarily, we explore cardiorespiratory fitness as a mediator of intervention effects and select baseline characteristics as moderators of intervention effects. TCS (n = 63) were randomly assigned to 12 weeks of supervised HIIT or usual care (UC). PROs included CRF, depression, anxiety, stress, self-esteem, sleep quality, and HRQoL assessed at baseline, post-intervention, and 3-month follow-up. TCS (median 7 years postdiagnosis) completed 99% of training sessions and achieved 98% of target training intensity. ANCOVA revealed that, compared to UC, HIIT significantly improved post-intervention CRF (p = 0.003), self-esteem (p = 0.029), and multiple HRQoL domains (ps ≤ 0.05). Effects on CRF (p = 0.031) and vitality (p = 0.015) persisted at 3-month follow-up. Cardiorespiratory fitness changes mediated CRF and HRQoL improvements. CRF effects were larger for TCS with an inactive lifestyle, lower fitness, higher testosterone, and clinical fatigue at baseline. HIIT significantly improves CRF and HRQoL in TCS. Mediation by cardiorespiratory fitness and moderation by clinical characteristics suggests opportunities for targeted exercise interventions to optimise PROs in TCS.

The mouse cochlea expresses a local hypothalamic-pituitary-adrenal equivalent signaling system and requires CRFR1 to establish normal hair cell innervation and cochlear sensitivity

PubMed Central

Graham, Christine E.; Vetter, Douglas E.

2011-01-01

Cells of the inner ear face constant metabolic and structural stress. Exposure to intense sound or certain drugs destroys cochlea hair cells, which in mammals do not regenerate. Thus, an endogenous stress response system may exist within the cochlea to protect it from everyday stressors. We recently described the existence of Corticotropin-Releasing Factor (CRF) in the mouse cochlea. The CRFR1 receptor is considered the primary and canonical target of CRF signaling, and systemically it plays an essential role in coordinating the body-wide stress response via activation of the hypothalamic-pituitary-adrenal (HPA) axis. Here we describe an essential role for CRFR1 in auditory system development and function, and offer the first description of a complete HPA equivalent signaling system resident within the cochlea. To reveal the role of CRFR1 activation in the cochlea, we have used mice carrying a null ablation of the CRFR1 gene. CRFR1−/− mice exhibited elevated auditory thresholds at all frequencies tested, indicating reduced sensitivity. Furthermore, our results suggest that CRFR1 has a developmental role affecting inner hair cell morphology and afferent and efferent synapse distribution. Given the role of HPA signaling in maintaining local homeostasis in other tissues, the presence of a cochlear HPA signaling system suggests important roles for CRFR1 activity in setting cochlear sensitivity, perhaps both neural and non-neural mechanisms. These data highlight the complex pleiotropic mechanisms modulated by CRFR1 signaling in the cochlea. PMID:21273411

Extensive Genetic Diversity of HIV-1 in Incident and Prevalent Infections among Malaysian Blood Donors: Multiple Introductions of HIV-1 Genotypes from Highly Prevalent Countries

PubMed Central

Chow, Wei Zhen; Bon, Abdul Hamid; Keating, Sheila; Anderios, Fread; Halim, Hazwan Abdul; Takebe, Yutaka; Kamarulzaman, Adeeba; Busch, Michael P.; Tee, Kok Keng

2016-01-01

Transfusion-transmissible infections including HIV-1 continue to pose major risks for unsafe blood transfusions due to both window phase infections and divergent viruses that may not be detected by donor screening assays. Given the recent emergence of several HIV-1 circulating recombinant forms (CRFs) in high-risk populations in the Southeast Asia region, we investigated the genetic diversity of HIV-1 among the blood donors in Kuala Lumpur, Malaysia. A total of 211 HIV-positive plasma samples detected among 730,188 donations to the National Blood Centre between 2013 and 2014 were provided (90.5% male, median age: 27.0 years old). Recent or long-term infection status at the time of donation was determined using a limiting antigen avidity enzyme immunoassay (LAg-Avidity EIA). HIV-1 gag-pol genes were amplified and sequenced from residual plasma for 149 cases followed by genotype determination using phylogenetic and recombination analyses. Transmitted antiretroviral resistance mutations were not observed among the blood donors, among which 22.7% were classified as recent or incident infections. Major circulating HIV-1 genotypes determined by neighbour-joining phylogenetic inference included CRF01_AE at 40.9% (61/149), CRF33_01B at 21.5% (32/149), and subtype B at 10.1% (15/149). Newly-described CRFs including CRF54_01B circulated at 4.0%, CRF74_01B at 2.0%, and CRF53_01B and CRF48_01B at 0.7% each. Interestingly, unique HIV-1 genotypes including African subtype G (8.7%), CRF45_cpx (1.3%), CRF02_AG (0.7%) and CRF07_BC (0.7%) from China were detected for the first time in the country. A cluster of subtype G sequences formed a distinct founder sub-lineage within the African strains. In addition, 8.7% (13/149) of HIV-infected donors had unique recombinant forms (URFs) including CRF01_AE/B' (4.7%), B'/C (2.7%) and B'/G (1.3%) recombinants. Detailed analysis identified similar recombinant structures with shared parental strains among the B'/C and B'/G URFs, some of which were sequenced from recently infected individuals, indicating the possible emergence and on-going spread of foreign clades of CRF candidates among the local population. The findings demonstrate extensive molecular complexity of HIV-1 among the infected blood donors in Malaysia, driven in part by the increased spread of recently described CRFs and multiple introductions of previously unreported genotypes from highly prevalent countries. PMID:27575746

Design and implementation of an institutional case report form library.

PubMed

Nahm, Meredith; Shepherd, John; Buzenberg, Ann; Rostami, Reza; Corcoran, Andrew; McCall, Jonathan; Pietrobon, Ricardo

2011-02-01

Case report forms (CRFs) are used to collect data in clinical research. Case report form development represents a significant part of the clinical trial process and can affect study success. Libraries of CRFs can preserve the organizational knowledge and expertise invested in CRF development and expedite the sharing of such knowledge. Although CRF libraries have been advocated, there have been no published accounts reporting institutional experiences with creating and using them. We sought to enhance an existing institutional CRF library by improving information indexing and accessibility. We describe this CRF library and discuss challenges encountered in its development and implementation, as well as future directions for continued work in this area. We transformed an existing but underused and poorly accessible CRF library into a resource capable of supporting and expediting clinical and translational investigation at our institution by (1) expanding access to the entire institution; (2) adding more form attributes for improved information retrieval; and (3) creating a formal information curation and maintenance process. An open-source content management system, Plone (Plone.org), served as the platform for our CRF library. We report results from these three processes. Over the course of this project, the size of the CRF library increased from 160 CRFs comprising an estimated total of 17,000 pages, to 177 CRFs totaling 1.5 gigabytes. Eighty-two of these CRFs are now available to researchers across our institution; 95 CRFs remain within a contractual confidentiality window (usually 5 years from database lock) and are not available to users outside of the Duke Clinical Research Institute (DCRI). Conservative estimates suggest that the library supports an average of 37 investigators per month. The resources needed to curate and maintain the CRF library require less than 10% of the effort of one full-time equivalent employee. Although we succeeded in expanding use of the CRF library, creating awareness of such institutional resources among investigators and research teams remains challenging and requires additional efforts to overcome. Institutions that have not achieved a critical mass of attractive research resources or effective dissemination mechanisms may encounter persistent difficulty attracting researchers to use institutional resources. Further, a useful CRF library requires both an initial investment of resources for development, as well as ongoing maintenance once it is established. CRF libraries can be established and made broadly available to institutional researchers. Curation - that is, indexing newly added forms - is required. Such a resource provides knowledge management capacity for institutions until standards and software are available to support widespread exchange of data and form definitions.

Extensive Genetic Diversity of HIV-1 in Incident and Prevalent Infections among Malaysian Blood Donors: Multiple Introductions of HIV-1 Genotypes from Highly Prevalent Countries.

PubMed

Chow, Wei Zhen; Bon, Abdul Hamid; Keating, Sheila; Anderios, Fread; Halim, Hazwan Abdul; Takebe, Yutaka; Kamarulzaman, Adeeba; Busch, Michael P; Tee, Kok Keng

2016-01-01

Transfusion-transmissible infections including HIV-1 continue to pose major risks for unsafe blood transfusions due to both window phase infections and divergent viruses that may not be detected by donor screening assays. Given the recent emergence of several HIV-1 circulating recombinant forms (CRFs) in high-risk populations in the Southeast Asia region, we investigated the genetic diversity of HIV-1 among the blood donors in Kuala Lumpur, Malaysia. A total of 211 HIV-positive plasma samples detected among 730,188 donations to the National Blood Centre between 2013 and 2014 were provided (90.5% male, median age: 27.0 years old). Recent or long-term infection status at the time of donation was determined using a limiting antigen avidity enzyme immunoassay (LAg-Avidity EIA). HIV-1 gag-pol genes were amplified and sequenced from residual plasma for 149 cases followed by genotype determination using phylogenetic and recombination analyses. Transmitted antiretroviral resistance mutations were not observed among the blood donors, among which 22.7% were classified as recent or incident infections. Major circulating HIV-1 genotypes determined by neighbour-joining phylogenetic inference included CRF01_AE at 40.9% (61/149), CRF33_01B at 21.5% (32/149), and subtype B at 10.1% (15/149). Newly-described CRFs including CRF54_01B circulated at 4.0%, CRF74_01B at 2.0%, and CRF53_01B and CRF48_01B at 0.7% each. Interestingly, unique HIV-1 genotypes including African subtype G (8.7%), CRF45_cpx (1.3%), CRF02_AG (0.7%) and CRF07_BC (0.7%) from China were detected for the first time in the country. A cluster of subtype G sequences formed a distinct founder sub-lineage within the African strains. In addition, 8.7% (13/149) of HIV-infected donors had unique recombinant forms (URFs) including CRF01_AE/B' (4.7%), B'/C (2.7%) and B'/G (1.3%) recombinants. Detailed analysis identified similar recombinant structures with shared parental strains among the B'/C and B'/G URFs, some of which were sequenced from recently infected individuals, indicating the possible emergence and on-going spread of foreign clades of CRF candidates among the local population. The findings demonstrate extensive molecular complexity of HIV-1 among the infected blood donors in Malaysia, driven in part by the increased spread of recently described CRFs and multiple introductions of previously unreported genotypes from highly prevalent countries.

Reinstatement of cocaine-seeking by hypocretin (orexin) in the ventral tegmental area: Independence from the local CRF network

PubMed Central

Wang, Bin; You, Zhi-Bing; Wise, Roy A

2009-01-01

Background Hypocretin (Hcrt), an arousal- and feeding-associated peptide is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine-seeking. Each is presumed to act at least in part through actions local to the VTA. Here we examined the possibility that VTA perfusion of Hcrt reinstates cocaine-seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF. Methods Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA. Results VTA perfusion of Hcrt-1 or footshock stress reinstated cocaine-seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks footshock-induced reinstatement and glutamate release. Conclusions While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine-seeking. PMID:19251246

CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba

PubMed Central

Kouri, Vivian; Khouri, Ricardo; Alemán‬, Yoan; Abrahantes, Yeissel; Vercauteren, Jurgen; Pineda-Peña, Andrea-Clemencia; Theys, Kristof; Megens, Sarah; Moutschen, Michel; Pfeifer, Nico; Van Weyenbergh, Johan; Pérez, Ana B.; Pérez, Jorge; Pérez, Lissette; Van Laethem, Kristel; Vandamme, Anne-Mieke

2015-01-01

Background Clinicians reported an increasing trend of rapid progression (RP) (AIDS within 3 years of infection) in Cuba. Methods Recently infected patients were prospectively sampled, 52 RP at AIDS diagnosis (AIDS-RP) and 21 without AIDS in the same time frame (non-AIDS). 22 patients were sampled at AIDS diagnosis (chronic-AIDS) retrospectively assessed as > 3 years infected. Clinical, demographic, virological, epidemiological and immunological data were collected. Pol and env sequences were used for subtyping, transmission cluster analysis, and prediction of resistance, co-receptor use and evolutionary fitness. Host, immunological and viral predictors of RP were explored through data mining. Findings Subtyping revealed 26 subtype B strains, 6 C, 6 CRF18_cpx, 9 CRF19_cpx, 29 BG-recombinants and other subtypes/URFs. All patients infected with CRF19 belonged to the AIDS-RP group. Data mining identified CRF19, oral candidiasis and RANTES levels as the strongest predictors of AIDS-RP. CRF19 was more frequently predicted to use the CXCR4 co-receptor, had higher fitness scores in the protease region, and patients had higher viral load at diagnosis. Interpretation CRF19 is a recombinant of subtype D (C-part of Gag, PR, RT and nef), subtype A (N-part of Gag, Integrase, Env) and subtype G (Vif, Vpr, Vpu and C-part of Env). Since subtypes D and A have been associated with respectively faster and slower disease progression, our findings might indicate a fit PR driving high viral load, which in combination with co-infections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba. PMID:26137563

Low cardiorespiratory fitness and coronary artery calcification: Complementary cardiovascular risk predictors in asymptomatic type 2 diabetics.

PubMed

Zafrir, Barak; Azaiza, Mohanad; Gaspar, Tamar; Dobrecky-Mery, Idit; Azencot, Mali; Lewis, Basil S; Rubinshtein, Ronen; Halon, David A

2015-08-01

Despite its well-established prognostic value, cardiorespiratory fitness (CRF) is not incorporated routinely in risk assessment tools. Whether low CRF provides additional predictive information in asymptomatic type 2 diabetics beyond conventional risk scores and coronary artery calcification (CAC) is unclear. We studied 600 type 2 diabetics aged 55-74 years without known coronary heart disease. CRF was quantified in metabolic equivalents (METs) by maximal treadmill testing and categorized as tertiles of percent predicted METs (ppMETs) achieved. CAC was calculated by non-enhanced computed tomography scans. The individual and joint association of both measures with an outcome event of all-cause mortality, myocardial infarction or stroke, was determined over a mean follow-up period of 80 ± 16 months. There were 72 (12%) events during follow-up. Low CRF was independently associated with event risk after adjustment for traditional risk factors and CAC (HR 2.25, 95% CI 1.41-3.57, p = 0.001). CRF (unfit/fit) allowed further outcome discrimination both amongst diabetics with low CAC scores (9.5% versus 2.0% event rate), and amongst diabetics with high CAC scores (23.5% versus 12.4% event rate), p < 0.001. The addition of CRF to a model comprising UKPDS and CAC scores improved the area under the curve for event prediction from 0.66 to 0.71, p = 0.03, with a positive continuous net reclassification improvement (NRI) of 0.451, p = 0.002. CRF, quantified by ppMETs, provided independent prognostic information which was additive to CAC. Low CRF may identify asymptomatic diabetic subjects at higher risk for all-cause mortality, myocardial infarction or stroke, despite low CAC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba.

