Dysfunction of mitochondrial dynamics in the brains of scrapie-infected mice

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

Choi, Hong-Seok; Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang, Gyeonggi-do 431-060; Choi, Yeong-Gon

Highlights: • Mfn1 and Fis1 are significantly increased in the hippocampal region of the ME7 prion-infected brain, whereas Dlp1 is significantly decreased in the infected brain. • Dlp1 is significantly decreased in the cytosolic fraction of the hippocampus in the infected brain. • Neuronal mitochondria in the prion-infected brains are enlarged and swollen compared to those of control brains. • There are significantly fewer mitochondria in the ME7-infected brain compared to the number in control brain. - Abstract: Mitochondrial dysfunction is a common and prominent feature of many neurodegenerative diseases, including prion diseases; it is induced by oxidative stress inmore » scrapie-infected animal models. In previous studies, we found swelling and dysfunction of mitochondria in the brains of scrapie-infected mice compared to brains of controls, but the mechanisms underlying mitochondrial dysfunction remain unclear. To examine whether the dysregulation of mitochondrial proteins is related to the mitochondrial dysfunction associated with prion disease, we investigated the expression patterns of mitochondrial fusion and fission proteins in the brains of ME7 prion-infected mice. Immunoblot analysis revealed that Mfn1 was up-regulated in both whole brain and specific brain regions, including the cerebral cortex and hippocampus, of ME7-infected mice compared to controls. Additionally, expression levels of Fis1 and Mfn2 were elevated in the hippocampus and the striatum, respectively, of the ME7-infected brain. In contrast, Dlp1 expression was significantly reduced in the hippocampus in the ME7-infected brain, particularly in the cytosolic fraction. Finally, we observed abnormal mitochondrial enlargement and histopathological change in the hippocampus of the ME7-infected brain. These observations suggest that the mitochondrial dysfunction, which is presumably caused by the dysregulation of mitochondrial fusion and fission proteins, may contribute to the

Transient ventricular dysfunction after an asphyxiation event: stress or hypoxia?

PubMed

Valletta, Mary E; Haque, Ikram; Al-Mousily, Faris; Udassi, Jai; Saidi, Arwa

2008-11-01

This report of a pediatric patient with acute upper airway obstruction causing asphyxiation emphasizes the need to maintain clinical suspicion for acquired myocardial dysfunction, despite the presumed role of noncardiogenic causes for pulmonary edema after an acute upper airway obstruction. Case report. A tertiary pediatric intensive care unit. A 10-year-old girl with no significant medical history who developed flash pulmonary edema and acute myocardial dysfunction after an acute upper airway obstruction. Serial echocardiograms, exercise stress test, and coronary angiography were performed. Serial pro-brain natriuretic peptide, troponins, and CK-MB levels were also followed. Troponin level normalized approximately 7 days after the acute event. CK-MB and pro-brain natriuretic peptide levels decreased but had not completely normalized by time of discharge. The patient was discharged home 10 days after the event on an anticipated 6-month course of metoprolol without any signs or symptoms of cardiac dysfunction. Myocardial dysfunction is rarely documented in children after an acute upper airway obstruction or an asphyxiation event. Pediatric intensivists and hospitalists should maintain a high degree of clinical suspicion and screen for possible myocardial dysfunction in the pediatric patient with an acute severe hypoxic event especially when accompanied by pulmonary edema. Prompt evaluation ensures appropriate support. Additionally, some role may exist for early adrenergic receptor blockade.

Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives

PubMed Central

Javed, Zeeshan; Qamar, Unaiza; Sathyapalan, Thozhukat

2015-01-01

There is an increasing deliberation regarding hypopituitarism following traumatic brain injury (TBI) and recent data have suggested that pituitary dysfunction is very common among survivors of patients having moderate-severe TBI which may evolve or resolve over time. Due to high prevalence of pituitary dysfunction after moderate-severe TBI and its association with increased morbidity and poor recovery and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences. The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible primary and secondary causes. Results of recent studies focusing on the incidence of hypopituitarism in the acute and chronic phases after TBI are varied in terms of severity and time of occurrence. Although the literature available does not show consistent values and there is difference in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI and patients should be carefully monitored. The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function up to 1 year after TBI. In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation. PMID:26693424

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

PubMed

Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

2016-12-01

Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

Dorsal brain stem syndrome: MR imaging location of brain stem tegmental lesions in neonates with oral motor dysfunction.

PubMed

Quattrocchi, C C; Longo, D; Delfino, L N; Cilio, M R; Piersigilli, F; Capua, M D; Seganti, G; Danhaive, O; Fariello, G

2010-09-01

The anatomic extent of brain stem damage may provide information about clinical outcome and prognosis in children with hypoxic-ischemic encephalopathy and oral motor dysfunction. The aim of this study was to retrospectively characterize the location and extent of brain stem lesions in children with oral motor dysfunction. From January 2005 to August 2009, 43 infants hospitalized at our institution were included in the study because of a history of hypoxic-ischemic events. Of this group, 14 patients showed oral motor dysfunction and brain stem tegmental lesions detected at MR imaging. MR imaging showed hypoxic-ischemic lesions in supra- and infratentorial areas. Six of 14 patients revealed only infratentorial lesions. Focal symmetric lesions of the tegmental brain stem were always present. The lesions appeared hyperintense on T2-weighted images and hypointense on IR images. We found a strong association (P < .0001) between oral motor dysfunction and infratentorial lesions on MR imaging. Oral motor dysfunction was associated with brain stem tegmental lesions in posthypoxic-ischemic infants. The MR imaging examination should be directed to the brain stem, especially when a condition of prolonged gavage feeding is necessary in infants.

Neuroscience Literacy: "Brain Tells" as Signals of Brain Dysfunction Affecting Daily Life.

PubMed

Royeen, Charlotte B; Brašić, James R; Dvorak, Leah; Provoziak-O'Brien, Casey; Sethi, Chetna; Ahmad, S Omar

2016-01-01

The structures and circuits of the central and the peripheral nervous systems provide the basis for thinking, speaking, experiencing sensations, and performing perceptual and motor activities in daily life. Healthy people experience normal functioning without giving brain functions a second thought, while dysfunction of the neural circuits may lead to marked impairments in cognition, communication, sensory awareness, and performing perceptual and motor tasks. Neuroscience literacy provides the knowledge to associate the deficits observed in patients with the underlying deficits in the structures and circuits of the nervous system. The purpose of this paper is to begin the conversation in this area via a neuroscience literacy model of "Brain Tells," defined as stereotypical or observable behaviors often associated with brain dysfunction. Occupational therapists and other allied health professionals should be alert for the signs of "Brain Tells" that may be early warning signs of brain pathology. We also suggest that neuroscience literacy be emphasized in training provided to public safety workers, teachers, caregivers, and health care professionals at all levels.

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease.

PubMed

Dulla, Chris G; Coulter, Douglas A; Ziburkus, Jokubas

2016-06-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer's disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. © The Author(s) 2015.

From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer’s Disease

PubMed Central

Dulla, Chris G.; Coulter, Douglas A.; Ziburkus, Jokubas

2015-01-01

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer’s disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction. PMID:25948650

Social dysfunction after pediatric traumatic brain injury: a translational perspective

PubMed Central

Ryan, Nicholas P.; Catroppa, Cathy; Godfrey, Celia; Noble-Haeusslein, Linda J.; Shultz, Sandy R.; O'Brien, Terence J.; Anderson, Vicki; Semple, Bridgette D.