PubMed

Kouri, Vivian; Khouri, Ricardo; Alemán, Yoan; Abrahantes, Yeissel; Vercauteren, Jurgen; Pineda-Peña, Andrea-Clemencia; Theys, Kristof; Megens, Sarah; Moutschen, Michel; Pfeifer, Nico; Van Weyenbergh, Johan; Pérez, Ana B; Pérez, Jorge; Pérez, Lissette; Van Laethem, Kristel; Vandamme, Anne-Mieke

2015-03-01

Clinicians reported an increasing trend of rapid progression (RP) (AIDS within 3 years of infection) in Cuba. Recently infected patients were prospectively sampled, 52 RP at AIDS diagnosis (AIDS-RP) and 21 without AIDS in the same time frame (non-AIDS). 22 patients were sampled at AIDS diagnosis (chronic-AIDS) retrospectively assessed as > 3 years infected. Clinical, demographic, virological, epidemiological and immunological data were collected. Pol and env sequences were used for subtyping, transmission cluster analysis, and prediction of resistance, co-receptor use and evolutionary fitness. Host, immunological and viral predictors of RP were explored through data mining. Subtyping revealed 26 subtype B strains, 6 C, 6 CRF18_cpx, 9 CRF19_cpx, 29 BG-recombinants and other subtypes/URFs. All patients infected with CRF19 belonged to the AIDS-RP group. Data mining identified CRF19, oral candidiasis and RANTES levels as the strongest predictors of AIDS-RP. CRF19 was more frequently predicted to use the CXCR4 co-receptor, had higher fitness scores in the protease region, and patients had higher viral load at diagnosis. CRF19 is a recombinant of subtype D (C-part of Gag, PR, RT and nef), subtype A (N-part of Gag, Integrase, Env) and subtype G (Vif, Vpr, Vpu and C-part of Env). Since subtypes D and A have been associated with respectively faster and slower disease progression, our findings might indicate a fit PR driving high viral load, which in combination with co-infections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba.

Exercise is an effective treatment modality for reducing cancer-related fatigue and improving physical capacity in cancer patients and survivors: a meta-analysis.

PubMed

McMillan, Elliott M; Newhouse, Ian J

2011-12-01

The use of exercise interventions to manage cancer-related fatigue (CRF) is a rapidly developing field of study. However, results are inconsistent and difficult to interpret across the literature, making it difficult to draw accurate conclusions regarding the true effectiveness of exercise interventions for CRF management. The aims of this study were to apply a meta-analysis to quantitatively assess the effects of exercise intervention strategies on CRF, and to elucidate appropriate exercise prescription guidelines. A systematic search of electronic databases and relevant journals and articles was conducted. Studies were eligible if subjects were over the age of 18 years, if they had been given a diagnosis of or had been treated for cancer, if exercise was used to treat CRF as a primary or secondary endpoint, and if the effects of the intervention were evaluated quantitatively and presented adequate statistical data for analysis. A total of 16 studies, representing 1426 participants (exercise, 759; control, 667) were included in a meta-analysis using a fixed-effects model. The standardized mean difference effect size (SMD) was used to test the effect of exercise on CRF between experimental and control groups. The results indicate a small but significant effect size in favour of the use of exercise interventions for reducing CRF (SMD 0.26, p < 0.001). Furthermore, aerobic exercise programs caused a significant reduction in CRF (SMD 0.21, p < 0.001) and overall, exercise was able to significantly improve aerobic and musculoskeletal fitness compared with control groups (p < 0.01). Further investigation is still required to determine the effects of exercise on potential underlying mechanisms related to the pathophysiology of CRF.

Normative reference values for the 20 m shuttle‐run test in a population‐based sample of school‐aged youth in Bogota, Colombia: the FUPRECOL study

PubMed Central

Palacios‐López, Adalberto; Humberto Prieto‐Benavides, Daniel; Enrique Correa‐Bautista, Jorge; Izquierdo, Mikel; Alonso‐Martínez, Alicia; Lobelo, Felipe

2016-01-01

Abstract Objectives Our aim was to determine the normative reference values of cardiorespiratory fitness (CRF) and to establish the proportion of subjects with low CRF suggestive of future cardio‐metabolic risk. Methods A total of 7244 children and adolescents attending public schools in Bogota, Colombia (55.7% girls; age range of 9–17.9 years) participated in this study. We expressed CRF performance as the nearest stage (minute) completed and the estimated peak oxygen consumption (V˙O2peak). Smoothed percentile curves were calculated. In addition, we present the prevalence of low CRF after applying a correction factor to account for the impact of Bogota's altitude (2625 m over sea level) on CRF assessment, and we calculated the number of participants who fell below health‐related FITNESSGRAM cut‐points for low CRF. Results Shuttles and V˙O2peak were higher in boys than in girls in all age groups. In boys, there were higher levels of performance with increasing age, with most gains between the ages of 13 and 17. The proportion of subjects with a low CRF, suggestive of future cardio‐metabolic risk (health risk FITNESSGRAM category) was 31.5% (28.2% for boys and 34.1% for girls; X2 P = .001). After applying a 1.11 altitude correction factor, the overall prevalence of low CRF was 11.5% (9.6% for boys and 13.1% for girls; X2 P = .001). Conclusions Our results provide sex‐ and age‐specific normative reference standards for the 20 m shuttle‐run test and estimated V˙O2peak values in a large, population‐based sample of schoolchildren from a large Latin‐American city at high altitude. PMID:27500986

[Comparison of the effects of different side-cut angles on corneal biomechanical properties after femtosecond laser assisted-laser in situ keratomileusis].

PubMed

Li, H; Wang, Y; Dou, R; Wang, L; Xu, L L; Li, X J; Zhang, J M

2017-01-11

Objective: To evaluate the effects of side-cut angles on corneal biomechanical properties after femtosecond laser assisted-laser in situ keratomileusis (FS-LASIK). Methods: In this clinical control study, 97 right eyes of 97 patients with myopia and myopic astigmatism undergoing FS-LASIK surgery were included randomly. Two types of side-cut angles were designed for the flap, 90° in 48 eyes and 130° in 49 eyes. The values of corneal resistance factor (CRF), cornea hysteresis (CH) and 37 biomechanical waveform parameters were measured using the ocular response analyzer preoperatively and at 1 and 3 months postoperatively. The comparison between the two groups at different follow-up time points was made with one-way analysis of variance, and the comparison among different follow-up time points in each group was performed with the repeated measures analysis of variance. Results: The mean CRF, CH, p area, h, dive1, dive2, w11 and w21 in both groups showed significant reduction at 1 month postoperatively (group 90°: CRF 10.49 vs. 6.85, CH 10.02 vs. 7.55, p1 area 3 537.54 vs. 1 918.07, h1 404.74 vs. 283.25, dive1 350.63 vs. 243.33, w11 10.50 vs. 7.58. group 130°: CRF 10.14 vs. 6.38, CH 9.93 vs. 7.13, p1 area 3 498.93 vs. 2 038.74, h1 411.93 vs. 304.49, dive1 352.51 vs. 265.12, w11 10.55 vs. 7.78. P< 0.001) . The mean CRF, CH, p area, w, h, dive1 and dive2 in both groups showed significant reduction at 3 months postoperatively (group 90°: CRF 10.49 vs. 6.60, CH 10.02 vs. 7.65, p1 area 3537.54 vs. 2042.91, h1 404.74 vs. 307.77, dive1 350.63 vs. 263.33, w11 10.50 vs. 7.58. group 130°: CRF 10.14 vs. 6.45, CH 9.93 vs. 7.67, p1 area 3 498.93 vs. 2 187.97, h1 411.93 vs. 327.39, dive1 352.51 vs. 284.26, w11 10.55 vs. 7.61. P< 0.001). The mean path in both groups showed significant increase at 1 and 3 months postoperatively (group 90°: path1 23.14 vs. 30.50 vs. 30.79. group 130°: path1 24.12 vs. 32.18 vs. 31.49. P< 0.001). The mean aplhf, bindex, dive2 and path2 between both groups at 1 month postoperatively showed significant difference ( F= 8.609, 7.482, 5.238, 4.885, P <0.05). The mean path11 between both groups at 3 months postoperatively showed significant difference ( F= 6.160, P <0.05). Conclusions: Corneal biomechanical properties significantly decrease after FS-LASIK, and different side-cut angles have some effect on corneal biomechanical properties after FS-LASIK. The corneal deformation is more stable after flap creation with an obtuse side-cut angle making the cornea under stress. Combined with waveform parameters of the ocular response analyzer, more subtle changes of corneal biomechanical properties can be found. (Chin J Ophthalmol, 2017, 53:23-32) .

Involvement of CRF but not NPY in the anxiety regulation via NMDA receptors.

PubMed

Wierońska, Joanna M; Szewczyk, Bernadeta; Pałucha, Agnieszka; Brański, Piotr; Smiałowska, Maria

2003-01-01

The study attempts to evaluate whether neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are involved in anxiogenic and anxiolytic reactions induced by NMDA receptor ligands. The animals were given MK-801 (1 mg/kg, ip), a non-competitive NMDA-receptor antagonist, which acts as anxiolytic agent, or NMDA (15 mg/kg, ip), which has an anxiogenic effect. The anxiogenic or anxiolytic actions of these compounds were evaluated in the plus-maze test. The animals, which were given MK-801, were administered BIBO 3304 (130 ng/0.5 microl/site) intraamygdalarly and the animals which were given NMDA were administered alpha-helical CRF (500 ng/0.5 microl/site). BIBO 3304 did not attenuate MK-801-induced anxiolysis and alpha-helical CRF abolished NMDA-induced anxiogenesis. Our results show that anxiogenic effect of NMDA is mediated via CRF1 receptors and anxiolytic action of MK-801 is not dependent on Y1 receptors.

Neonatal isolation delays the developmental decline of long-term depression in the CA1 region of rat hippocampus.

PubMed

Ku, Hsiao-Yun; Huang, Yu-Fei; Chao, Pei-Hsuan; Huang, Chiung-Chun; Hsu, Kuei-Sen

2008-11-01

Activity-dependent alterations of synaptic efficacy or connectivity are essential for the development, signal processing, and learning and memory functions of the nervous system. It was observed that, in particular in the CA1 region of the hippocampus, low-frequency stimulation (LFS) became progressively less effective at inducing long-term depression (LTD) with advancing developmental age. The physiological factors regulating this developmental plasticity change, however, have not yet been elucidated. Here we examined the hypothesis that neonatal isolation (once per day for 1 h from postnatal days 1-7) is able to alter processes underlying the developmental decline of LTD. We confirm that the magnitude of LTD induced by LFS (900 stimuli at 1 Hz) protocol correlates negatively with developmental age and illustrates that neonatal isolation delays this developmental decline via the activation of corticotrophin-releasing factor (CRF) system. Furthermore, this modulation appears to be mediated by an increased transcription of N-methyl-D-aspartate receptor NR2B subunits. We also demonstrate that intracerebroventricular injection of CRF postnatally mimicked the effect of neonatal isolation to increase the expression of NR2B subunits and delayed the developmental decline of LTD, which was specifically blocked by CRF receptor 1 antagonist NBI27914 pretreatment. These results suggest a novel role for CRF in regulating developmental events in the hippocampus and indicate that although maternal deprivation is stressful for neonate, appropriate neonatal isolation can serve to promote an endocrine state that may regulate the gradual developmental change in the induction rules for synaptic plasticity in the hippocampal CA1 region.

A stochastically fully connected conditional random field framework for super resolution OCT

NASA Astrophysics Data System (ADS)

Boroomand, A.; Tan, B.; Wong, A.; Bizheva, K.

2017-02-01

A number of factors can degrade the resolution and contrast of OCT images, such as: (1) changes of the OCT pointspread function (PSF) resulting from wavelength dependent scattering and absorption of light along the imaging depth (2) speckle noise, as well as (3) motion artifacts. We propose a new Super Resolution OCT (SR OCT) imaging framework that takes advantage of a Stochastically Fully Connected Conditional Random Field (SF-CRF) model to generate a Super Resolved OCT (SR OCT) image of higher quality from a set of Low-Resolution OCT (LR OCT) images. The proposed SF-CRF SR OCT imaging is able to simultaneously compensate for all of the factors mentioned above, that degrade the OCT image quality, using a unified computational framework. The proposed SF-CRF SR OCT imaging framework was tested on a set of simulated LR human retinal OCT images generated from a high resolution, high contrast retinal image, and on a set of in-vivo, high resolution, high contrast rat retinal OCT images. The reconstructed SR OCT images show considerably higher spatial resolution, less speckle noise and higher contrast compared to other tested methods. Visual assessment of the results demonstrated the usefulness of the proposed approach in better preservation of fine details and structures of the imaged sample, retaining biological tissue boundaries while reducing speckle noise using a unified computational framework. Quantitative evaluation using both Contrast to Noise Ratio (CNR) and Edge Preservation (EP) parameter also showed superior performance of the proposed SF-CRF SR OCT approach compared to other image processing approaches.

Physiotherapy programme reduces fatigue in patients with advanced cancer receiving palliative care: randomized controlled trial.