2016-01-01

Social dysfunction is common after traumatic brain injury (TBI), contributing to reduced quality of life for survivors. Factors which influence the emergence, development or persistence of social deficits after injury remain poorly understood, particularly in the context of ongoing brain maturation during childhood. Aberrant social interactions have recently been modeled in adult and juvenile rodents after experimental TBI, providing an opportunity to gain new insights into the underlying neurobiology of these behaviors. Here, we review our current understanding of social dysfunction in both humans and rodent models of TBI, with a focus on brain injuries acquired during early development. Modulators of social outcomes are discussed, including injury-related and environmental risk and resilience factors. Disruption of social brain network connectivity and aberrant neuroendocrine function are identified as potential mechanisms of social impairments after pediatric TBI. Throughout, we highlight the overlap and disparities between outcome measures and findings from clinical and experimental approaches, and explore the translational potential of future research to prevent or ameliorate social dysfunction after childhood TBI. PMID:26949224

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

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

PubMed Central

Mittal, Anubhav; Hickey, Anthony JR; Chai, Chau C; Loveday, Benjamin PT; Thompson, Nichola; Dare, Anna; Delahunt, Brett; Cooper, Garth JS; Windsor, John A; Phillips, Anthony RJ

2011-01-01

Introduction Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. Methods Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n = 8), saline control; Group 2 (n = 6), caerulein-induced mild acute pancreatitis; Group 3 (n = 7) sham surgical controls; and Group 4 (n = 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. Results Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. Conclusions The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis. PMID:21492333

Update of Endocrine Dysfunction following Pediatric Traumatic Brain Injury.

PubMed

Reifschneider, Kent; Auble, Bethany A; Rose, Susan R

2015-07-31

Traumatic brain injuries (TBI) are common occurrences in childhood, often resulting in long term, life altering consequences. Research into endocrine sequelae following injury has gained attention; however, there are few studies in children. This paper reviews the pathophysiology and current literature documenting risk for endocrine dysfunction in children suffering from TBI. Primary injury following TBI often results in disruption of the hypothalamic-pituitary-adrenal axis and antidiuretic hormone production and release, with implications for both acute management and survival. Secondary injuries, occurring hours to weeks after TBI, result in both temporary and permanent alterations in pituitary function. At five years after moderate to severe TBI, nearly 30% of children suffer from hypopituitarism. Growth hormone deficiency and disturbances in puberty are the most common; however, any part of the hypothalamic-pituitary axis can be affected. In addition, endocrine abnormalities can improve or worsen with time, having a significant impact on children's quality of life both acutely and chronically. Since primary and secondary injuries from TBI commonly result in transient or permanent hypopituitarism, we conclude that survivors should undergo serial screening for possible endocrine disturbances. High indices of suspicion for life threatening endocrine deficiencies should be maintained during acute care. Additionally, survivors of TBI should undergo endocrine surveillance by 6-12 months after injury, and then yearly, to ensure early detection of deficiencies in hormonal production that can substantially influence growth, puberty and quality of life.

Update of Endocrine Dysfunction following Pediatric Traumatic Brain Injury

PubMed Central

Reifschneider, Kent; Auble, Bethany A.; Rose, Susan R.

2015-01-01

Traumatic brain injuries (TBI) are common occurrences in childhood, often resulting in long term, life altering consequences. Research into endocrine sequelae following injury has gained attention; however, there are few studies in children. This paper reviews the pathophysiology and current literature documenting risk for endocrine dysfunction in children suffering from TBI. Primary injury following TBI often results in disruption of the hypothalamic-pituitary-adrenal axis and antidiuretic hormone production and release, with implications for both acute management and survival. Secondary injuries, occurring hours to weeks after TBI, result in both temporary and permanent alterations in pituitary function. At five years after moderate to severe TBI, nearly 30% of children suffer from hypopituitarism. Growth hormone deficiency and disturbances in puberty are the most common; however, any part of the hypothalamic-pituitary axis can be affected. In addition, endocrine abnormalities can improve or worsen with time, having a significant impact on children’s quality of life both acutely and chronically. Since primary and secondary injuries from TBI commonly result in transient or permanent hypopituitarism, we conclude that survivors should undergo serial screening for possible endocrine disturbances. High indices of suspicion for life threatening endocrine deficiencies should be maintained during acute care. Additionally, survivors of TBI should undergo endocrine surveillance by 6–12 months after injury, and then yearly, to ensure early detection of deficiencies in hormonal production that can substantially influence growth, puberty and quality of life. PMID:26287247

Acute Gonadotroph and Somatotroph Hormonal Suppression after Traumatic Brain Injury

PubMed Central

Wagner, Justin; Dusick, Joshua R.; McArthur, David L.; Cohan, Pejman; Wang, Christina; Swerdloff, Ronald; Boscardin, W. John

2010-01-01

Abstract Hormonal dysfunction is a known consequence of moderate and severe traumatic brain injury (TBI). In this study we determined the incidence, time course, and clinical correlates of acute post-TBI gonadotroph and somatotroph dysfunction. Patients had daily measurement of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol, growth hormone, and insulin-like growth factor-1 (IGF-1) for up to 10 days post-injury. Values below the fifth percentile of a healthy cohort were considered abnormal, as were non-measurable growth hormone (GH) values. Outcome measures were frequency and time course of hormonal suppression, injury characteristics, and Glasgow Outcome Scale (GOS) score. The cohort consisted of 101 patients (82% males; mean age 35 years; Glasgow Coma Scale [GCS] score ≤8 in 87%). In men, 100% had at least one low testosterone value, and 93% of all values were low; in premenopausal women, 43% had at least one low estradiol value, and 39% of all values were low. Non-measurable GH levels occurred in 38% of patients, while low IGF-1 levels were observed in 77% of patients, but tended to normalize within 10 days. Multivariate analysis revealed associations of younger age with low FSH and low IGF-1, acute anemia with low IGF-1, and older age and higher body mass index (BMI) with low GH. Hormonal suppression was not predictive of GOS score. These results indicate that within 10 days of complicated mild, moderate, and severe TBI, testosterone suppression occurs in all men and estrogen suppression occurs in over 40% of women. Transient somatotroph suppression occurs in over 75% of patients. Although this acute neuroendocrine dysfunction may not be TBI-specific, low gonadal steroids, IGF-1, and GH may be important given their putative neuroprotective functions. PMID:20214417

Viral infection leading to brain dysfunction: more prevalent than appreciated?

PubMed Central

van den Pol, Anthony N.

2009-01-01

Virus infections of the brain can lead to transient or permanent neurologic or psychiatric dysfunction. Some of the complexities in establishing the causal role of viruses in brain disease are explored here. PMID:19840542

Right ventricular dysfunction in acute pulmonary embolism: NT-proBNP vs. troponin T.

PubMed

Cotugno, Marilena; Orgaz-Molina, Jacinto; Rosa-Salazar, Vladimir; Guirado-Torrecillas, Leticia; García-Pérez, Bartolomé

2017-04-21

Dysfunction of the right ventricle (RV) is a parameter of severity in acute pulmonary embolism (PE). Echocardiographic assessment is not always possible in accident and emergency, hence the need to predict the presence of RV dysfunction using easily measurable parameters. To analyse the value of NT-proBNP and troponin T as markers of RV dysfunction in patients with acute PE. Secondarily, to assess the relationship between RV failure and clinical parameters related to PE. Analytical, observational, cross-sectional and retrospective study comparing the values NT-proBNP, troponin T and presenting symptoms of PE among patients with and without RV dysfunction. One hundred seventy-two patients (52 with RV failure,120 without) were included. All symptoms occurred with similar frequency between the 2groups except dyspnea and syncope (more common in the group with RV failure). Both NT-proBNP and troponin T had significantly higher values in the group of patients with RV dysfunction. However, in the multivariate analysis, NT-proBNP had a higher explanatory value for RV failure than troponin T. NT-proBNP is a diagnostic parameter of RV dysfunction with higher sensitivity in the context of acute PE. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

New Diagnostic Terminology for Minimal Brain Dysfunction.

ERIC Educational Resources Information Center

Shaywitz, Bennett A.; And Others

1979-01-01

Minimal brain dysfunction has been redefined by the American Psychological Association as attention deficit disorder (ADD) and subdivided into categories with and without hyperactivity. The revised 'Diagnostic and Statistical Manual' (DSM III) is now undergoing field trials. Journal Availability: C. V. Mosby Company, 11830 Westline Industrial…

Intratracheal Milrinone Bolus Administration During Acute Right Ventricular Dysfunction After Cardiopulmonary Bypass.