PubMed

Pyszora, Anna; Budzyński, Jacek; Wójcik, Agnieszka; Prokop, Anna; Krajnik, Małgorzata

2017-09-01

Cancer-related fatigue (CRF) is a common and relevant symptom in patients with advanced cancer that significantly decreases their quality of life. The aim of this study was to evaluate the effect of a physiotherapy programme on CRF and other symptoms in patients diagnosed with advanced cancer. The study was designed as a randomized controlled trial. Sixty patients diagnosed with advanced cancer receiving palliative care were randomized into two groups: the treatment group (n = 30) and the control group (n = 30). The therapy took place three times a week for 2 weeks. The 30-min physiotherapy session included active exercises, myofascial release and proprioceptive neuromuscular facilitation (PNF) techniques. The control group did not exercise. The outcomes included Brief Fatigue Inventory (BFI), Edmonton Symptom Assessment Scale (ESAS) and satisfaction scores. The exercise programme caused a significant reduction in fatigue scores (BFI) in terms of severity of fatigue and its impact on daily functioning. In the control group, no significant changes in the BFI were observed. Moreover, the physiotherapy programme improved patients' general well-being and reduced the intensity of coexisting symptoms such as pain, drowsiness, lack of appetite and depression. The analysis of satisfaction scores showed that it was also positively evaluated by patients. The physiotherapy programme, which included active exercises, myofascial release and PNF techniques, had beneficial effects on CRF and other symptoms in patients with advanced cancer who received palliative care. The results of the study suggest that physiotherapy is a safe and effective method of CRF management.

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

PubMed

Mochizuki, Michiyo; Kori, Masakuni; Kobayashi, Katsumi; Yano, Takahiko; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Gyorkos, Albert C; Corrette, Christopher P; Cho, Suk Young; Pratt, Scott A; Aso, Kazuyoshi

2016-03-24

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.

Interaction of Gender and Hepatitis C in Risk of Chronic Renal Failure After Liver Transplantation.

PubMed

Ip, Stephen; Hussaini, Trana; Daulat, Aliya; Partovi, Nilufar; Erb, Siegfried R; Yoshida, Eric M; Marquez, Vladimir

2017-01-01

Chronic renal failure (CRF) is a significant cause of morbidity and mortality in post-liver transplantation (LT) recipients. The risk factors associated with the development of renal dysfunction are not clearly elucidated. To examine the risk factors in the development of CRF in these patients. Retrospective case-cohort of liver transplant patients without baseline kidney dysfunction who developed chronic renal failure during their follow-up. Of 370 patients, 254 met the inclusion criteria. 30% (76) of these patients had CRF of which 57% (43) were male. Age, estimated glomerular filtration rate (eGFR) at discharge, and HCV infection were found to be risk factors for CRF post-LT. The odds ratio of developing CRF was 1.4 (0.6-3.3) in males with HCV, 1.6 (0.7-3.9) in females without HCV and 4.4 (1.5-13.2) among females with HCV when compared to men without HCV. In this cohort of LT receipients of a major Canadian city, age, eGFR, and HCV infection were risk factors for CRF. Female gender and HCV increased this odds by a factor of more than 4.

Correlation of cardiorespiratory fitness with risk factors for cardiovascular disease in children with type 1 diabetes mellitus.

PubMed

Miculis, Cristiane P; de Campos, Wagner; Gasparotto, Guilherme S; Silva, Michael P; Mascarenhas, Luis P; Boguszewski, Margaret C S

2012-01-01

The objective of this study was to correlate CRF with cardiovascular risk factors in T1DM children. Fifty children and adolescents aged between 9 and 17 years with no diabetes complications and a mean diabetes duration of 4.6 years were selected. Antropometric, sexual maturation and blood pressure data were evaluated. CRF level was assessed with a 20-m shuttle run test. Laboratory tests were performed to verify fasting lipids and glycated hemoglobin. Statistical analyses were made with Pearson partial correlation, t test, and one-way ANOVA, with p≤0.05. After adjustment for body adiposity and sexual maturity, inverse correlations among CRF and TC, TG, TC/HDL-C, TG/HDL-C, non-HDL-C, and SBP were statistically significant. Variables differing by sex included weight Z score, BMI Z score, skinfold thickness, percentage of body fat, and DBP. Boys had higher CRF compared to girls. CRF and TC differed significantly by sexual maturation status. An inverse and significant relationship between CRF and most lipid profile's components and SBP in poor controlled T1DM children and adolescents was found, independently of body adiposity. Copyright © 2012 Elsevier Inc. All rights reserved.

Perceptions about cancer-related fatigue among cancer patients using Q methodology.

PubMed

Bang, Ho Yoon; Yeun, Eun Ja; Ham, Eunmi; Jeon, Misoon; An, Jeong Hwa

2016-02-01

Cancer-related fatigue (CRF) is a common subjective feeling and disabling symptom complex experienced by patients with cancer. This study aimed to identify the subjective perceptions of Korean patients with cancer about CRF to help the development of basic intervention strategies for these patients. Q methodology was used to examine the subjective perceptions of patients with cancer about CRF. Thirty-one patients with cancer, hospitalized at a university hospital in Seoul, Korea, were recruited into this study and classified 41 selected Q statements using a nine-point scale. Data were analysed using PC-QUANL for Windows. Data analysis revealed that distinct perceptions about CRF do exist among Korean patients with cancer. Three types of perceptions were identified: dominant self-reliance, positive-conformist and self-deprecating exhaustion. These three types explained 53.0% of the variance (40.2%, 8.2% and 4.6%, respectively). This study identified three types of perceptions about CRF among Korean patients with cancer. These findings provide baseline data to develop customised interventions for caring strategies. This study also informs health professionals in other countries about the perceptions of Korean patients with cancer about CRF. Copyright © 2015 Elsevier Ltd. All rights reserved.

Are lower levels of cardiorespiratory fitness associated with incident depression? A systematic review of prospective cohort studies.

PubMed

Schuch, Felipe B; Vancampfort, Davy; Sui, Xuemei; Rosenbaum, Simon; Firth, Joseph; Richards, Justin; Ward, Philip B; Stubbs, Brendon

2016-12-01

Physical activity (PA) is protective from future depression, however, the potential impact of cardiorespiratory fitness (CRF) on the development of depression is less clear. We aimed to investigate if lower levels of CRF are associated with a higher risk for depression onset. Major electronic databases were searched, from inception to January 2016 for prospective cohort studies evaluating the association between CRF and incident depression. Pooled hazard ratio (HR) with 95% confidence intervals (CIs) were calculated. Methodological quality was evaluated using the Newcastle-Ottawa scale (NOS). Three prospective studies were identified and data from two studies were pooled. Our data provide preliminary evidence found that people with low CRF and medium CRF were at increased risk of developing depression (n=1,128,290, HR=1.76, 95% CI 1.61-1.91, p<0.001, I 2 =11.88, and HR=1.23, 95% CI 1.20-1.38, p<0.001, I 2 =0, respectively). Considered alongside the wider benefits of higher levels of CRF, these findings further support the rationale for interventions specifically targeting fitness, in order to reduce the significant burden associated with depression. Copyright © 2016 Elsevier Inc. All rights reserved.

Subtype B was the dominant strain among HIV type 1 infections except for the population of men who have sex with men in Harbin City, China.

PubMed

Shao, Bing; Li, Wen-Jing; Liu, Ting; Li, Qing-Hai; Li, Hang; Chang, Man-Li; Huang, Chao-Qun; Wang, Fu-Xiang; Wang, Bin-You

2013-09-01

We sought to identify the prevalent subtypes and study the genetic variation of HIV-1 circulating in HIV infections in Harbin City, China. Forty-seven samples from the env V3-V4 region were successfully sequenced and analyzed, which involved thirty-one men who have sex with men (MSM), eight heterosexuals, seven former plasma donors (FPD)/blood transfusion recipients (BT), and one injection drug user (IDU). In all, 46.8% of CRF01_AE, 40.4% of subtype B, and 12.8% of CRF07_BC were identified. CRF01_AE (64.5%) was the dominant strain in MSM, and subtype B (81.2%) was the chief strain in other infected subjects except for the MSM population. Among all the genotypes, the B subtype possesses greater diversity of the tetramer on the tip of V3 loop than CRF07_BC and CRF01_AE, in which the peculiar GWGR was commonly found. Because nationwide there is a trend toward the increasing presence of CRF01_AE, a consecutive surveillance campaign was necessary among all HIV vulnerable populations in this locality.

Modeling OAE responses to short tones

NASA Astrophysics Data System (ADS)

Duifhuis, Hendrikus; Siegel, Jonathan

2015-12-01

In 1999 Shera and Guinan postulated that otoacoustic emissions evoked by low-level transient stimuli are generated by coherent linear reflection (CRF or CLR). This hypothesis was tested experimentally, e.g., by Siegel and Charaziak[10] by measuring emissions evoked by short (1 ms) tone pips in chinchilla. Using techniques in which supplied level and recorded spectral information were used Siegel and Charaziak concluded that much of the emission was generated by a mechanism in a region extending basally from the peak of the traveling wave and that the action of the suppressor is to remove emission generators evoked by the tone-pip and not to generate nonlinear artifacts in regions basal to the peak region. The original formulation of the CRF theory does not account for these results This study addresses relevant cochlear model predictions.

Enhanced motivation for food reward induced by stress and attenuation by corticotrophin-releasing factor receptor antagonism in rats: implications for overeating and obesity

PubMed Central

Liu, Xiu

2014-01-01

Rationale Overeating beyond individuals’ homeostatic needs critically contributes to obesity. The neurobehavioral mechanisms underlying the motivation to consume excessive foods with high calories are not fully understood. Objective The present study examined whether a pharmacological stressor, yohimbine enhances the motivation to procure food reward with an emphasis on comparisons between standard lab chow and high-fat foods. The effects of corticotropin-releasing factor receptor (CRF1) blockade by a CFR1 selective antagonist NBI on the stress-enhanced motivation for food reward were also assessed. Methods Male Sprague-Dawley rats with chow available ad libitum in their home cages were trained to press a lever under a progressive-ratio schedule for deliveries of either standard or high-fat food pellets. For testing yohimbine stress effects, rats received an intraperitoneal administration of yohimbine 10 min before start of the test sessions. For testing effects of CRF1 receptor blockade on stress responses, NBI was administered 20 min prior to yohimbine challenge. Results The rats emitted higher levels of lever responses to procure the high-fat food pellets compared with their counterparts on standard food pellets. Yohimbine challenge facilitated lever responses for the reward in all of the rats, whereas the effect was more robust in the rats on high-fat food pellets compared with their counterparts on standard food pellets. An inhibitory effect of pretreatment with NBI was observed on the enhancing effect of yohimbine challenge but not on the responses under baseline condition without yohimbine administration. Conclusions Stress challenge significantly enhanced the motivation of satiated rats to procure extra food reward, especially the high-fat food pellets. Activation of CRF1 receptors is required for the stress-enhanced motivation for food reward. These results may have implications for our better understanding of the biobehavioral mechanisms of overeating and obesity. PMID:25510859

Tumor Growth Increases Neuroinflammation, Fatigue and Depressive-like Behavior Prior to Alterations in Muscle Function

PubMed Central

Norden, Diana M.; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J.; Wold, Loren E.; Reiser, Peter J.; Godbout, Jonathan P.; McCarthy, Donna O.

2014-01-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. PMID:25102452

Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function.

PubMed

Norden, Diana M; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J; Wold, Loren E; Reiser, Peter J; Godbout, Jonathan P; McCarthy, Donna O

2015-01-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. Copyright © 2014 Elsevier Inc. All rights reserved.

Muscular strength and incident hypertension in normotensive and prehypertensive men.

PubMed

Maslow, Andréa L; Sui, Xuemei; Colabianchi, Natalie; Hussey, Jim; Blair, Steven N

2010-02-01

The protective effects of cardiorespiratory fitness (CRF) on hypertension (HTN) are well known; however, the association between muscular strength and incidence of HTN has yet to be examined. This study evaluated the strength-HTN association with and without accounting for CRF. Participants were 4147 men (age = 20-82 yr) in the Aerobics Center Longitudinal Study for whom an age-specific composite muscular strength score was computed from measures of a one-repetition maximal leg and a one-repetition maximal bench press. CRF was quantified by maximal treadmill exercise test time in minutes. Cox proportional hazards regression analysis was used to estimate hazard ratios (HR) and 95% confidence intervals of incident HTN events according to exposure categories. During a mean follow-up of 19 yr, there were 503 incident HTN cases. Multivariable-adjusted (excluding CRF) HR of HTN in normotensive men comparing middle- and high-strength thirds to the lowest third were not significant at 1.17 and 0.84, respectively. Multivariable-adjusted (excluding CRF) HR of HTN in baseline prehypertensive men comparing middle- and high-strength thirds to the lowest third were significant at 0.73 and 0.72 (P = 0.01 each), respectively. The association between muscular strength and incidence of HTN in baseline prehypertensive men was no longer significant after control for CRF (P = 0.26). The study indicated that middle and high levels of muscular strength were associated with a reduced risk of HTN in prehypertensive men only. However, this relationship was no longer significant after controlling for CRF.

Preclinical evidence implicating corticotropin-releasing factor signaling in ethanol consumption and neuroadaptation

PubMed Central

Phillips, T. J.; Reed, C.; Pastor, R.

2016-01-01

The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF1) in EtOH-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with EtOH drinking, although additional data are needed. These results suggest that CRF1 antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects. PMID:25565358

Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects.

PubMed

Carpenter, Linda L; Tyrka, Audrey R; McDougle, Christopher J; Malison, Robert T; Owens, Michael J; Nemeroff, Charles B; Price, Lawrence H

2004-04-01

Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression. Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period. The present study was designed to determine whether major depression and a history of perceived early adversity in childhood are independently associated with elevated CSF CRF concentrations in adults. In this case-control study, 27 medication-free adults with major depression and 25 matched controls underwent standardized lumbar puncture for collection of a single CSF sample at 1200. Subjects provided data about significant adverse early-life experiences and rated their global perceived level of stress during pre-school and preteen years on a six-point Likert scale. The mean difference in CSF CRF between depressed patients and controls did not reach statistical significance. In a regression model, perceived early-life stress was a significant predictor of CSF CRF, but depression was not. Perinatal adversity and perceived adversity in the preteen adversity years (ages 6-13 years) were both independently associated with decreasing CSF CRF concentrations. The relationship observed between perceived early-life stress and adult CSF CRF concentrations in this study closely parallels recent preclinical findings. More work is needed to elucidate the critical nature and timing of early events that may be associated with enduring neuroendocrine changes in humans.