PubMed

Gebhard, Caroline Eva; Desjardins, Georges; Gebhard, Cathérine; Gavra, Paul; Denault, André Y

2017-04-01

To evaluate intratracheal milrinone (tMil) administration for rapid treatment of right ventricular (RV) dysfunction as a novel route after cardiopulmonary bypass. Retrospective analysis. Single-center study. The study comprised 7 patients undergoing cardiac surgery who exhibited acute RV dysfunction after cardiopulmonary bypass. After difficult weaning caused by cardiopulmonary bypass-induced acute RV dysfunction, milrinone was administered as a 5-mg bolus inside the endotracheal tube. RV function improvement, as indicated by decreasing pulmonary artery pressure and changes of RV waveforms, was observed in all 7 patients. Adverse effects of tMil included dynamic RV outflow tract obstruction (2 patients) and a decrease in systemic mean arterial pressure (1 patient). tMil may be an effective, rapid, and easily applicable therapeutic alternative to inhaled milrinone for the treatment of acute RV failure during cardiac surgery. However, sufficiently powered clinical trials are needed to confirm these findings. Copyright © 2017 Elsevier Inc. All rights reserved.

Minimal Brain Dysfunction: Associations with Perinatal Complications.

ERIC Educational Resources Information Center

Nichols, Paul L.

Examined with over 28,000 7-year-old children whose mothers registered for prenatal care was the relationship between perinatal complications and such characteristics as poor school achievement, hyperactivity, and neurological soft signs associated with the diagnosis of minimal brain dysfunction (MBD). Ten perinatal antecedents were studied:…

Compound mechanism hypothesis on +Gz induced brain injury and dysfunction of learning and memory

NASA Astrophysics Data System (ADS)

Sun, Xi-Qing; Li, Jin-Sheng; Cao, Xin-Sheng; Wu, Xing-Yu

2005-08-01

We systematically studied the effect of high- sustained +Gz on the brain and its mechanism in past ten years by animal centrifuge experiments. On the basis of the facts we observed and the more recent advances in acceleration physiology, we put forward a compound mechanism hypothesis to offer a possible explanation for +Gz-induced brain injury and dysfunction of learning and memory. It states that, ischemia during high G exposure might be the main factor accounting for +Gz-induced brain injury and dysfunction of learning and memory, including transient depression of brain energy metabolism, disturbance of ion homeostasis, increased blood-brain barrier permeability, increased brain nitric oxide synthase expression, and the protective effect of heat shock protein 70. In addition, the large rapid change of intracranial pressure and increased stress during +Gz exposure, and the hemorrheologic change after +Gz exposure might be one of the important factors accounting for +Gz-induced brain injury and dysfunction of learning and memory.

Public Education for Children with Brain Dysfunction.

ERIC Educational Resources Information Center

Rappaport, Sheldon R.

A foreword by William M. Cruickshank introduces a book designed to provide information on the problems of children with brain dysfunction and to furnish guidelines to habilitation. Subjects discussed are the status of education for these children, preparing the community for a school program, selection of school and preparation of the principal,…

Disulfiram-induced acute organic brain syndrome.

PubMed

Kump, J G; Flaten, P A; Greenlaw, C W

1979-08-01

Reversible acute organic brain syndrome is described in a patient receiving disulfiram, 250 mg daily. Slowing of the electroencephalogram (3 to 4 cycles per second) in the occipital region resolved ten days after discontinuation of disulfiram. Acute organic brain syndrome induced by disulfiram is not rare but is often not correlated, and it should always be considered a possibility in patients receiving disulfiram therapy.

Altered caudate connectivity is associated with executive dysfunction after traumatic brain injury

PubMed Central

De Simoni, Sara; Jenkins, Peter O; Bourke, Niall J; Fleminger, Jessica J; Jolly, Amy E; Patel, Maneesh C; Leech, Robert; Sharp, David J

2018-01-01

Abstract Traumatic brain injury often produces executive dysfunction. This characteristic cognitive impairment often causes long-term problems with behaviour and personality. Frontal lobe injuries are associated with executive dysfunction, but it is unclear how these injuries relate to corticostriatal interactions that are known to play an important role in behavioural control. We hypothesized that executive dysfunction after traumatic brain injury would be associated with abnormal corticostriatal interactions, a question that has not previously been investigated. We used structural and functional MRI measures of connectivity to investigate this. Corticostriatal functional connectivity in healthy individuals was initially defined using a data-driven approach. A constrained independent component analysis approach was applied in 100 healthy adult dataset from the Human Connectome Project. Diffusion tractography was also performed to generate white matter tracts. The output of this analysis was used to compare corticostriatal functional connectivity and structural integrity between groups of 42 patients with traumatic brain injury and 21 age-matched controls. Subdivisions of the caudate and putamen had distinct patterns of functional connectivity. Traumatic brain injury patients showed disruption to functional connectivity between the caudate and a distributed set of cortical regions, including the anterior cingulate cortex. Cognitive impairments in the patients were mainly seen in processing speed and executive function, as well as increased levels of apathy and fatigue. Abnormalities of caudate functional connectivity correlated with these cognitive impairments, with reductions in right caudate connectivity associated with increased executive dysfunction, information processing speed and memory impairment. Structural connectivity, measured using diffusion tensor imaging between the caudate and anterior cingulate cortex was impaired and this also correlated with

Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

PubMed

Bar-Klein, Guy; Lublinsky, Svetlana; Kamintsky, Lyn; Noyman, Iris; Veksler, Ronel; Dalipaj, Hotjensa; Senatorov, Vladimir V; Swissa, Evyatar; Rosenbach, Dror; Elazary, Netta; Milikovsky, Dan Z; Milk, Nadav; Kassirer, Michael; Rosman, Yossi; Serlin, Yonatan; Eisenkraft, Arik; Chassidim, Yoash; Parmet, Yisrael; Kaufer, Daniela; Friedman, Alon

2017-06-01

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Synthetic Marijuana Induced Acute Nonischemic Left Ventricular Dysfunction.

PubMed

Elsheshtawy, Moustafa; Sriganesh, Priatharsini; Virparia, Vasudev; Patel, Falgun; Khanna, Ashok

2016-01-01

Synthetic marijuana is an uptrending designer drug currently widely spread in the US. We report a case of acute deterioration of nonischemic left ventricular dysfunction after exposure to synthetic marijuana. This case illustrates the importance of history taking in cardiac patients and identifies a negative cardiovascular effect of synthetic marijuana known as K2, not yet well detected by urine toxicology screening tools.

Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people.

PubMed

Bridges, Leslie R; Andoh, Joycelyn; Lawrence, Andrew J; Khoong, Cheryl H L; Poon, Wayne; Esiri, Margaret M; Markus, Hugh S; Hainsworth, Atticus H

2014-11-01

The blood-brain barrier protects brain tissue from potentially harmful plasma components. Small vessel disease (SVD; also termed arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis, and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and immunoglobulin G, which are assumed to reflect blood-brain barrier dysfunction, in deep gray matter (DGM; anterior caudate-putamen) and deep subcortical white matter (DWM) in the brains of a well-characterized cohort of donated brains with minimal Alzheimer disease pathology (Braak Stages 0-II) (n = 84; aged 65 years or older). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and immunoglobulin G was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that, in aged brains, plasma extravasation and hence local blood-brain barrier dysfunction are common but do not support an association with SVD.

Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

PubMed Central

Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

2016-01-01

Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. PMID:26235983

Source localization of intermittent rhythmic delta activity in a patient with acute confusional migraine: cross-spectral analysis using standardized low-resolution brain electromagnetic tomography (sLORETA).

PubMed

Kim, Dae-Eun; Shin, Jung-Hyun; Kim, Young-Hoon; Eom, Tae-Hoon; Kim, Sung-Hun; Kim, Jung-Min

2016-01-01

Acute confusional migraine (ACM) shows typical electroencephalography (EEG) patterns of diffuse delta slowing and frontal intermittent rhythmic delta activity (FIRDA). The pathophysiology of ACM is still unclear but these patterns suggest neuronal dysfunction in specific brain areas. We performed source localization analysis of IRDA (in the frequency band of 1-3.5 Hz) to better understand the ACM mechanism. Typical IRDA EEG patterns were recorded in a patient with ACM during the acute stage. A second EEG was obtained after recovery from ACM. To identify source localization of IRDA, statistical non-parametric mapping using standardized low-resolution brain electromagnetic tomography was performed for the delta frequency band comparisons between ACM attack and non-attack periods. A difference in the current density maximum was found in the dorsal anterior cingulated cortex (ACC). The significant differences were widely distributed over the frontal, parietal, temporal and limbic lobe, paracentral lobule and insula and were predominant in the left hemisphere. Dorsal ACC dysfunction was demonstrated for the first time in a patient with ACM in this source localization analysis of IRDA. The ACC plays an important role in the frontal attentional control system and acute confusion. This dysfunction of the dorsal ACC might represent an important ACM pathophysiology.