A Large-scale Survey of CRF55_01B from Men-Who-Have-Sex-with-Men in China: implying the Evolutionary History and Public Health Impact.

PubMed

Han, Xiaoxu; Takebe, Yutaka; Zhang, Weiqing; An, Minghui; Zhao, Bin; Hu, Qinghai; Xu, Junjie; Wu, Hao; Wu, Jianjun; Lu, Lin; Chen, Xi; Liang, Shu; Wang, Zhe; Yan, Hongjing; Fu, Jihua; Cai, Weiping; Zhuang, Minghua; Liao, Christina; Shang, Hong

2015-12-15

The HIV-1 epidemic among men-who-have-sex-with-men (MSM) continues to expand in China, involving the co-circulation of several different lineages of HIV-1 strains, including subtype B and CRF01_AE. This expansion has created conditions that facilitate the generation of new recombinant strains. A molecular epidemiologic survey among MSM in 11 provinces/cities around China was conducted from 2008 to 2013. Based on pol nucleotide sequences, a total of 19 strains (1.95%) belonged to the CRF55_01B were identified from 975 MSM in 7 provinces, with the prevalence range from 1.5% to 12.5%. Near full length genome (NFLG) sequences from six epidemiologically-unlinked MSM were amplified for analyzing evolutionary history, an identical genome structure composed of CRF01_AE and subtype B with four unique recombination breakpoints in the pol region were identified. Bayesian molecular clock analyses for both CRF01_AE and B segments indicated that the estimated time of the most recent common ancestors of CRF55_01B was around the year 2000. Our study found CRF55_01B has spread throughout the most provinces with high HIV-1 prevalence and highlights the importance of continual surveillance of dynamic changes in HIV-1 strains, the emergence of new recombinants, and the need for implementing effective prevention measures specifically targeting the MSM population in China.

Reduced rates of controlled-release fertilizer lower potential nitrogen leaching from a Wisconsin bare-root tree nursery

Treesearch

Ryosuke Fujinuma; Nick J. Balster; Hyung-Kyung. Lee

2011-01-01

Controlled-release fertilizer (CRF) typically increases nitrogen (N) fertilizer uptake and lowers N lost from the rooting zone via leaching. However, questions remain as to whether lower rates of CRF could further increase this efficiency, especially in sandy bare-root nurseries in Wisconsin. We hypothesized that: 1) a reduced CRF application at 60 percent of the...

Ice Water Classification Using Statistical Distribution Based Conditional Random Fields in RADARSAT-2 Dual Polarization Imagery

NASA Astrophysics Data System (ADS)

Zhang, Y.; Li, F.; Zhang, S.; Hao, W.; Zhu, T.; Yuan, L.; Xiao, F.

2017-09-01

In this paper, Statistical Distribution based Conditional Random Fields (STA-CRF) algorithm is exploited for improving marginal ice-water classification. Pixel level ice concentration is presented as the comparison of methods based on CRF. Furthermore, in order to explore the effective statistical distribution model to be integrated into STA-CRF, five statistical distribution models are investigated. The STA-CRF methods are tested on 2 scenes around Prydz Bay and Adélie Depression, where contain a variety of ice types during melt season. Experimental results indicate that the proposed method can resolve sea ice edge well in Marginal Ice Zone (MIZ) and show a robust distinction of ice and water.

Comparison of SF-36 vitality scale and Fatigue Symptom Inventory in assessing cancer-related fatigue.

PubMed

Brown, Linda F; Kroenke, Kurt; Theobald, Dale E; Wu, Jingwei

2011-08-01

Cancer-related fatigue (CRF) is an important symptom in clinical practice and research. The best way to measure it, however, remains unsettled. The SF-36 vitality scale, a general measure of energy/fatigue, is a frequently cited measure. With only four items, however, its ability to adequately represent multiple CRF facets has been questioned. The 13-item Fatigue Symptom Inventory (FSI) was developed to assess multidimensional aspects of CRF. Our objectives were to assess the convergent validity and to compare the sensitivity to change of the two scales. We administered both scales at 1 month (n = 68) and 6 months (n = 96) to a subset of heterogeneous patients receiving treatment in 16 cancer centers who were enrolled in a clinical trial of pain and depression. Distributions of standardized response means (SRMs) were compared to assess sensitivity to change. Results of both scales were compared to scores on a single fatigue item from the Patient Health Questionnaire (PHQ). Mean scores for both the FSI and the vitality scale demonstrated clinically significant fatigue in the sample. The vitality scale was strongly correlated with all three FSI scales (r = -0.68 to -0.77). The vitality and FSI scales also correlated strongly with the PHQ fatigue item. Moreover, distributions of SRMs for both scales were approximately normal. Both the FSI and the vitality scale are supported as valid measures of CRF. Both demonstrated sensitivity to change across a range of effect sizes. The vitality scale may be an excellent choice when brevity is paramount; the FSI may be more appropriate when tapping specific dimensions is warranted.

Effect of corticotropin-releasing factor receptor antagonist on psychologically suppressed masculine sexual behavior in rats.

PubMed

Miwa, Yoshiji; Nagase, Keiko; Oyama, Nobuyuki; Akino, Hironobu; Yokoyama, Osamu

2011-03-01

Corticotropin-releasing factor (CRF) coordinates various responses of the body to stress, and CRF receptors are important targets of treatment for stress-related disorders. To investigate the effect of a nonselective CRF receptor antagonist, astressin, on suppression of masculine sexual behavior by psychological stress in rats. First, we investigated the influence of psychological stress, induced 2 hours per day for three consecutive days, on sexual behavior. Then, rats were divided into 4 groups: a control group, an astressin administration group (A), a psychological stress loading group (PS), and a psychological stress loading and astressin administration group (PS + A). The rats were exposed to sham or psychological stress for three consecutive days. After the last stress loading, the rats were injected with vehicle or astressin, and their sexual behavior was observed. We also measured serum levels of adrenocorticotropic hormone (ACTH). The effects of astressin on sexual behavior and serum levels of ACTH in rats affected by psychological stress were determined. Sexual behavior was reduced after psychological stress loading. The PS rats had significantly longer mount, intromission, and ejaculation latencies and lower ejaculation frequency than did the control, A, and PS + A rats. The intromission latency and ejaculation frequency in the PS + A rats did not achieve the level observed in the controls. There was no significant difference in these parameters between the control and A rats. Serum ACTH levels were significantly lower in PS + A rats than in PS rats. Psychologically suppressed masculine sexual behavior could be partially recovered with astressin administration in rats. These data provide a rationale for the further study of CRF receptor antagonists as novel agents for treating psychological sexual disorders. © 2010 International Society for Sexual Medicine.

Effects of topical travoprost 0.004% on intraocular pressure and corneal biomechanical properties in an animal model.

PubMed

Lazcano-Gomez, Gabriel; Ancona-Lezama, David; Gil-Carrasco, Felix; Jimenez-Roman, Jesus

2016-01-01

To determine whether topical application of travoprost 0.004% induces changes in corneal biomechanical properties affecting intraocular pressure (IOP) values in rabbits. Both eyes of 10 New Zealand rabbits were measured 3 times with the Ocular Response Analyzer (ORA) before treatment. Each measurement included corneal hysteresis (CH), corneal resistance factor (CRF), corneal-corrected IOP (IOPcc), and Goldmann equivalent IOP (IOPg). A drop of travoprost 0.004% was applied once daily in right eyes for 3 months; left eyes received no treatments. After 3 months of treatment both eyes of all rabbits were again measured 3 times. After complete keratectomy of both eyes, tissues prepared with hematoxylin-eosin stain were analyzed by means of light microscopy. The mean pre- and post-treatment IOPg, respectively, for right eyes was 9.92 ± 5.64 mm Hg and 7.62 ± 2.99 mm Hg (P = 0.027); IOPcc, 19.81 ± 5.25 mm Hg and 17.79 ± 4.09 mm Hg (P = 0.063); CRF, 1.65 ± 1.63 mm Hg and 2.18 ± 2.50 mm Hg (P = 0.266); and CH, 2.79 ± 1.74 mm Hg and 2.64 ± 2.08 mm Hg (P = 0.72). Mean post-treatment right and left eye IOPg values were, respectively, 7.62 ± 2.99 and 10.30 ± 4.40 (P = 0.002); IOPcc, 17.79 ± 4.09 mm Hg and 20.37 ± 4.32 mm Hg (P = 0.009); CRF, 1.65 ± 1.63 mm Hg and 2.17 ± 2.47 mm Hg (P = 0.274); and CH, 2.79 ± 1.74 mm Hg and 2.54 ± 2.08 mm Hg (P = 0.575). No difference in CH and CRF was observed between treated and untreated eyes. Post-treatment reduction of IOP in treated eyes was a direct hypotensive effect of travoprost 0.004% and was not affected by changes in corneal biomechanical properties (CH and CRF), resulting in real lower IOP values.

Effects of topical travoprost 0.004% on intraocular pressure and corneal biomechanical properties in an animal model

PubMed Central

Lazcano-Gomez, Gabriel; Ancona-Lezama, David; Gil-Carrasco, Felix; Jimenez-Roman, Jesus

2016-01-01

Purpose To determine whether topical application of travoprost 0.004% induces changes in corneal biomechanical properties affecting intraocular pressure (IOP) values in rabbits. Methods Both eyes of 10 New Zealand rabbits were measured 3 times with the Ocular Response Analyzer (ORA) before treatment. Each measurement included corneal hysteresis (CH), corneal resistance factor (CRF), corneal-corrected IOP (IOPcc), and Goldmann equivalent IOP (IOPg). A drop of travoprost 0.004% was applied once daily in right eyes for 3 months; left eyes received no treatments. After 3 months of treatment both eyes of all rabbits were again measured 3 times. After complete keratectomy of both eyes, tissues prepared with hematoxylin-eosin stain were analyzed by means of light microscopy. Results The mean pre- and post-treatment IOPg, respectively, for right eyes was 9.92 ± 5.64 mm Hg and 7.62 ± 2.99 mm Hg (P = 0.027); IOPcc, 19.81 ± 5.25 mm Hg and 17.79 ± 4.09 mm Hg (P = 0.063); CRF, 1.65 ± 1.63 mm Hg and 2.18 ± 2.50 mm Hg (P = 0.266); and CH, 2.79 ± 1.74 mm Hg and 2.64 ± 2.08 mm Hg (P = 0.72). Mean post-treatment right and left eye IOPg values were, respectively, 7.62 ± 2.99 and 10.30 ± 4.40 (P = 0.002); IOPcc, 17.79 ± 4.09 mm Hg and 20.37 ± 4.32 mm Hg (P = 0.009); CRF, 1.65 ± 1.63 mm Hg and 2.17 ± 2.47 mm Hg (P = 0.274); and CH, 2.79 ± 1.74 mm Hg and 2.54 ± 2.08 mm Hg (P = 0.575). No difference in CH and CRF was observed between treated and untreated eyes. Conclusions Post-treatment reduction of IOP in treated eyes was a direct hypotensive effect of travoprost 0.004% and was not affected by changes in corneal biomechanical properties (CH and CRF), resulting in real lower IOP values. PMID:27330476

Cardiorespiratory Fitness as a Mediator of the Influence of Diet on Obesity in Children.

PubMed

Lahoz-García, Noelia; García-Hermoso, Antonio; Milla-Tobarra, Marta; Díez-Fernández, Ana; Soriano-Cano, Alba; Martínez-Vizcaíno, Vicente

2018-03-16

The association between diet and obesity has been widely studied and it continues to be controversial; however, the extent to which cardiorespiratory fitness (CRF) acts as a confounder or mediator in this relation has not been analyzed. The aim of this study is to examine if the relation between diet and obesity is mediated by CRF. In this cross-sectional study, fat mass (by electronic bioimpedance) was measured in 320 schoolchildren, aged 9-11 years. Diet was measured through two computerised 24-h dietary recalls and CRF was assessed by the 20-m shuttle run test. Simple mediation analyses were fitted. CRF acts as a partial mediator in the negative relationship between dietary factors (energy intake/weight, carbohydrate intake/weight, protein intake/weight, and fat intake/weight) and fat mass. The percentage of mediation ranged from 24.3 to 33.2%. Thus, Spanish schoolchildren with higher levels of energy and macronutrients intake had lower adiposity levels, especially when they had good levels of CRF.

Top-Down Visual Saliency via Joint CRF and Dictionary Learning.

PubMed

Yang, Jimei; Yang, Ming-Hsuan

2017-03-01

Top-down visual saliency is an important module of visual attention. In this work, we propose a novel top-down saliency model that jointly learns a Conditional Random Field (CRF) and a visual dictionary. The proposed model incorporates a layered structure from top to bottom: CRF, sparse coding and image patches. With sparse coding as an intermediate layer, CRF is learned in a feature-adaptive manner; meanwhile with CRF as the output layer, the dictionary is learned under structured supervision. For efficient and effective joint learning, we develop a max-margin approach via a stochastic gradient descent algorithm. Experimental results on the Graz-02 and PASCAL VOC datasets show that our model performs favorably against state-of-the-art top-down saliency methods for target object localization. In addition, the dictionary update significantly improves the performance of our model. We demonstrate the merits of the proposed top-down saliency model by applying it to prioritizing object proposals for detection and predicting human fixations.