Blood–brain barrier dysfunction and epilepsy: Pathophysiologic role and therapeutic approaches

PubMed Central

Marchi, Nicola; Granata, Tiziana; Ghosh, Chaitali; Janigro, Damir

2016-01-01

The blood–brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte–endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB-centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs. PMID:22905812

Pituitary Dysfunction after Blast Traumatic Brain Injury: The UK BIOSAP Study

PubMed Central

Baxter, David; Sharp, David J; Feeney, Claire; Papadopoulou, Debbie; Ham, Timothy E; Jilka, Sagar; Hellyer, Peter J; Patel, Maneesh C; Bennett, Alexander N; Mistlin, Alan; McGilloway, Emer; Midwinter, Mark; Goldstone, Anthony P

2013-01-01

Objective Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury. Methods Nineteen male soldiers with moderate to severe bTBI (median age = 28.3 years) and 39 male controls with moderate to severe nonblast TBI (nbTBI; median age = 32.3 years) underwent full dynamic endocrine assessment between 2 and 48 months after injury. In addition, soldiers had structural brain magnetic resonance imaging, including diffusion tensor imaging (DTI), and cognitive assessment. Results Six of 19 (32.0%) soldiers with bTBI, but only 1 of 39 (2.6%) nbTBI controls, had anterior pituitary dysfunction (p = 0.004). Two soldiers had hyperprolactinemia, 2 had growth hormone (GH) deficiency, 1 had adrenocorticotropic hormone (ACTH) deficiency, and 1 had combined GH/ACTH/gonadotrophin deficiency. DTI measures of white matter structure showed greater traumatic axonal injury in the cerebellum and corpus callosum in those soldiers with pituitary dysfunction than in those without. Soldiers with pituitary dysfunction after bTBI also had a higher prevalence of skull/facial fractures and worse cognitive function. Four soldiers (21.1%) commenced hormone replacement(s) for hypopituitarism. Interpretation We reveal a high prevalence of anterior pituitary dysfunction in soldiers suffering moderate to severe bTBI, which was more frequent than in a matched group of civilian moderate to severe nbTBI subjects. We recommend that all patients with moderate to severe bTBI should routinely have comprehensive assessment of endocrine function. Ann Neurol 2013;74:527–536 PMID

Occurrence of oculomotor dysfunctions in acquired brain injury: a retrospective analysis.

PubMed

Ciuffreda, Kenneth J; Kapoor, Neera; Rutner, Daniella; Suchoff, Irwin B; Han, M E; Craig, Shoshana

2007-04-01

The purpose of this retrospective study was to determine the frequency of occurrence of oculomotor dysfunctions in a sample of ambulatory outpatients who have acquired brain injury (ABI), either traumatic brain injury (TBI) or cerebrovascular accident (CVA), with associated vision symptoms. Medical records of 220 individuals with either TBI (n = 160) or CVA (n = 60) were reviewed retrospectively. This was determined by a computer-based query spanning the years 2000 through 2003, for the frequency of occurrence of oculomotor dysfunctions including accommodation, version, vergence, strabismus, and cranial nerve (CN) palsy. The majority of individuals with either TBI (90%) or CVA (86.7%) manifested an oculomotor dysfunction. Accommodative and vergence deficits were most common in the TBI subgroup, whereas strabismus and CN palsy were most common in the CVA subgroup. The frequency of occurrence of versional deficits was similar in each diagnostic subgroup. These new findings should alert the clinician to the higher frequency of occurrence of oculomotor dysfunctions in these populations and the associated therapeutic, rehabilitative, and quality-of-life implications.

Clinical characteristics of acute encephalopathy with acute brain swelling: A peculiar type of acute encephalopathy.

PubMed

Nukui, Megumi; Kawawaki, Hisashi; Inoue, Takeshi; Kuki, Ichiro; Okazaki, Shin; Amo, Kiyoko; Togawa, Masao; Ishikawa, Junichi; Rinka, Hiroshi; Shiomi, Masashi

2018-06-07

Acute encephalopathy has been observed with acute brain swelling (ABS) that is characterized by rapid progression to whole-brain swelling. The objective of this study was to describe the clinical characteristics of ABS. We encountered four patients with ABS and retrospectively investigated their clinical data with a medical chart review. Three patients had seizure clustering or status epilepticus in the clinical course. Signs of elevated intracranial pressure (ICP) appeared 3-9 h after the first convulsive attack in three patients. In all patients, signs of brainstem involvement appeared 1-8 h after signs of elevated ICP. Mild hyponatremia that progressed after signs of elevated ICP appeared was noted in three patients. Brain CT revealed mild brain swelling in the initial phase, which rapidly progressed to whole-brain swelling. No focal abnormalities were detected on brain MRI in one patient. Continuous electroencephalography was initially normal, but in two patients, high-amplitude slow waves appeared with rapid changes before signs of brainstem involvement. Although recovery was achieved without sequelae in two patients, outcome was fatal for the other two. The pathogenesis of ABS has yet to be clarified, but clinical features in our patients are not consistent with any established subtypes of acute encephalopathy. Therefore, we believe that ABS should be recognized as a new type of acute encephalopathy. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Electrophysiology and functional MRI in post-acute mild traumatic brain injury.

PubMed

Gosselin, Nadia; Bottari, Carolina; Chen, Jen-Kai; Petrides, Michael; Tinawi, Simon; de Guise, Elaine; Ptito, Alain

2011-03-01

Symptoms persisting beyond the acute phase (>2 months) after a mild traumatic brain injury (MTBI) are often reported, but their origin remains controversial. Some investigators evoke dysfunctional cerebral mechanisms, while others ascribe them to the psychological consequences of the injury. We address this controversy by exploring possible cerebral dysfunction with functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) in a group of patients during the post-acute phase. Fourteen MTBI symptomatic patients (5.7±2.9 months post-injury) were tested with fMRI and ERP using a visual externally ordered working memory task, and were compared with 23 control subjects. Attenuated blood oxygen level dependent (BOLD) signal changes in the left and right mid-dorsolateral prefrontal cortex (mid-DLPFC), the putamen, the body of the caudate nucleus, and the right thalamus were found in the MTBI group compared with the control group. Moreover, symptom severity and BOLD signal changes were correlated: patients with more severe symptoms had lower BOLD signal changes in the right mid-DLPFC. For ERP, a group×task interaction was observed for N350 amplitude. A larger amplitude for the working memory task than for the control task was found in control subjects, but not in MTBI subjects, who had weak amplitudes for both tasks. This study confirms that persistent symptoms after MTBI cannot be uniquely explained by psychological factors, such as depression and/or malingering, and indicates that they can be associated with cerebral dysfunction. ERP reveals decreased amplitude of the N350 component, while fMRI demonstrates that the more severe the symptoms, the lower the BOLD signal changes in the mid-DLPFC.

[Brain oedema and acute liver failure].

PubMed

Spahr, L

2003-04-01

Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

Molecular mechanisms of cognitive dysfunction following traumatic brain injury

PubMed Central

Walker, Kendall R.; Tesco, Giuseppina

2013-01-01

Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration. PMID:23847533

Pituitary disorders as a predictor of apathy and executive dysfunction in adult survivors of childhood brain tumors.

PubMed

Fox, Michelle E; King, Tricia Z

2016-11-01

The relationship between apathy and endocrine dysfunction, both frequent outcomes of neurological insult, has not yet been investigated in brain tumor survivors. The present study aimed to assess the relationship between pituitary disorders and apathy and other facets of executive function in long-term adult survivors of childhood brain tumors and to differentiate between apathy and depression in this population. Seventy-six adult survivors of childhood brain tumors at least 5 years past diagnosis participated. An informant completed the Frontal Systems Behavior Scale (FrSBe), and 75 of the 76 participants completed a Structured Clinical Interview for the DSM-IV-TR (SCID). Information on neuroendocrine dysfunction was obtained through medical chart review. Clinically significant levels of apathy on the FrSBe were identified in 41% of survivors. Pituitary dysfunction significantly explained 9% of the variance in apathy scores and affected whether an individual presented with clinical levels of apathy. Pituitary dysfunction predicted higher levels of executive dysfunction but did not impact whether a participant reached clinical levels of executive dysfunction. A past major depressive episode (MDE) significantly predicted current apathy but showed no relationship with pituitary disorders. Radiation treatment predicted pituitary dysfunction but not the differences in apathy or executive functions. Apathy and executive dysfunction in survivors of childhood brain tumors are strongly predicted by pituitary dysfunction, and individuals with pituitary dysfunction are more likely to present with clinical levels of apathy as adults. Clinical levels of apathy may present absent of current depression, and pituitary dysfunction impacts apathy uniquely. © 2016 Wiley Periodicals, Inc.

[Traumatic brain injury and anterior pituitary dysfunction. Regarding 33 cases: Evolution profile over a six-month period].

PubMed

Sanoussi, S; Ali, A; Laouali, H; Assoumane, I; Chaibou Maman, S; Baoua, M

2013-01-01

To measure anterior pituitary dysfunction in traumatic brain injury (TBI) and assess the correlations between this disorder, clinical signs and brain lesions. This was a prospective, longitudinal and analytic study conducted in the department of neurosurgery at the National Hospital of Niamey and the institute of radioisotopes of Niamey University between November 2009 and November 2010. All patients admitted for head trauma were included in the study. They were followed-up for 6 months and underwent clinical, hormonal and CT scan analysis. The hormonal studies targeted gonadotroph hormone, growth hormone (GH), corticotroph, lactotroph, and thyreotroph axes. Thirty-three patients were included in the study. The sex ratio was 15.4:1. The mean age was 28.21 years. Glasgow coma scale score was between 7 and 12 in 52% of cases, with brain contusions in 54.5% of cases. In the acute phase, hypogonadism was reported in 64% of cases, and growth hormone deficiency in 58% of cases. Hormonal follow-up at three months showed GH deficiency in 48% of cases with an elevated luteinizing hormone (LH) in 42% of cases. At sixth months, a rise in LH was observed in 55% with GH deficiency in 52% of cases. Surgical procedures were performed in 21% of cases. At 6 months a post-concussion syndrome was observed in 48.48% of cases. These pituitary dysfunctions are common and should be investigated into the management of TBI. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

[Neuroendocrine dysfunction and brain damage. A consensus statement].

PubMed

Leal-Cerro, Alfonso; Rincón, María Dolores; Domingo, Manel Puig

2009-01-01

This consensus statement aims to enhance awareness of the incidence and risks of hypopituitarism in patients with traumatic brain injury (TBI) and/or brain hemorrhages among physicians treating patients with brain damage. The importance of this problem is related not only to the frequency of TBI but also to its prevalence in younger populations. The consequences of TBI are characterized by a series of symptoms that depend on the type of sequels related to neuroendocrine dysfunction. The signs and symptoms of hypopituitarism are often confused with those of other sequels of TBI. Consequently, patients with posttraumatic hypopituitarism may receive suboptimal rehabilitation unless the underlying hormone deficiency is identified and treated. This consensus is based on the recommendation supported by expert opinion that patients with a TBI and/or brain hemorrhage should undergo endocrine evaluation in order to assess pituitary function and, if deficiency is detected, should receive hormone replacement therapy.

Pathological anxiety and function/dysfunction in the brain's fear/defense circuitry.

PubMed

Lang, Peter J; McTeague, Lisa M; Bradley, Margaret M

2014-01-01

Research from the University of Florida Center for the Study of Emotion and Attention aims to develop neurobiological measures that objectively discriminate among symptom patterns in patients with anxiety disorders. From this perspective, anxiety and mood pathologies are considered to be brain disorders, resulting from dysfunction and maladaptive plasticity in the neural circuits that determine fearful/defensive and appetitive/reward behavior (Insel et al., 2010). We review recent studies indicating that an enhanced probe startle reflex during the processing of fear memory cues (mediated by cortico-limbic circuitry and thus indicative of plastic brain changes), varies systematically in strength over a spectrum-wide dimension of anxiety pathology-across and within diagnoses-extending from strong focal fear reactions to a consistently blunted reaction in patients with more generalized anxiety and comorbid mood disorders. Preliminary studies with functional magnetic resonance imaging (fMRI) encourage the hypothesis that fear/defense circuit dysfunction covaries with this same dimension of psychopathology. Plans are described for an extended study of the brain's motivation circuitry in anxiety spectrum patients, with the aim of defining the specifics of circuit dysfunction in severe disorders. A sub-project explores the use of real-time fMRI feedback in circuit analysis and as a modality to up-regulate circuit function in the context of blunted affect.

Brain endothelial dysfunction in cerebral adrenoleukodystrophy.

PubMed

Musolino, Patricia L; Gong, Yi; Snyder, Juliet M T; Jimenez, Sandra; Lok, Josephine; Lo, Eng H; Moser, Ann B; Grabowski, Eric F; Frosch, Matthew P; Eichler, Florian S

2015-11-01

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

HttQ111/+ Huntington's Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction.

PubMed

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St Claire, Jason; Guide, Jolene R; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E; Carroll, Jeffrey B; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C

2018-01-01

Successful disease-modifying therapy for Huntington's disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life.

Acute organic brain syndrome: a review of 100 cases.

PubMed

Purdie, F R; Honigman, B; Rosen, P

1981-09-01

A retrospective review of 100 admissions to Denver General Hospital with a diagnosis of acute organic brain syndrome was conducted. A total of 44% of the patients were found to have a chronic organic brain syndrome with a superimposed acute insult which caused decompensation. The other 56% of patients developed acute organic brain syndromes de novo for a variety of reasons. The most common etiologic factors producing decompensation of the chronic OBS were infections (in 23%) and environmental changes (in 17%). The most common etiologic factor causing AOBS de novo was drug-related. In most cases, a toxicologic screen, lumbar puncture, and CT scan of the brain should be a part of the investigation of any patient with AOBS.

Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction.

PubMed

Pitel, Anne Lise; Segobin, Shailendra H; Ritz, Ludivine; Eustache, Francis; Beaunieux, Hélène

2015-07-01

Two brain networks are particularly affected by the harmful effect of chronic and excessive alcohol consumption: the circuit of Papez and the frontocerebellar circuit, in both of which the thalamus plays a key role. Shrinkage of the thalamus is more severe in alcoholics with Korsakoff's syndrome (KS) than in those without neurological complication (AL). In accordance with the gradient effect of thalamic abnormalities between AL and KS, the pattern of brain dysfunction in the Papez's circuit results in anterograde amnesia in KS and only mild-to-moderate episodic memory disorders in AL. On the opposite, dysfunction of the frontocerebellar circuit results in a similar pattern of working memory and executive deficits in the AL and KS. Several hypotheses, mutually compatible, can be drawn to explain that the severe thalamic shrinkage observed in KS has different consequences in the neuropsychological profile associated with the two brain networks. Copyright © 2014. Published by Elsevier Ltd.

Stress hormonal changes in the brain and plasma after acute noise exposure in mice.