Cardiorespiratory Fitness as a Mediator of the Influence of Diet on Obesity in Children

PubMed Central

Lahoz-García, Noelia; Milla-Tobarra, Marta; Soriano-Cano, Alba

2018-01-01

The association between diet and obesity has been widely studied and it continues to be controversial; however, the extent to which cardiorespiratory fitness (CRF) acts as a confounder or mediator in this relation has not been analyzed. The aim of this study is to examine if the relation between diet and obesity is mediated by CRF. In this cross-sectional study, fat mass (by electronic bioimpedance) was measured in 320 schoolchildren, aged 9–11 years. Diet was measured through two computerised 24-h dietary recalls and CRF was assessed by the 20-m shuttle run test. Simple mediation analyses were fitted. CRF acts as a partial mediator in the negative relationship between dietary factors (energy intake/weight, carbohydrate intake/weight, protein intake/weight, and fat intake/weight) and fat mass. The percentage of mediation ranged from 24.3 to 33.2%. Thus, Spanish schoolchildren with higher levels of energy and macronutrients intake had lower adiposity levels, especially when they had good levels of CRF. PMID:29547513

Emergence of recombinant forms in geographic regions with co-circulating HIV subtypes in the dynamic HIV-1 epidemic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Ming; Letiner, Thomas K; Korber, Bette T

2009-01-01

We have reexamined the subtype designations of {approx}10,000 subtype A, B, C, G, and AG, BC, BF recombinant sequences, and compared the results of the new analysis with their published designations. Intersubtype recombinants dominate HIV epidemics in three different geographical regions. The circulating recombinant from (CRF) CRF02-AG, common in West Central Africa, appears to result from a recombination event that occurred early in the divergence between subtypes A and G, although additional more recent recombination events may have contributed to the breakpoint pattern in this recombinant lineage as well. The Chinese recombinant epidemic strains CRF07 and CRF08, in contrast, resultmore » from recent recombinations between more contemporary strains. Nevertheless, CRF07 and CRF08 contributed to many subsequent recombination events. The BF recombinant epidemics in two HIV-1 epicenters in South America are not independent and BF epidemics in South America have an unusually high fraction of unique recombinant forms (URFs) that have each been found only once and carry distinctive breakpoints. Taken together, these analyses reveal a complex and dynamic picture of the current HIV-1 epidemic, and suggest a means of grouping and tracking relationships between viruses through preservation of shared breakpints.« less

Associations Between Cardiorespiratory Fitness and Overweight With Academic Performance in 12-Year-Old Brazilian Children.

PubMed

de Almeida Santana, Carla Caroliny; Farah, Breno Quintella; de Azevedo, Liane Beretta; Hill, James O; Gunnarsdottir, Thrudur; Botero, João Paulo; do Prado, Edna Cristina; do Prado, Wagner Luiz

2017-05-01

Obesity has been associated with poor academic achievement, while cardiorespiratory fitness (CRF) has been linked to academic success. To investigate whether CRF is associated with academic performance in Brazilian students, independently of body mass index (BMI), fatness and socioeconomic status (SES). 392 5th and 6th grade students (193 girls) (12.11 ± 0.75 years old) were evaluated in 2012. Skinfold thickness measures were performed, and students were classified according to BMI-percentile. CRF was estimated by a 20-meter shuttle run test, and academic achievement by standardized math and Portuguese tests. Multiple linear regression analyses were conducted to explore the association between academic performance and CRF, adjusted for SES, skinfold thickness or BMI-percentile. Among girls CRF was associated with higher academic achievement in math (β = 0.146;p = .003) and Portuguese (β = 0.129;p = .004) in crude and adjusted analyses. No significant association was found among boys. BMI was not associated with overall academic performance. There was a weak negative association between skinfold thickness and performance in mathematics in boys (β =- 0.030;p = .04), but not in girls. The results highlight the importance of maintaining high fitness levels in girls throughout adolescence a period commonly associated with reductions in physical activity levels and CRF.

Conditional Random Field (CRF)-Boosting: Constructing a Robust Online Hybrid Boosting Multiple Object Tracker Facilitated by CRF Learning

PubMed Central

Yang, Ehwa; Gwak, Jeonghwan; Jeon, Moongu

2017-01-01

Due to the reasonably acceptable performance of state-of-the-art object detectors, tracking-by-detection is a standard strategy for visual multi-object tracking (MOT). In particular, online MOT is more demanding due to its diverse applications in time-critical situations. A main issue of realizing online MOT is how to associate noisy object detection results on a new frame with previously being tracked objects. In this work, we propose a multi-object tracker method called CRF-boosting which utilizes a hybrid data association method based on online hybrid boosting facilitated by a conditional random field (CRF) for establishing online MOT. For data association, learned CRF is used to generate reliable low-level tracklets and then these are used as the input of the hybrid boosting. To do so, while existing data association methods based on boosting algorithms have the necessity of training data having ground truth information to improve robustness, CRF-boosting ensures sufficient robustness without such information due to the synergetic cascaded learning procedure. Further, a hierarchical feature association framework is adopted to further improve MOT accuracy. From experimental results on public datasets, we could conclude that the benefit of proposed hybrid approach compared to the other competitive MOT systems is noticeable. PMID:28304366

Fitness and Adiposity Are Independently Associated with Cardiometabolic Risk in Youth

PubMed Central

Buchan, Duncan S.; Young, John D.; Boddy, Lynne M.; Malina, Robert M.; Baker, Julien S.

2013-01-01

Purpose. The purpose of the study was to examine the independent associations of adiposity and cardiorespiratory fitness with clustered cardiometabolic risk. Methods. A cross-sectional sample of 192 adolescents (118 boys), aged 14–16 years, was recruited from a South Lanarkshire school in the West of Scotland. Anthropometry and blood pressure were measured, and blood samples were taken. The 20 m multistage fitness test was the indicator of cardiorespiratory fitness (CRF). A clustered cardiometabolic risk score was constructed from HDL-C (inverted), LDL-C, HOMA, systolic blood pressure, and triglycerides. Interleukin-6, C-reactive protein, and adiponectin were also measured and examined relative to the clustered cardiometabolic risk score, CRF, and adiposity. Results. Although significant, partial correlations between BMI and waist circumference (WC) and both CRF and adiponectin were negative and weak to moderate, while correlations between the BMI and WC and CRP were positive but weak to moderate. Weak to moderate negative associations were also evident for adiponectin with CRP, IL-6, and clustered cardiometabolic risk. WC was positively associated while CRF was negatively associated with clustered cardiometabolic risk. With the additional adjustment for either WC or CRF, the independent associations with cardiometabolic risk persisted. Conclusion. WC and CRF are independently associated with clustered cardiometabolic risk in Scottish adolescents. PMID:23984329

Stress and visceral pain: from animal models to clinical therapies

PubMed Central

Larauche, Muriel; Mulak, Agata; Taché, Yvette

2011-01-01

Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain. PMID:21575632

Muscular Strength and Incident Hypertension in Normotensive and Prehypertensive Men

PubMed Central

Maslow, Andréa L.; Sui, Xuemei; Colabianchi, Natalie; Hussey, Jim; Blair, Steven N.

2009-01-01

The protective effects of cardiorespiratory fitness (CRF) on hypertension (HTN) are well known; however, the association between muscular strength and incidence of HTN has yet to be examined. Purpose This study evaluated the strength-HTN association with and without accounting for CRF. Methods Participants were 4147 men (20–82 years) in the Aerobics Center Longitudinal Study for whom an age-specific composite muscular strength score was computed from measures of a 1-repetition maximal leg and a 1-repetition maximal bench press. CRF was quantified by maximal treadmill exercise test time in minutes. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals of incident HTN events according to exposure categories. Results During a mean follow-up of 19 years, there were 503 incident HTN cases. Multivariable-adjusted (excluding CRF) HRs of hypertension in normotensive men comparing middle and high strength thirds to the lowest third were not significant at 1.17 and 0.84, respectively. Multivariable-adjusted (excluding CRF) HRs of hypertension in baseline prehypertensive men comparing middle and high strength thirds to the lowest third were significant at 0.73 and 0.72 (p=.01 each), respectively. The association between muscular strength and incidence of HTN in baseline prehypertensive men was no longer significant after control for CRF (p=.26). Conclusions The study indicated that middle and high levels of muscular strength were associated with a reduced risk of HTN in prehypertensive men only. However, this relationship was no longer significant after controlling for CRF. PMID:19927030

Cardiorespiratory fitness and exercise-induced ST segment depression in assessing the risk of sudden cardiac death in men.

PubMed

Hagnäs, Magnus J; Lakka, Timo A; Kurl, Sudhir; Rauramaa, Rainer; Mäkikallio, Timo H; Savonen, Kai; Laukkanen, Jari A

2017-03-01

The aim of this study was to investigate whether information on both cardiorespiratory fitness (CRF) and exercise-induced ST segment depression improves the prediction of sudden cardiac death (SCD) in men. The study was based on a population sample of 2328 men aged 42-60 years, who were followed up for on average 19 years. CRF was assessed with maximal exercise test using respiratory gas analysis, expressed in metabolic equivalents (METs) and dichotomised at eight METs. Exercise-induced ST segment depression was defined as 1 mm ST segment depression in ECG. Altogether 165 SCDs occurred during the follow-up. Men with low CRF (<8 METs) and exercise-induced ST segment depression had 4.8-fold (95% CI 2.9 to 7.9) higher risk of SCD than men with high CRF and without exercise-induced ST segment depression (p=0.013 for interaction) after adjustment for other cardiovascular risk factors. Men with high CRF and exercise-induced ST segment depression did not have a statistically significantly higher risk of SCD (HR 1.9, 95% CI 0.9 to 3.8) than men with high CRF and without exercise-induced ST segment depression. The combination of low CRF and exercise-induced ST segment depression was associated with a markedly increased risk of SCD in men. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Phylodynamic Analysis Revealed That Epidemic of CRF07_BC Strain in Men Who Have Sex with Men Drove Its Second Spreading Wave in China.

PubMed

Zhang, Min; Jia, Dijing; Li, Hanping; Gui, Tao; Jia, Lei; Wang, Xiaolin; Li, Tianyi; Liu, Yongjian; Bao, Zuoyi; Liu, Siyang; Zhuang, Daomin; Li, Jingyun; Li, Lin

2017-10-01

CRF07_BC was originally formed in Yunnan province of China in 1980s and spread quickly in injecting drug users (IDUs). In recent years, it has been introduced into men who have sex with men (MSM) and become the most dominant strain in China. In this study, we performed a comprehensively phylodynamic analysis of CRF07_BC sequences from China. All CRF07_BC sequences identified in China were retrieved from database. More sequences obtained in our laboratory were added to make the dataset more representative. A maximum-likelihood (ML) tree was constructed with PhyML3.0. Maximum clade credibility (MCC) tree and effective population size were predicted by using Markov Chains Monte Carlo sampling method with Beast software. A total of 610 CRF07_BC sequences coving 1,473 bp of the gag gene (from 817 to 2,289 according to HXB2 calculator) were included into the dataset. Three epidemic clusters were identified; two clusters comprised sequences from IDUs, while one cluster mainly contained sequences from MSMs. The time of the most recent common ancestor of clusters that composed of sequences from MSMs was estimated to be in 2000. Two rapid spreading waves of effective population size of CRF07_BC infections were identified in the skyline plot. The second wave coincided with the expanding of MSM cluster. The results indicated that the control of CRF07_BC infections in MSMs would help to decrease its epidemic in China.

Cardiorespiratory fitness and risk of type 2 diabetes mellitus: A 23-year cohort study and a meta-analysis of prospective studies.

PubMed

Zaccardi, Francesco; O'Donovan, Gary; Webb, David R; Yates, Thomas; Kurl, Sudhir; Khunti, Kamlesh; Davies, Melanie J; Laukkanen, Jari A

2015-11-01

To investigate the association between cardiorespiratory fitness (CRF) and type 2 diabetes mellitus (T2DM) in a cohort of middle-age Finnish men and to summarise the current evidence in a meta-analysis of prospective studies. CRF was measured at baseline in a random population-based sample of 2520 subjects by assessing oxygen uptake during maximal exercise. Cox regression analysis was used to estimate the association between CRF, expressed as metabolic equivalents (METs), and the risk of T2DM adjusted for potential confounders; this estimate was then pooled with the results of other prospective studies in a meta-analysis. Mean (SD) baseline age and CRF were 53 (5) years and 8.7 (2.1) METs, respectively. During 23 years of follow-up, 153 (6.1%) participants developed T2DM. The hazard ratio per 1-MET higher CRF, adjusted for age, body mass index, systolic blood pressure, serum HDL-cholesterol, and family history of T2DM, was 0.93 (95% confidence interval (CI): 0.84, 1.02; p = 0.109); further adjustment for smoking, education, and socioeconomic status did not materially change the estimate. In a random-effects meta-analysis of eight studies (92,992 participants and 8564 T2DM cases) combining maximally adjusted estimates, the pooled risk ratio of T2DM per 1-MET higher CRF level was 0.95 (95% CI: 0.93, 0.98; p = 0.003; I(2) = 81%), corresponding to 23 fewer cases per 100,000 person-years based on the assumption of a causal link between CRF and T2DM. These data suggest that there is an inverse relationship between CRF and T2DM that is largely independent of other risk factors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparisons of leisure-time physical activity and cardiorespiratory fitness as predictors of all-cause mortality in men and women.

PubMed

Lee, D-C; Sui, X; Ortega, F B; Kim, Y-S; Church, T S; Winett, R A; Ekelund, U; Katzmarzyk, P T; Blair, S N

2011-05-01

To examine the combined associations and relative contributions of leisure-time physical activity (PA) and cardiorespiratory fitness (CRF) with all-cause mortality. Prospective cohort study. Setting Aerobics centre longitudinal study. 31,818 men and 10 555 women who received a medical examination during 1978-2002. Assessment of risk factors Leisure-time PA assessed by self-reported questionnaire; CRF assessed by maximal treadmill test. Main outcome measures All-cause mortality until 31 December 2003. There were 1492 (469 per 10,000) and 230 (218 per 10,000) deaths in men and women, respectively. PA and CRF were positively correlated in men (r = 0.49) and women (r = 0.47) controlling for age (p < 0.001 for both). PA was inversely associated with mortality in multivariable Cox regression analysis among men, but the association was eliminated after further adjustment for CRF. No significant association of PA with mortality was observed in women. CRF was inversely associated with mortality in men and women, and the associations remained significant after further adjustment for PA. In the PA and CRF combined analysis, compared with the reference group "not meeting the recommended PA (< 500 metabolic equivalent-minute/week) and unfit", the relative risks (95% CIs) of mortality were 0.62 (0.54 to 0.72) and 0.61 (0.44 to 0.86) in men and women "not meeting the recommended PA and fit", 0.96 (0.61 to 1.53) and 0.93 (0.33 to 2.58) in men and women "meeting the recommended PA and unfit" and 0.60 (0.51 to 0.70) and 0.56 (0.37 to 0.85) in men and women "meeting the recommended PA and fit", respectively. CRF was more strongly associated with all-cause mortality than PA; therefore, improving CRF should be encouraged in unfit individuals to reduce risk of mortality and considered in the development of future PA guidelines.

Normative reference values for the 20 m shuttle-run test in a population-based sample of school-aged youth in Bogota, Colombia: the FUPRECOL study.

PubMed

Ramírez-Vélez, Robinson; Palacios-López, Adalberto; Humberto Prieto-Benavides, Daniel; Enrique Correa-Bautista, Jorge; Izquierdo, Mikel; Alonso-Martínez, Alicia; Lobelo, Felipe

2017-01-01

Our aim was to determine the normative reference values of cardiorespiratory fitness (CRF) and to establish the proportion of subjects with low CRF suggestive of future cardio-metabolic risk. A total of 7244 children and adolescents attending public schools in Bogota, Colombia (55.7% girls; age range of 9-17.9 years) participated in this study. We expressed CRF performance as the nearest stage (minute) completed and the estimated peak oxygen consumption (V˙O 2peak ). Smoothed percentile curves were calculated. In addition, we present the prevalence of low CRF after applying a correction factor to account for the impact of Bogota's altitude (2625 m over sea level) on CRF assessment, and we calculated the number of participants who fell below health-related FITNESSGRAM cut-points for low CRF. Shuttles and V˙O 2peak were higher in boys than in girls in all age groups. In boys, there were higher levels of performance with increasing age, with most gains between the ages of 13 and 17. The proportion of subjects with a low CRF, suggestive of future cardio-metabolic risk (health risk FITNESSGRAM category) was 31.5% (28.2% for boys and 34.1% for girls; X 2 P = .001). After applying a 1.11 altitude correction factor, the overall prevalence of low CRF was 11.5% (9.6% for boys and 13.1% for girls; X 2 P = .001). Our results provide sex- and age-specific normative reference standards for the 20 m shuttle-run test and estimated V˙O 2peak values in a large, population-based sample of schoolchildren from a large Latin-American city at high altitude. © 2016 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc.

Association between Neighborhood Walkability, Cardiorespiratory Fitness and Body-Mass Index

PubMed Central

Hoehner, Christine M.; Handy, Susan L.; Yan, Yan; Blair, teven N.; Berrigan, David

2011-01-01

Many studies have found cross-sectional associations between characteristics of the neighborhood built environment and physical activity (PA) behavior. However, most are based on self-reported PA, which is known to result in overestimation of PA and differential misclassification by demographic and biological characteristics. Cardiorespiratory fitness (CRF) is an objective marker of PA because it is primarily determined by PA. Furthermore, it is causally related to long-term health outcomes. Therefore, analyses of the association between CRF and built environment could strengthen arguments for the importance of built environment influences on health. We examined the association between neighborhood walkability and CRF and body-mass index (BMI). This cross-sectional analysis included 16,543 adults (5,017 women, 11,526 men) aged 18–90 years with home addresses in Texas who had a comprehensive clinical examination between 1987 and 2005. Outcomes included CRF from total duration on a maximal exercise treadmill test and measured BMI. Three neighborhood walkability factors emerged from principal components analyses of block-group measures derived from the U.S. Census. In multilevel adjusted analyses, the neighborhood walkability factors were significantly associated with CRF and BMI among men and women in the expected direction. An interaction between one of the neighborhood factors and age was also observed. The interaction suggested that living in neighborhoods with older homes and with residents traveling shorter distances to work was more strongly positively associated with CRF among younger adults and more strongly negatively associated with BMI among older adults. In conclusion, neighborhood characteristics hypothesized to support more PA and less driving were associated with higher levels of CRF and lower BMI. Demonstration of an association between built environment characteristics and CRF is a significant advance over past studies based on self-reported PA. Nevertheless, stronger causal evidence depends on more robust study designs and sophisticated measures of the environment, behavior, and their physiological consequences. PMID:22030212

The association between physical activity and risk of mortality is modulated by grip strength and cardiorespiratory fitness: evidence from 498 135 UK-Biobank participants

PubMed Central

Celis-Morales, Carlos A.; Lyall, Donald M.; Anderson, Jana; Iliodromiti, Stamatina; Fan, Yu; Ntuk, Uduakobong E.; Mackay, Daniel F.; Pell, Jill P.; Sattar, Naveed; Gill, Jason M.R.

2017-01-01

Aims It is unclear whether the potential benefits of physical activity differ according to level of cardiorespiratory fitness (CRF) or strength. The aim of this study was to determine whether the association between physical activity and mortality is moderated by CRF and grip strength sufficiently to inform health promotion strategies. Methods and results 498 135 participants (54.7% women) from the UK Biobank were included (CRF data available in 67 702 participants). Exposure variables were grip strength, CRF, and physical activity. All-cause mortality and cardiovascular disease (CVD) events were the outcomes. 8591 died over median 4.9 years [IQR 4.3–5.5] follow-up. There was a significant interaction between total physical activity and grip strength (P < 0.0001) whereby the higher hazard of mortality associated with lower physical activity was greatest among participants in the lowest tertile for grip strength (hazard ratio, HR:1.11 [95% CI 1.09–1.14]) and lowest among those in the highest grip strength tertile (HR:1.04 [1.01–1.08]). The interaction with CRF did not reach statistical significance but the pattern was similar. The association between physical activity and mortality was larger among those in the lowest tertile of CRF (HR:1.13 [1.02–1.26]) than those in the highest (HR:1.03 [0.91–1.16]). The pattern for CVD events was similar. Conclusions These data provide novel evidence that strength, and possibly CRF, moderate the association between physical activity and mortality. The association between physical activity and mortality is strongest in those with the lowest strength (which is easily measured), and the lowest CRF, suggesting that these sub-groups could benefit most from interventions to increase physical activity. PMID:28158566

Relation Between Estimated Cardiorespiratory Fitness and Atrial Fibrillation (from the Reasons for Geographic and Racial Differences in Stroke Study).

PubMed

Bose, Abhishek; O'Neal, Wesley T; Bennett, Aleena; Judd, Suzanne E; Qureshi, Waqas T; Sui, Xuemei; Howard, Virginia J; Howard, George; Soliman, Elsayed Z

2017-06-01

Estimated cardiorespiratory fitness (e-CRF) based on readily available clinical and self-reported data is a promising alternative to the costly traditional assessment of CRF using exercise equipment, but its role as a predictor for incident atrial fibrillation (AF) is unclear. This study included 10,126 participants (54.5% women, 35% African-American, mean age 63.2 years) from the Reasons for Geographic and Racial Differences in Stroke study who were free of AF at baseline. Baseline (2003 to 2007) e-CRF was determined using a previously validated nonexercise algorithm. Incident AF cases were identified at a follow-up examination by electrocardiogram and self-reported medical history of previous physician diagnosis. After a median follow-up of 9.4 years, 906 participants (8.9%) developed AF. In a multivariable logistic regression model adjusted for sociodemographics and baseline cardiovascular disease risk factors as well as incident coronary heart disease, heart failure, and stroke, each 1-metabolic equivalent of task increase in e-CRF was associated with a 5% lower risk of AF development (odds ratio [95% CI] 0.95 [0.92 to 0.99]; p = 0.0129). This association was stronger in women (OR [95% CI] 0.85 (0.79, 0.92) than in men (OR (95% CI) 0.88 (0.84, 0.93), interaction p value = 0.05. No significant interactions by age, race, history of cardiovascular disease, or physical limitations were observed. In conclusion, e-CRF using a nonexercise algorithm is a useful predictor of incident AF, which is consistent with previous reports using traditional CRF. This suggests that e-CRF using nonexercise algorithms may serve as a useful alternative to CRF measured by costly and time-consuming exercise testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Cardiorespiratory fitness and cardiovascular risk in patients with ankylosing spondylitis: a cross-sectional comparative study.

PubMed

Halvorsen, Silje; Vøllestad, Nina Køpke; Provan, Sella Arrestad; Semb, Anne Grete; van der Heijde, Désirée; Hagen, Kåre Birger; Dagfinrud, Hanne

2013-06-01

To investigate the associations between cardiorespiratory fitness (CRF) and the level of cardiovascular (CV) risk factors in patients with ankylosing spondylitis (AS) and controls. In a cross-sectional comparative study, CRF was measured with a maximal treadmill test for estimation of peak oxygen uptake. Metabolic syndrome (MS), body composition, traditional CV risk factors, and inflammatory markers were assessed. Multivariable linear regression models were used to study the associations between CRF and CV risk factors. All models were adjusted for age, sex, and smoking, and for inflammation when C-reactive protein (CRP) level or erythrocyte sedimentation rate (ESR) were not already included as dependent variables. A total of 126 patients (mean ± SD age 47.9 ± 10.8 years) and 111 controls (mean ± SD age 52.1 ± 11.1 years) were included. There were significant inverse associations between CRF and body mass index, waist circumference, triglycerides, CRP level, and ESR (P < 0.001-0.03) for patients and controls. Also, significant associations were found between CRF and high-density lipoprotein (HDL) cholesterol (β = 0.03, P < 0.001) and blood pressure (BP; β = -0.9 for systolic and β = -0.6 for diastolic; P < 0.01) in controls, but these associations were not found in patients (β = 0, P = 0.69 for HDL cholesterol; β = -0.04, P = 0.87 for systolic pressure; and β = -0.14, P = 0.34 for diastolic pressure) (additional adjustments for medication). Higher CRF was associated with a lower risk for MS in both patients (odds ratio [OR] 0.91, P = 0.03) and controls (OR 0.89, P = 0.01). CRF was associated with favorable levels of CV risk factors and lower risk of MS in both AS patients and controls. However, established findings of an association between CRF and BP and HDL cholesterol in healthy adults were not confirmed in AS patients. Copyright © 2013 by the American College of Rheumatology.

Evaluating the cloud radiative forcing over East Asia during summer simulated by CMIP5 models

NASA Astrophysics Data System (ADS)

Lin, Z.; Wang, Y.; Liu, X.

2017-12-01

A large degree of uncertainty in global climate models (GCMs) can be attributed to the representation of clouds and its radiative forcing (CRF). In this study, the simulated CRFs, total cloud fraction (CF) and cloud properties over East Asia from 20 CMIP5 AMIP models are evaluated and compared with multiple satellite observations, and the possible causes for the CRF bias in the CMIP5 models are then investigated. Based on the satellite observation, strong Long wave CRF (LWCRF) and Short wave CRF (SWCRF) are found to be located over Southwestern China, with minimum SWCRF less than -130Wm-2 and this is associated with the large amount of cloud in the region. By contrast, weak CRFs are located over Northwest China and Western Pacific region because of less cloud amount. In Northeastern China, the strong SWCRF and week LWCRF can be found due to the dominant low-level cloud. In Eastern China, the CRFs is moderate due to the co-existence of the multi-layer cloud. CMIP5 models can basically capture the structure of CRFs in East Asia, with the spatial correlation coefficient between 0.5 and 0.9. But most models underestimate CRFs in East Asia, which is highly associated with the underestimation of cloud amount in the region. The performance of CMIP5 models varies in different part of East Asian region, with a larger deviation in Eastern China (EC). Further investigation suggests that, underestimation of the cloud amount in EC can lead to the weak bias of CRFs in EC, however, this CRF bias can be cancelled out by the overestimation effect of CRF due to excessive cloud optical depth (COD) simulated by the models. The annual cycle of simulated CRF over Eastern China is also examined, and it is found, CMIP models are unable to reproduce the northward migration of CRF in summer monsoon season, which is closely related with northward shift of East Asian summer monsoon rain belt.

Involvement of CRFR1 in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

PubMed Central

Sevelinges, Yannick; Zanoletti, Olivia

2016-01-01

Abstract Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR1 antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF6–33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR1 antagonist indicates their dependence on CRFR1 actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders. PMID:27844053

Involvement of CRFR1 in the Basolateral Amygdala in the Immediate Fear Extinction Deficit.

PubMed

Hollis, Fiona; Sevelinges, Yannick; Grosse, Jocelyn; Zanoletti, Olivia; Sandi, Carmen

2016-01-01

Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR 1 antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF 6-33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser 845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR 1 antagonist indicates their dependence on CRFR 1 actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.

Correlating Corneal Biomechanics and Ocular Biometric Properties with Lamina Cribrosa Measurements in Healthy Subjects.

PubMed

Pérez Bartolomé, Francisco; Martínez de la Casa, Jose María; Camacho Bosca, Irene; Sáenz-Francés, Federico; Aguilar Munoa, Soledad; Martín Juan, Alberto; Garcia-Feijoo, Julian

2018-01-01

To examine interrelations between corneal biomechanics, ocular biometric variables and optic disc size (ODS), lamina cribosa depth (LCD) or thickness (LCT) in a healthy population. In a cross-sectional case-control study, the following measurements were made in 81 eyes of 81 participants: axial length, anterior chamber depth, lens thickness, and central corneal thickness using the optical biometer Lenstar LS900; and corneal hysteresis (CH), corneal resistance factor (CRF), Goldman-correlated intraocular pressure (IOPg), and corneal-compensated IOP (IOPcc) using the Ocular Response Analyzer. Serial horizontal enhanced depth imaging optical coherence tomography (EDI OCT) B-scans of the optic nerve head were obtained in each participant. Mean ODS, mean LCD, and mean LCT were measured in 11 equally spaced horizontal B-scans, excluding the LC insertion area under Bruch's membrane and scleral rim. LCD was measured in 74 of 81 eyes (91.36%); LCT in 60/81 (75.3%); ODS in 81/81 (100%). CRF was poorly, but significantly, correlated with LCT (Pearson's R = 0.264; P = 0.045). IOPcc, IOPg, CH, and ocular biometrics variables were poorly (non-significantly) correlated with LCD, LCT, and ODS. CRF was poorly but directly correlated with LCT. No association was detected between CH or ocular biometric variables and ODS, LCD, or LCT.