PubMed

Jin, Sang Gyun; Kim, Min Jung; Park, So Young; Park, Shi Nae

2017-06-01

To investigate the effects of acute noise stress on two amine stress hormones, norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain and plasma of mice after noise exposure. Mice were grouped into the control and noise groups. Mice in the noise group were exposed to white noise of 110dB sound pressure level for 60min. Auditory brainstem response thresholds, distortion product otoacoustic emissions, the organ of Corti grading scores, western blots of NE/5-HIAA in the whole brain and hippocampus, and the plasma levels of NE/5-HIAA were compared between the two groups. Significant hearing loss and cochlear damage were demonstrated in the noise group. NE and 5-HIAA in the hippocampus were elevated in the noise group (p=0.019/0.022 for NE/5-HIAA vs. the control). Plasma levels of NE and 5-HIAA were not statistically different between the groups (p=0.052/0.671 for NE/5-HIAA). Hearing loss with outer hair cell dysfunction and morphological changes of the organ of Corti after noise exposure in C57BL/6 mice proved the reliability of our animal model as an acute noise stress model. NE and 5-HIAA are suggested to be the potential biomarkers for acute noise stress in the hippocampus. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adolescent Executive Dysfunction in Daily Life: Relationships to Risks, Brain Structure and Substance Use

PubMed Central

Clark, Duncan B.; Chung, Tammy; Martin, Christopher S.; Hasler, Brant P.; Fitzgerald, Douglas H.; Luna, Beatriz; Brown, Sandra A.; Tapert, Susan F.; Brumback, Ty; Cummins, Kevin; Pfefferbaum, Adolf; Sullivan, Edith V.; Pohl, Kilian M.; Colrain, Ian M.; Baker, Fiona C.; De Bellis, Michael D.; Nooner, Kate B.; Nagel, Bonnie J.

2017-01-01

During adolescence, problems reflecting cognitive, behavioral and affective dysregulation, such as inattention and emotional dyscontrol, have been observed to be associated with substance use disorder (SUD) risks and outcomes. Prior studies have typically been with small samples, and have typically not included comprehensive measurement of executive dysfunction domains. The relationships of executive dysfunction in daily life with performance based testing of cognitive skills and structural brain characteristics, thought to be the basis for executive functioning, have not been definitively determined. The aims of this study were to determine the relationships between executive dysfunction in daily life, measured by the Behavior Rating Inventory of Executive Function (BRIEF), cognitive skills and structural brain characteristics, and SUD risks, including a global SUD risk indicator, sleep quality, and risky alcohol and cannabis use. In addition to bivariate relationships, multivariate models were tested. The subjects (n = 817; ages 12 through 21) were participants in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. The results indicated that executive dysfunction was significantly related to SUD risks, poor sleep quality, risky alcohol use and cannabis use, and was not significantly related to cognitive skills or structural brain characteristics. In multivariate models, the relationship between poor sleep quality and risky substance use was mediated by executive dysfunction. While these cross-sectional relationships need to be further examined in longitudinal analyses, the results suggest that poor sleep quality and executive dysfunction may be viable preventive intervention targets to reduce adolescent substance use. PMID:29180956

Acute brain trauma

PubMed Central

Martin, GT

2016-01-01

In the 20th century, the complications of head injuries were controlled but not eliminated. The wars of the 21st century turned attention to blast, the instant of impact and the primary injury of concussion. Computer calculations have established that in the first 5 milliseconds after the impact, four independent injuries on the brain are inflicted: 1) impact and its shockwave, 2) deceleration, 3) rotation and 4) skull deformity with vibration (or resonance). The recovery, pathology and symptoms after acute brain trauma have always been something of a puzzle. The variability of these four modes of injury, along with a variable reserve of neurones, explains some of this problem. PMID:26688392

Successful use of high-dose cytarabine in a patient with acute myeloid leukemia and severe hepatic dysfunction.

PubMed

Barker, Jacob A; Marini, Bernard L; Bixby, Dale; Perissinotti, Anthony J

2016-12-01

Acute myeloid leukemia is a hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and other tissues. Prognosis is poor with 5-year survival rates ranging from 5-65% depending on demographic and clinical features. Outcomes are worse for patients that have an antecedent myeloproliferative neoplasm that evolves to acute myeloid leukemia, with a survival rate of <10%. Treatment for acute myeloid leukemia has remained cytarabine and an anthracycline given in the standard 3 + 7 regimen. However, for patients with liver dysfunction this regimen, among many others, cannot be given safely. There is currently a lack of data regarding the use of cytarabine in patients with severe hepatic dysfunction. In this case report, we present a patient with secondary acute myeloid leukemia who successfully received a modified regimen of high-dose cytarabine while in severe hepatic dysfunction (bilirubin >15 mg/dL). © The Author(s) 2015.

Autonomic Dysfunction Predicts Clinical Outcomes After Acute Ischemic Stroke: A Prospective Observational Study.

PubMed

Xiong, Li; Tian, Ge; Leung, Howan; Soo, Yannie O Y; Chen, Xiangyan; Ip, Vincent H L; Mok, Vincent C T; Chu, Winnie C W; Wong, Ka Sing; Leung, Thomas W H

2018-01-01

Central autonomic dysfunction increases stroke morbidity and mortality. We aimed to investigate whether poststroke autonomic dysfunction graded by Ewing battery can predict clinical outcome. In this prospective observational study, we assessed autonomic function of ischemic stroke patients within 7 days from symptom onset by Ewing battery. On the basis of the magnitude of autonomic dysfunction, we stratified patients into significant (definite, severe, or atypical) or minor (normal or early) autonomic function impairment groups and correlated the impairment with the 3-month modified Rankin Scale score (good outcome: modified Rankin Scale score 0≈2; poor outcome: modified Rankin Scale score 3≈6). Among the 150 patients enrolled (mean age, 66.4±9.9 years; 70.7% males), minor autonomic dysfunction was identified in 36 patients (24.0%), and significant autonomic dysfunction was identified in 114 patients (76.0%) based on Ewing battery. In 3 months, a poor functional outcome was found in 32.5% of significant group patients compared with 13.9% in the minor group ( P =0.031). Crude odds ratios of the magnitude of autonomic dysfunction and 3-month unfavorable functional outcome after acute ischemic stroke were 2.979 (95% confidence interval, 1.071-8.284; P =0.036). After adjusting for confounding variables with statistical significance between the 2 functional outcome subgroups identified in univariate analysis (including sex and National Institutes of Health Stroke Scale score on admission), the magnitude of autonomic dysfunction still independently predicted an unfavorable outcome, with an odds ratio of 3.263 (95% confidence interval, 1.141-9.335; P =0.027). Autonomic dysfunction gauged by Ewing battery predicts poor functional outcome after acute ischemic stroke. © 2017 American Heart Association, Inc.

Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

PubMed Central

2014-01-01

This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood–brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer’s disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke. PMID:25120903

Deanol in minimal brain dysfunction.

PubMed

Lewis, J A; Lewis, B S

1977-12-01

The literature on minimal brain dysfunction is confused, confusing and controversial. The statements that the condition exists, needs treatment, and that treatment may be pharmacological, are more expressions of faith than accepted fact. We believe they are true (within limits not discussed in the article). Furthermore, there is evidence that some patients with MBD are hypo-aroused, while others are not. The role of deanol in the treatment of MBD is still unclear, because of the complexities of identifying appropriate patients in terms of levels of arousal, as well as identifying appropriate measures of response. There is sufficient support for an effect of deanol in the literature to justify further investigation. Further studies should attend to important methodological problems as discussed.

Impaired Pituitary Axes Following Traumatic Brain Injury

PubMed Central

Scranton, Robert A.; Baskin, David S.

2015-01-01

Pituitary dysfunction following traumatic brain injury (TBI) is significant and rarely considered by clinicians. This topic has received much more attention in the last decade. The incidence of post TBI anterior pituitary dysfunction is around 30% acutely, and declines to around 20% by one year. Growth hormone and gonadotrophic hormones are the most common deficiencies seen after traumatic brain injury, but also the most likely to spontaneously recover. The majority of deficiencies present within the first year, but extreme delayed presentation has been reported. Information on posterior pituitary dysfunction is less reliable ranging from 3%–40% incidence but prospective data suggests a rate around 5%. The mechanism, risk factors, natural history, and long-term effect of treatment are poorly defined in the literature and limited by a lack of standardization. Post TBI pituitary dysfunction is an entity to recognize with significant clinical relevance. Secondary hypoadrenalism, hypothyroidism and central diabetes insipidus should be treated acutely while deficiencies in growth and gonadotrophic hormones should be initially observed. PMID:26239686

Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice

PubMed Central

Gauba, Esha; Guo, Lan; Du, Heng

2017-01-01

Brain aging is the known strongest risk factor for Alzheimer’s disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD. PMID:27834780

Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice.