Influence of the color of composite resin foundation and luting cement on the final color of lithium disilicate ceramic systems.

PubMed

Dede, Doğu Ömür; Sahin, Onur; Özdemir, Oğuz Süleyman; Yilmaz, Burak; Celik, Ersan; Köroğlu, AySegül

2017-01-01

Lithium disilicate restorations are commonly used, particularly in the anterior region. The color of the underlying composite resin foundation (CRF) and luting cement may negatively affect the color of lithium disilicate ceramic restorations. The purpose of this in vitro study was to investigate the effect of CRF and resin cement materials on the color of lithium disilicate ceramics in 2 different translucencies. Twenty disks (11×1.5 mm, shade A2) were fabricated from medium-opacity (mo) (n=10) and high-translucency (ht) (n=10) lithium disilicate (Lds) blocks (IPS e.max Press). Five CRF disks (11×3 mm) were fabricated in 5 different shades (A1, A2, A3, B2, C2) and 30 resin cement disks (11×0.2 mm) in the shades of translucent (Tr), universal (Un=A2), and white-opaque (Wo). Ceramic specimens were placed on each CRF, and the resin cement combination and color was measured with a spectrophotometer. CIELAB color coordinates were recorded, and the color coordinates of both ceramics on the shades of the A2 CRF and resin cement were saved as the control. Color differences (ΔE 00 ) between the control and test groups were calculated. Data were analyzed with 3-way analysis ANOVA and compared with the Tukey HSD test (α=.05). The ΔE 00 values were influenced by the shades of the CRF, resin cement materials, and also their interactions (P<.05). The ΔE 00 values were not affected by the ceramic type. The ΔE 00 values of the Wo cement groups (1.73 to 2.96) were significantly higher than those of the other cement shades (0.88 to 1.29) for each ceramic type and CRF shade (P<.05). Lithium disilicate ceramics in 2 different translucencies were similarly influenced by the color of the underlying cement and CRF. When translucent and universal cement shades were used, the core shade did not affect the final color of the ceramics. White opaque cement caused clinically unacceptable color changes in both ceramics on all shades of CRFs except the C2 CRF and when high translucency ceramic was used on the A2 CRF. These changes were clinically acceptable, but perceptible. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Tackling the mortality from long-term exposure to outdoor air pollution in megacities: Lessons from the Greater Cairo case study.

PubMed

Wheida, Ali; Nasser, Amira; El Nazer, Mostafa; Borbon, Agnes; Abo El Ata, Gehad A; Abdel Wahab, Magdy; Alfaro, Stephane C

2018-01-01

The poor outdoor air quality in megacities of the developing world and its impact on health is a matter of concern for both the local populations and the decision-makers. The objective of this work is to quantify the mortality attributable to long-term exposure to PM2.5, NO 2 , and O 3 in Greater Cairo (Egypt). We analyze the temporal and spatial variability of the three pollutants concentrations measured at 18 stations of the area. Then, we apply the method recommended by the WHO to estimate the excess mortality. In this assessment, three different shapes (log-linear, linear, and log-log) of the concentration-response functions (CRF) are used. With PM2.5 concentrations varying from 50 to more than 100µg/m 3 in the different sectors of the megacity, the spatial variability of this pollutant is found to be one important cause of uncertainty on the excess mortality associated with it. Also important is the choice of the CRF. With the average (75µg/m 3 ) PM2.5 concentration and the most favorable log-log shape of the CRF, 11% (CI, 9-14%) of the non-accidental mortality in the population older than 30 years can still be attributed to PM2.5, which corresponds to 12520 (CI, 10240-15930) yearly premature deaths. Should the Egyptian legal 70µg/m 3 PM10 limit (corresponding to approximately 37.5µg/m 3 for PM2.5) be met, this number would be reduced to 7970, meaning that 4550 premature deaths could be avoided each year. Except around some industrial or traffic hot spots, NO 2 concentration is found to be below the 40µg/m 3 air quality guideline of the WHO. However, the average concentration (34µg/m 3 ) of this gas exceeds the stricter 10µg/m 3 recommendation of the HRAPIE project and it is thus estimated that from 7850 to 10470 yearly deaths can be attributed to NO 2 . Finally, with the ozone concentration measured at one station only, it is found that, depending on the choice of the CRF, between 2.4% and 8.8% of the mortality due to respiratory diseases can be attributed to this gas. In Greater Cairo, PM2.5 and NO 2 constitute major health risks. The best estimate is that in the population older than 30 years, 11% and 8% of the non-accidental mortality can be attributed to these two pollutants, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

Urinary neutrophil gelatinase associated lipocalin as a biomarker in ifosfamide induced chronic renal failure.

PubMed

Kesik, V; Demirkaya, E; Buyukpamukçu, M

2015-12-01

Neutrophil gelatinase associated lipocalin (NGAL) have been used with great success in acute renal failure and in some cases in chronic nephrotoxicity. In this work, we aimed to investigate urinary NGAL as an early marker of chronic renal failure (CRF). We investigated urinary NGAL of 29 children treated with ifosfamide chemotherapy and compared them with those of 12 healthy children. Urinary β2 microglobulin, serum cystatin C, and creatinine clearance analyses were also studied. The median age was 11 years (4-21) and median remission time was 4.3 years (1.8-14.4). The cumulative dose of ifosfamide was 36 g. Glomerular filtration rate was decreased in 41.4% and urine β2 microglobulin levels and serum cystatin C levels were elevated in 31% of the patients. As the remission time increased, serum creatinine and cystatin C levels were also increased. The sensitivity for β2 microglobulin and cystatin C in demonstrating CRF was 35.2% and 23% and specificity was 33.2% and 50% respectively. The 24-hour urine NGAL cut-off level for demonstrating CRF was found to be 1.065 ng/mL/24 hours. The sensitivity and specificity for this cut-off value were 83% and 77%, respectively. NGAL levels were significantly higher in the study group as compared with the control group. Although ifosfamide treatment was suggested to be safe with no complication of renal failure under a dose of 80 g/m2, chronic renal failure and deficits in glomerular and tubular function could be seen when the remission time increased. Elevated NGAL levels may be a good option in determining CRF.

Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor.

PubMed

Browne, Caleb J; Fletcher, Paul J

2016-09-01

Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner.

The Impact of Stress on Tumor Growth; the Significance of Peripheral Corticotropin Releasing Factor

DTIC Science & Technology

2009-05-01

peripheral CRF on breast cancer . Aim of our studies was to determine the impact of peripheral CRF on breast tumor growth and propose a novel potential... breast cancer growth and metastasis. 15. SUBJECT TERMS Stress, Corticotropin Releasing Factor, Wnt, 4T1 mammary epithelial cells 16. SECURITY...13 4 Introduction Aim of the grant proposal was to investigate the role of peripheral CRF on breast cancer cell growth and

Figure-ground organization and the emergence of proto-objects in the visual cortex.

PubMed

von der Heydt, Rüdiger

2015-01-01

A long history of studies of perception has shown that the visual system organizes the incoming information early on, interpreting the 2D image in terms of a 3D world and producing a structure that provides perceptual continuity and enables object-based attention. Recordings from monkey visual cortex show that many neurons, especially in area V2, are selective for border ownership. These neurons are edge selective and have ordinary classical receptive fields (CRF), but in addition their responses are modulated (enhanced or suppressed) depending on the location of a 'figure' relative to the edge in their receptive field. Each neuron has a fixed preference for location on one side or the other. This selectivity is derived from the image context far beyond the CRF. This paper reviews evidence indicating that border ownership selectivity reflects the formation of early object representations ('proto-objects'). The evidence includes experiments showing (1) reversal of border ownership signals with change of perceived object structure, (2) border ownership specific enhancement of responses in object-based selective attention, (3) persistence of border ownership signals in accordance with continuity of object perception, and (4) remapping of border ownership signals across saccades and object movements. Findings 1 and 2 can be explained by hypothetical grouping circuits that sum contour feature signals in search of objectness, and, via recurrent projections, enhance the corresponding low-level feature signals. Findings 3 and 4 might be explained by assuming that the activity of grouping circuits persists and can be remapped. Grouping, persistence, and remapping are fundamental operations of vision. Finding these operations manifest in low-level visual areas challenges traditional views of visual processing. New computational models need to be developed for a comprehensive understanding of the function of the visual cortex.

Figure–ground organization and the emergence of proto-objects in the visual cortex

PubMed Central

von der Heydt, Rüdiger

2015-01-01

A long history of studies of perception has shown that the visual system organizes the incoming information early on, interpreting the 2D image in terms of a 3D world and producing a structure that provides perceptual continuity and enables object-based attention. Recordings from monkey visual cortex show that many neurons, especially in area V2, are selective for border ownership. These neurons are edge selective and have ordinary classical receptive fields (CRF), but in addition their responses are modulated (enhanced or suppressed) depending on the location of a ‘figure’ relative to the edge in their receptive field. Each neuron has a fixed preference for location on one side or the other. This selectivity is derived from the image context far beyond the CRF. This paper reviews evidence indicating that border ownership selectivity reflects the formation of early object representations (‘proto-objects’). The evidence includes experiments showing (1) reversal of border ownership signals with change of perceived object structure, (2) border ownership specific enhancement of responses in object-based selective attention, (3) persistence of border ownership signals in accordance with continuity of object perception, and (4) remapping of border ownership signals across saccades and object movements. Findings 1 and 2 can be explained by hypothetical grouping circuits that sum contour feature signals in search of objectness, and, via recurrent projections, enhance the corresponding low-level feature signals. Findings 3 and 4 might be explained by assuming that the activity of grouping circuits persists and can be remapped. Grouping, persistence, and remapping are fundamental operations of vision. Finding these operations manifest in low-level visual areas challenges traditional views of visual processing. New computational models need to be developed for a comprehensive understanding of the function of the visual cortex. PMID:26579062

Stress during a Critical Postnatal Period Induces Region-Specific Structural Abnormalities and Dysfunction of the Prefrontal Cortex via CRF1

PubMed Central

Yang, Xiao-Dun; Liao, Xue-Mei; Uribe-Mariño, Andrés; Liu, Rui; Xie, Xiao-Meng; Jia, Jiao; Su, Yun-Ai; Li, Ji-Tao; Schmidt, Mathias V; Wang, Xiao-Dong; Si, Tian-Mei

2015-01-01

During the early postnatal period, environmental influences play a pivotal role in shaping the development of the neocortex, including the prefrontal cortex (PFC) that is crucial for working memory and goal-directed actions. Exposure to stressful experiences during this critical period may disrupt the development of PFC pyramidal neurons and impair the wiring and function of related neural circuits. However, the molecular mechanisms of the impact of early-life stress on PFC development and function are not well understood. In this study, we found that repeated stress exposure during the first postnatal week hampered dendritic development in layers II/III and V pyramidal neurons in the dorsal agranular cingulate cortex (ACd) and prelimbic cortex (PL) of neonatal mice. The deleterious effects of early postnatal stress on structural plasticity persisted to adulthood only in ACd layer V pyramidal neurons. Most importantly, concurrent blockade of corticotropin-releasing factor receptor 1 (CRF1) by systemic antalarmin administration (20 μg/g of body weight) during early-life stress exposure prevented stress-induced apical dendritic retraction and spine loss in ACd layer V neurons and impairments in PFC-dependent cognitive tasks. Moreover, the magnitude of dendritic regression, especially the shrinkage of apical branches, of ACd layer V neurons predicted the degree of cognitive deficits in stressed mice. Our data highlight the region-specific effects of early postnatal stress on the structural plasticity of prefrontal pyramidal neurons, and suggest a critical role of CRF1 in modulating early-life stress-induced prefrontal abnormalities. PMID:25403725

Macroweather Predictions and Climate Projections using Scaling and Historical Observations

NASA Astrophysics Data System (ADS)

Hébert, R.; Lovejoy, S.; Del Rio Amador, L.

2017-12-01

There are two fundamental time scales that are pertinent to decadal forecasts and multidecadal projections. The first is the lifetime of planetary scale structures, about 10 days (equal to the deterministic predictability limit), and the second is - in the anthropocene - the scale at which the forced anthropogenic variability exceeds the internal variability (around 16 - 18 years). These two time scales define three regimes of variability: weather, macroweather and climate that are respectively characterized by increasing, decreasing and then increasing varibility with scale.We discuss how macroweather temperature variability can be skilfully predicted to its theoretical stochastic predictability limits by exploiting its long-range memory with the Stochastic Seasonal and Interannual Prediction System (StocSIPS). At multi-decadal timescales, the temperature response to forcing is approximately linear and this can be exploited to make projections with a Green's function, or Climate Response Function (CRF). To make the problem tractable, we exploit the temporal scaling symmetry and restrict our attention to global mean forcing and temperature response using a scaling CRF characterized by the scaling exponent H and an inner scale of linearity τ. An aerosol linear scaling factor α and a non-linear volcanic damping exponent ν were introduced to account for the large uncertainty in these forcings. We estimate the model and forcing parameters by Bayesian inference using historical data and these allow us to analytically calculate a median (and likely 66% range) for the transient climate response, and for the equilibrium climate sensitivity: 1.6K ([1.5,1.8]K) and 2.4K ([1.9,3.4]K) respectively. Aerosol forcing typically has large uncertainty and we find a modern (2005) forcing very likely range (90%) of [-1.0, -0.3] Wm-2 with median at -0.7 Wm-2. Projecting to 2100, we find that to keep the warming below 1.5 K, future emissions must undergo cuts similar to Representative Concentration Pathway (RCP) 2.6 for which the probability to remain under 1.5 K is 48%. RCP 4.5 and RCP 8.5-like futures overshoot with very high probability. This underscores that over the next century, the state of the environment will be strongly influenced by past, present and future economical policies.