PubMed

Gauba, Esha; Guo, Lan; Du, Heng

2017-01-01

Brain aging is the known strongest risk factor for Alzheimer's disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD.

Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro

PubMed Central

Üllen, Andreas; Fauler, Günter; Bernhart, Eva; Nusshold, Christoph; Reicher, Helga; Leis, Hans-Jörg; Malle, Ernst; Sattler, Wolfgang

2012-01-01

2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase–hydrogen peroxide–chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood–brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting. PMID:22982051

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

PubMed

Hainsworth, Atticus H; Minett, Thais; Andoh, Joycelyn; Forster, Gillian; Bhide, Ishaan; Barrick, Thomas R; Elderfield, Kay; Jeevahan, Jamuna; Markus, Hugh S; Bridges, Leslie R

2017-10-01

We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T 2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P =0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P =0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P =0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P =0.007). Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers. © 2017 American Heart Association, Inc.

Development of the Korean Academy of Medical Sciences Guideline for Rating the Impairment in the Brain Injured and Brain Diseased Persons with Motor Dysfunction

PubMed Central

Baik, Jong Sam; Jang, Seong Ho; Park, Dong Sik

2009-01-01

To develop an objective and scientific method to evaluate the brain injured and brain diseased persons with motor dysfunction, American Medical Association's Guides to the Evaluation of Permanent Impairment was used as an exemplar. After the motor dysfunction due to brain injury or brain disease was confirmed, active range of motion and muscle strength of affected extremities were measured. Also, the total function of extremities was evaluated through the assessment of activities of daily living, fine coordination of hand, balance and gait. Then, the total score of manual muscle test and functional assessment of impaired upper and lower extremity were added, respectively. Spasticity of upper and lower extremity was used as minus factors. Patients with movement disorder such as Parkinson's disease were assessed based on the degree of dysfunction in response to medication. We develop a new rating system based on the concept of total score. PMID:19503680

Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

PubMed

Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

2017-08-01

Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

Acute brain herniation from lead toxicity.

PubMed

Berkowitz, Sheldon; Tarrago, Rod

2006-12-01

A 4-year-old black boy was admitted to the hospital with vomiting, low-grade fever, and dehydration that were thought to be caused by viral gastroenteritis. He proceeded over the next 12 hours to rapidly deteriorate with brain herniation leading to brain death. The ultimate cause of death was found to be acute lead intoxication from a swallowed foreign body.

Brain lesion-pattern analysis in patients with olfactory dysfunctions following head trauma

PubMed Central

Lötsch, Jörn; Ultsch, Alfred; Eckhardt, Maren; Huart, Caroline; Rombaux, Philippe; Hummel, Thomas

2016-01-01

The presence of cerebral lesions in patients with neurosensory alterations provides a unique window into brain function. Using a fuzzy logic based combination of morphological information about 27 olfactory-eloquent brain regions acquired with four different brain imaging techniques, patterns of brain damage were analyzed in 127 patients who displayed anosmia, i.e., complete loss of the sense of smell (n = 81), or other and mechanistically still incompletely understood olfactory dysfunctions including parosmia, i.e., distorted perceptions of olfactory stimuli (n = 50), or phantosmia, i.e., olfactory hallucinations (n = 22). A higher prevalence of parosmia, and as a tendency also phantosmia, was observed in subjects with medium overall brain damage. Further analysis showed a lower frequency of lesions in the right temporal lobe in patients with parosmia than in patients without parosmia. This negative direction of the differences was unique for parosmia. In anosmia, and also in phantosmia, lesions were more frequent in patients displaying the respective symptoms than in those without these dysfunctions. In anosmic patients, lesions in the right olfactory bulb region were much more frequent than in patients with preserved sense of smell, whereas a higher frequency of carriers of lesions in the left frontal lobe was observed for phantosmia. We conclude that anosmia, and phantosmia, are the result of lost function in relevant brain areas whereas parosmia is more complex, requiring damaged and intact brain regions at the same time. PMID:26937377

Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro.

PubMed

Ullen, Andreas; Fauler, Günter; Bernhart, Eva; Nusshold, Christoph; Reicher, Helga; Leis, Hans-Jörg; Malle, Ernst; Sattler, Wolfgang

2012-11-01

2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood-brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute organic brain syndrome due to drug-induced eosinophilia.

PubMed

Ng, S C; Lee, M K; Teh, A

1989-11-01

A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome.

Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia.

PubMed

Fellah, Slim; Cheung, Yin T; Scoggins, Matthew A; Zou, Ping; Sabin, Noah D; Pui, Ching-Hon; Robison, Leslie L; Hudson, Melissa M; Ogg, Robert J; Krull, Kevin R

2018-05-21

The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated. Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided. Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate. Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.

PubMed

Ballarini, Tommaso; Iaccarino, Leonardo; Magnani, Giuseppe; Ayakta, Nagehan; Miller, Bruce L; Jagust, William J; Gorno-Tempini, Maria Luisa; Rabinovici, Gil D; Perani, Daniela

2016-12-01

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer's disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18 F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty-five percent of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18 F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Acute caffeine administration effect on brain activation patterns in mild cognitive impairment.

PubMed

Haller, Sven; Montandon, Marie-Louise; Rodriguez, Cristelle; Moser, Dominik; Toma, Simona; Hofmeister, Jeremy; Sinanaj, Indrit; Lovblad, Karl-Olof; Giannakopoulos, Panteleimon

2014-01-01

Previous studies showed that acute caffeine administration enhances task-related brain activation in elderly individuals with preserved cognition. To explore the effects of this widely used agent on cognition and brain activation in early phases of cognitive decline, we performed a double-blinded, placebo-controlled functional magnetic resonance imaging (fMRI) study during an n-back working memory task in 17 individuals with mild cognitive impairment (MCI) compared to 17 age-matched healthy controls (HC). All individuals were regular caffeine consumers with an overnight abstinence and given 200 mg caffeine versus placebo tablets 30 minutes before testing. Analyses included assessment of task-related activation (general linear model), functional connectivity (tensorial-independent component analysis, TICA), baseline perfusion (arterial spin labeling, ASL), grey matter density (voxel-based morphometry, VBM), and white matter microstructure (tract-based spatial statistics, TBSS). Acute caffeine administration induced a focal activation of the prefrontal areas in HC with a more diffuse and posteromedial activation pattern in MCI individuals. In MCI, TICA documented a significant caffeine-related enhancement in the prefrontal cortex, supplementary motor area, ventral premotor and parietal cortex as well as the basal ganglia and cerebellum. The absence of significant group differences in baseline ASL perfusion patterns supports a neuronal rather than a purely vascular origin of these differences. The VBM and TBSS analyses excluded potentially confounding differences in grey matter density and white matter microstructure between MCI and HC. The present findings suggest a posterior displacement of working memory-related brain activation patterns after caffeine administration in MCI that may represent a compensatory mechanism to counterbalance a frontal lobe dysfunction.

Pseudo-acute myocardial infarction due to transient apical ventricular dysfunction syndrome (Takotsubo syndrome).

PubMed

Maciel, Bruno Araújo; Cidrão, Alan Alves de Lima; Sousa, Italo Bruno Dos Santos; Ferreira, José Adailson da Silva; Messias Neto, Valdevino Pedro

2013-03-01

Takotsubo syndrome is characterized by predominantly medial-apical transient left ventricular dysfunction, which is typically triggered by physical or emotional stress. The present article reports the case of a 61-year-old female patient presenting with dizziness, excessive sweating, and sudden state of ill feeling following an episode involving intense emotional stress. The physical examination and electrocardiogram were normal upon admission, but the troponin I and creatine kinase-MB concentrations were increased. Acute myocardial infarction without ST segment elevation was suspected, and coronary angiography was immediately performed, which showed severe diffuse left ventricular hypokinesia, medial-apical systolic ballooning, and a lack of significant coronary injury. The patient was referred to the intensive care unit and was successfully treated with supportive therapy. As this case shows, Takotsubo syndrome might simulate the clinical manifestations of acute myocardial infarction, and coronary angiography is necessary to distinguish between both myocardial infarction and myocardial infarction in the acute stage. The present patient progressed with spontaneous resolution of the ventricular dysfunction without any sequelae.