The cloud-radiative forcing of the U.S. landfalling atmospheric rivers

NASA Astrophysics Data System (ADS)

Luo, Qianwen

Atmospheric rivers (ARs) are narrow channels in the atmosphere that transport an enormous amount of moisture from the tropics to the higher latitudes. Streaks of highly reflective clouds are observed along with the ARs in satellite imagery. These clouds both influence the moisture transport of ARs, as well as modify the Earth-Atmospheric energy budget through pathways such as cloud-radiative forcing (CRF). This dissertation studies the CRF of the U.S. Landfalling ARs in weather and climate scales. Three crucial questions are addressed. First, how do clouds produced by the ARs modulate the moisture and heat balance of the Earth-Atmospheric system? Even though studies of ARs date back to the 90s, past research has been primarily focused on their hydrological impacts. We addressed this research gap by comparing the dominant types of precipitating clouds and convection of two ARs. Through quantifying their effects on the energy balance in the midlatitudes, we found that when deep convection was the dominant cloud types of an AR, impressive CRF cooling was produced. Second, what are the sufficient climate conditions for the extensive CRF in the continental U.S.? We studied 60 ARs that reached the California coast (the Southwest ARs) and 60 ARs that reached Pacific Northwest during Nov-Mar, 2000-2008. It was found that when these West-Coast ARs were followed by the moisture surge from the Gulf of Mexico (the Gulf-Coast AR), it resulted in apparent statewide CRF. Such condition happened more frequently in the Southwest-AR scenario. Third, how does the subgrid-scale-convection-induced CRF influence the moisture transport of ARs?We ran two WRF ARW simulations for a Southwest-AR that was followed by a Gulf-Coast AR. The only difference between the two simulations was one considered the CRF of subgrid-scale clouds while the other did not. By comparing the two simulations, we found that the subgrid-scale-convection-induced CRF helped prolong the lifespan of clouds in an AR, thus enabling moisture to be transported further downstream. In short, this work helps improve our understanding of CRF of the U.S. landfalling ARs from both weather and climate perspectives. Our results are useful for validating the representation of clouds and radiation processes in weather and climate models, thereby help to improve AR predictions.

Evidence of substance P autocrine circuitry that involves TNF-α, IL-6, and PGE2 in endogenous pyrogen-induced fever.

PubMed

Brito, Haissa Oliveira; Barbosa, Felipe L; Reis, Renata Cristiane Dos; Fraga, Daniel; Borges, Beatriz S; Franco, Celia R C; Zampronio, Aleksander Roberto

2016-04-15

Substance P (SP) is involved in fever that is induced by lipopolysaccharide (LPS) but not by interleukin-1β or macrophage inflammatory protein-1α. Intracerebroventricular (i.c.v.) administration of the neurokinin-1 (NK1) receptor antagonist SR140333B in rats reduced fever that was induced by an i.c.v. injection of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), corticotropin-releasing factor (CRF), endothelin-1 (ET-1), and morphine (MOR). Furthermore, an i.c.v. injection of SP induced a febrile response that was inhibited by indomethacin concomitant with an increase in PGE2 levels in cerebrospinal fluid. Lipopolysaccharide and PGE2 caused higher expression and internalization of NK1 receptors in the hypothalamus which were prevented by SR140333B. These data suggest that SP is an important mediator of fever, in which it induces a prostaglandin-dependent response and is released after TNF-α, IL-6, PGE2, CRF, endogenous opioids, and ET-1. Copyright © 2016 Elsevier B.V. All rights reserved.

Osthole protects against inflammation in a rat model of chronic kidney failure via suppression of nuclear factor-κB, transforming growth factor-β1 and activation of phosphoinositide 3-kinase/protein kinase B/nuclear factor (erythroid-derived 2)-like 2 signaling.

PubMed

Huang, Tao; Dong, Zhen

2017-10-01

Multiple pharmacological applications of osthole have been previously recognized, including antioxidant, anti-inflammatory, anti‑platelet and estrogenic effects, and resistance to pain. The present study investigated the protective effects of osthole against inflammation in a rat model of chronic kidney failure (CRF) and the underlying mechanisms. Osthole treatment with significantly reversed CRF‑induced changes in serum creatinine, calcium, phosphorus and blood urea nitrogen levels in CRF rats. Male Sprague‑Dawley rats (age, 8 weeks) received 200 mg/kg 2% adenine suspension to induce CRF in the model group. In the osthole‑treated group, rats received 200 mg/kg 2% adenine suspension + osthole (40 mg/kg, intravenously). The results revealed that treatment with osthole significantly inhibited CRF‑induced tumor necrosis factor‑α, interleukin (IL)‑8 and IL‑6 expression, and suppressed nuclear factor‑κB (NF‑κB) protein expression in CRF rats. Osthole treatment significantly attenuated the protein expression of transforming growth factor‑β1 (TGF‑β1), reduced monocyte chemoattractant protein‑1 activity and increased the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt) ratio in CRF rats. These results suggested that osthole protects against inflammation in a rat model of CRF via suppression of NF‑κB and TGF‑β1, and activation of PI3K/Akt/nuclear factor (erythroid‑derived 2)‑like 2 signaling. Therefore, osthole may represent a potential therapeutic agent for the treatment of CRF.

A lower cardiorespiratory fitness is associated to an unhealthy status among children and adolescents from Bogotá, Colombia.

PubMed

Gualteros, Julián Alberto; Torres, Jorge Andrés; Umbarila-Espinosa, Luz Marina; Rodríguez-Valero, Francisco Javier; Ramírez-Vélez, Robinson

2015-11-01

Several studies have shown that low cardiorespiratory fitness (CRF) is a significant independent risk factor for future cardiometabolic disease in adult life. The aim of this study was to examine the relationship between CRF and health status in children and adolescents in Bogotá, Colombia. A cross-sectional study was conducted in 921 children and adolescents aged 9-17 years living in the metropolitan area of the District of Bogotá, Colombia (2,480m asl). CRF was assessed with the 20m shuttle run test (Course-Navette) according to ALPHA-FITNESS and FITNESSGRAM standards. Blood pressure, waist circumference, hip circumference, body composition (body fat percentage, fat body mass, and fat-free mass by bioimpedance), skin fold calipers, body mass index, and sexual maturity (Tanner) were used as indicators of physical health. After adjusting for sex, age, and sexual maturity, significant inverse relationships were seen between CRF and body mass index (r=-0.107), body fat percentage (r=-0.197), fat body mass (r=-0.159), skin fold (r=-0.246), and waist circumference (r=-0.169); P<.001. Schoolchildren with low CRF levels showed OR 6.06 (95% CI 3.98-9.24) increase in body fat by bioimpedance; OR 4.04 (95% CI 1.83-9.11) risk of overweight/obese by body mass index and OR 2.47 (95% CI 1.14-5.37) abdominal obesity due to increased waist circumference. Approximately two thirds of participants had a CRF level suggesting future cardiovascular disease. Early identification of children and adolescents with low CRF levels will allow for implementing interventions to prevent cardiometabolic disease in adulthood. Copyright © 2015 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

The course of cancer related fatigue up to ten years in early breast cancer patients: What impact in clinical practice?

PubMed

Fabi, Alessandra; Falcicchio, Chiara; Giannarelli, Diana; Maggi, Gabriella; Cognetti, Francesco; Pugliese, Patrizia

2017-08-01

Little is known about the cancer related fatigue (CRF) along cancer course and risk factors that could predict CRF development and persistence in breast cancer (BC) survivors. This prospective study detected incidence, timing of onset, duration of CRF, impact on QoL and psychological distress. Seventy-eight early BC patients, undergoing chemotherapy (CT) followed or not by hormonal therapy were assessed for QoL and psychological distress by EORTC QLQC30 and HADs questionnaires. Fatigue was investigated with mix methods, structured interview and psychometric measures. A qualitative analysis was added to assess the behavioral pattern of CRF. Low fatigue levels were identified after surgery (9%), increasing during (49%) and at the end of CT (47%), maintaining after 1 year (31%) and declining up to ten years of follow-up. Prevalence of CRF was higher at the end of CT and lower at follow-up. At the end and after 1 and 2 years from CT, persistence of CRF was associated to anxiety in 20%, 11% and 5% and to depression in 15%, 10% and 5% respectively. A relationship between CRF and psychological distress was observed; patients presenting depression and anxiety before CT were at higher risk for fatigue onset at a later period. A relationship between fatigue and QoL was noted at the end of CT. Our study shows the fatigue timely trend in early BC patients from surgery, CT and follow-up. Identification of biological, psychological, social predictor factors related to fatigue could be helpful for early interventions in patients at higher risk of developing fatigue. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Risky choice and brain CRF after adolescent ethanol vapor exposure and social stress in adulthood.

PubMed

Boutros, Nathalie; Der-Avakian, Andre; Semenova, Svetlana; Lee, Soon; Markou, Athina

2016-09-15

Adolescent ethanol exposure increases risky choice and alters corticotropin releasing factor (CRF) systems in adulthood. The impact of stress on risky choice after adolescent intermittent ethanol (AIE) exposure is not known. We investigated time-specific effects of AIE vapor exposure during early adolescence on risky choice after stress or no stress in adulthood. Male Wistar rats were exposed to air or AIE vapor on postnatal days 28-42 (adolescence) and were exposed to 10days of social defeat or no stress on postnatal days 172-181 (adulthood). Risky choice was assessed in the probability discounting task under baseline conditions and after days 1 and 10 of social defeat. CRF and CRF receptor 1 (CRFR1) mRNA levels were assessed in the prefrontal cortex (PFC) and the central nucleus of the amygdala (CeA) 24h post-stress to evaluate persistent effects of stress on the brain. AIE exposure had no effect on risky choice either at baseline or after social defeat. Additionally, neither acute nor chronic social defeat affected risky choice in air-exposed rats. In the PFC, chronic social defeat selectively decreased CRF mRNA levels in air-exposed rats and increased CRFR1 mRNA levels in all rats. AIE exposure increased CRF mRNA levels in the CeA with no effect of social stress. Our results indicate no effect of ethanol exposure via vapor during early adolescence on risky choice, while our previous findings indicated that AIE exposure via gavage affected risky choice. Both AIE exposure and social defeat altered CRF and CRFR1 mRNA levels in the brain. Copyright © 2016 Elsevier B.V. All rights reserved.

The relationship between corneal biomechanics and anterior segment parameters in the early stage of orthokeratology: A pilot study.

PubMed

Chen, Renai; Mao, Xinjie; Jiang, Jun; Shen, Meixiao; Lian, Yan; Zhang, Bin; Lu, Fan

2017-05-01

To investigate the relationship between corneal biomechanics and anterior segment parameters in the early stage of overnight orthokeratology.Twenty-three eyes from 23 subjects were involved in the study. Corneal biomechanics, including corneal hysteresis (CH) and corneal resistance factor (CRF), and parameters of the anterior segment, including corneal curvature, central corneal thickness (CCT), and corneal sublayers' thickness, were measured at baseline and day 1 and 7 after wearing orthokeratology lens. One-way analysis of variance with repeated measures was used to compare the longitudinal changes and partial least squares linear regression was used to explore the relationship between corneal biomechanics and anterior segment parameters.At baseline, CH and CRF were positively correlated with CCT (r = 0.244, P = .008 for CH; r = 0.249, P < .001 for CRF), central stroma thickness (CST) (r = 0.241, P = .008 for CH; r = 0.244, P = .002 for CRF) and central Bowman layer thickness (CBT) (r = 0.138, P = .039 for CH; r = 0.171, P = .006 for CRF). Both CH and CRF significantly decreased from day 1 after orthokeratology. The corneal curvature and the epithelium thickness also significantly decreased, while the stromal layer thickened significantly from day 1 after orthokeratology. There was no correlation between the changes of corneal biomechanics and anterior segment parameters at day 1 and 7 after orthokeratology.While corneal biomechanics were positively correlated with CCT, CST, and CBT, the changes of CH and CRF were not correlated with the changes of corneal curvature, CCT, and corneal sublayers' thickness in the early stage of orthokeratology in our study.

Favorable Cardiovascular Risk Profile Is Associated With Lower Healthcare Costs and Resource Utilization: The 2012 Medical Expenditure Panel Survey.

PubMed

Valero-Elizondo, Javier; Salami, Joseph A; Ogunmoroti, Oluseye; Osondu, Chukwuemeka U; Aneni, Ehimen C; Malik, Rehan; Spatz, Erica S; Rana, Jamal S; Virani, Salim S; Blankstein, Ron; Blaha, Michael J; Veledar, Emir; Nasir, Khurram

2016-03-01

The American Heart Association's 2020 Strategic Goals emphasize the value of optimizing risk factor status to reduce the burden of morbidity and mortality. In this study, we aimed to quantify the overall and marginal impact of favorable cardiovascular risk factor (CRF) profile on healthcare expenditure and resource utilization in the United States among those with and without cardiovascular disease (CVD). The study population was derived from the 2012 Medical Expenditure Panel Survey (MEPS). Direct and indirect costs were calculated for all-cause healthcare resource utilization. Variables of interest included CVD diagnoses (coronary artery disease, stroke, peripheral artery disease, dysrhythmias, or heart failure), ascertained by International Classification of Diseases, Ninth Edition, Clinical Modification codes, and CRF profile (hypertension, diabetes mellitus, hypercholesterolemia, smoking, physical activity, and obesity). Two-part econometric models were used to study expenditure data. The final study sample consisted of 15 651 MEPS participants (58.5±12 years, 54% female). Overall, 5921 (37.8%) had optimal, 7002 (44.7%) had average, and 2728 (17.4%) had poor CRF profile, translating to 54.2, 64.1, and 24.9 million adults in United States, respectively. Significantly lower health expenditures were noted with favorable CRF profile across CVD status. Among study participants with established CVD, overall healthcare expenditures with optimal and average CRF profile were $5946 and $3731 less compared with those with poor CRF profile. The respective differences were $4031 and $2560 in those without CVD. Favorable CRF profile is associated with significantly lower medical expenditure and healthcare utilization among individuals with and without established CVD. © 2016 American Heart Association, Inc.