Pseudo-acute myocardial infarction due to transient apical ventricular dysfunction syndrome (Takotsubo syndrome)

PubMed Central

Maciel, Bruno Araújo; Cidrão, Alan Alves de Lima; Sousa, Ítalo Bruno dos Santos; Ferreira, José Adailson da Silva; Messias Neto, Valdevino Pedro

2013-01-01

Takotsubo syndrome is characterized by predominantly medial-apical transient left ventricular dysfunction, which is typically triggered by physical or emotional stress. The present article reports the case of a 61-year-old female patient presenting with dizziness, excessive sweating, and sudden state of ill feeling following an episode involving intense emotional stress. The physical examination and electrocardiogram were normal upon admission, but the troponin I and creatine kinase-MB concentrations were increased. Acute myocardial infarction without ST segment elevation was suspected, and coronary angiography was immediately performed, which showed severe diffuse left ventricular hypokinesia, medial-apical systolic ballooning, and a lack of significant coronary injury. The patient was referred to the intensive care unit and was successfully treated with supportive therapy. As this case shows, Takotsubo syndrome might simulate the clinical manifestations of acute myocardial infarction, and coronary angiography is necessary to distinguish between both myocardial infarction and myocardial infarction in the acute stage. The present patient progressed with spontaneous resolution of the ventricular dysfunction without any sequelae. PMID:23887762

Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

PubMed

Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

2012-12-21

The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

HttQ111/+ Huntington’s Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction

PubMed Central

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St. Claire, Jason; Guide, Jolene R.; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E.; Carroll, Jeffrey B.; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C.

2018-01-01

Background: Successful disease-modifying therapy for Huntington’s disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. Objective: To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Methods: Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. Results: B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. Conclusions: These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life. PMID:29480209

Acute high-altitude hypoxic brain injury: Identification of ten differential proteins

PubMed Central

Li, Jianyu; Qi, Yuting; Liu, Hui; Cui, Ying; Zhang, Li; Gong, Haiying; Li, Yaxiao; Li, Lingzhi; Zhang, Yongliang

2013-01-01

Hypobaric hypoxia can cause severe brain damage and mitochondrial dysfunction, and is involved in hypoxic brain injury. However, little is currently known about the mechanisms responsible for mitochondrial dysfunction in hypobaric hypoxic brain damage. In this study, a rat model of hypobaric hypoxic brain injury was established to investigate the molecular mechanisms associated with mitochondrial dysfunction. As revealed by two-dimensional electrophoresis analysis, 16, 21, and 36 differential protein spots in cerebral mitochondria were observed at 6, 12, and 24 hours post-hypobaric hypoxia, respectively. Furthermore, ten protein spots selected from each hypobaric hypoxia subgroup were similarly regulated and were identified by mass spectrometry. These detected proteins included dihydropyrimidinase-related protein 2, creatine kinase B-type, isovaleryl-CoA dehydrogenase, elongation factor Ts, ATP synthase beta-subunit, 3-mercaptopyruvate sulfurtransferase, electron transfer flavoprotein alpha-subunit, Chain A of 2-enoyl-CoA hydratase, NADH dehydrogenase iron-sulfur protein 8 and tropomyosin beta chain. These ten proteins are all involved in the electron transport chain and the function of ATP synthase. Our findings indicate that hypobaric hypoxia can induce the differential expression of several cerebral mitochondrial proteins, which are involved in the regulation of mitochondrial energy production. PMID:25206614

Acute organic brain syndrome due to drug-induced eosinophilia.

PubMed Central

Ng, S. C.; Lee, M. K.; Teh, A.

1989-01-01

A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome. PMID:2616421

Pupillary and Heart Rate Reactivity in Children with Minimal Brain Dysfunction

ERIC Educational Resources Information Center

Zahn, Theodore P.; And Others

1978-01-01

In an attempt to replicate and extend previous findings on autonomic arousal and responsivity in children with minimal brain dysfunction (MBD), pupil size, heart rate, skin conductance, and skin temperature were recorded from 32 MBD and 45 control children (6-13 years old). (Author/CL)

Proton Magnetic Resonance Spectroscopy and MRI Reveal No Evidence for Brain Mitochondrial Dysfunction in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Corrigan, Neva M.; Shaw, Dennis. W. W.; Richards, Todd L.; Estes, Annette M.; Friedman, Seth D.; Petropoulos, Helen; Artru, Alan A.; Dager, Stephen R.

2012-01-01

Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ([superscript 1]HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally…

Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis

PubMed Central

Mayr, Florian B.; Yende, Sachin; Linde-Zwirble, Walter T.; Peck-Palmer, Octavia M.; Barnato, Amber E.; Weissfeld, Lisa A.; Angus, Derek C.

2013-01-01

Context Severe sepsis, defined as infection complicated by acute organ dysfunction, occurs more frequently and leads to more deaths in black than in white individuals. The optimal approach to minimize these disparities is unclear. Objective To determine the extent to which higher severe sepsis rates in black than in white patients are due to higher infection rates or to a higher risk of acute organ dysfunction. Design, Setting, and Participants Analysis of infection-related hospitalizations from the 2005 hospital discharge data of 7 US states and infection-related emergency department visits from the 2003-2007 National Hospital Ambulatory Care Survey. Main Outcome Measure Age- and sex-standardized severe sepsis and infection hospitalization rates and the risk of acute organ dysfunction. Results Of 8 661 227 non–childbirth-related discharges, 2 261 857 were associated with an infection, and of these, 381 787 (16.8%) had severe sepsis. Black patients had a 67% higher age- and sex-standardized severe sepsis rate than did white patients (9.4; 95% confidence interval [CI], 9.3-9.5 vs 5.6; 95% CI, 5.6-5.6 per 1000 population; P<.001) and 80% higher standardized mortality (1.8, 95% CI, 1.8-1.9 vs 1.0, 95% CI, 1.0-1.1 per 1000 population; P<.001). The higher severe sepsis rate was explained by both a higher infection rate in black patients (47.3; 95% CI, 47.1-47.4 vs 34.0; 95% CI, 33.9-34.0 per 1000 population; incidence rate ratio, 1.39; P<.001) and a higher risk of developing acute organ dysfunction (age- and sex-adjusted odds ratio [OR],1.29; 95% CI, 1.27-1.30; P<.001). Differences in infection presented broadly across different sites and etiology of infection and for community- and hospital-acquired infections and occurred despite a lower likelihood of being admitted for infection from the emergency department (adjusted OR, 0.70; 95% CI, 0.64-0.76; P<.001). The higher risk of organ dysfunction persisted but was attenuated after adjusting for age, sex, comorbid

Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report.

PubMed

Ohara, Nobumasa; Yoneoka, Yuichiro; Seki, Yasuhiro; Akiyama, Katsuhiko; Arita, Masataka; Ohashi, Kazumasa; Suzuki, Kazuo; Takada, Toshinori

2017-08-24

Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. An 83-year-old Japanese man developed acute anterior hypopituitarism; he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

A porcine model for acute ischaemic right ventricular dysfunction.

PubMed

Haraldsen, Pernille; Lindstedt, Sandra; Metzsch, Carsten; Algotsson, Lars; Ingemansson, Richard

2014-01-01

To establish an experimental model for acute ischaemic isolated right ventricular dysfunction and the subsequent haemodynamic changes. An open-chest porcine model with ischaemic dysfunction of the right ventricle induced by ligation of the three main branches supporting the right ventricular free wall. Invasive monitoring of mean arterial blood pressure (MAP), central venous pressure (CVP), left atrial pressure (LAP) and right ventricular pressure (RVP); ultrasonic measurement of cardiac output (CO) and calculation of haemodynamic parameters such as stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and right ventricular stroke work (RVSW) using standard formulae. The ischaemic challenge to the right ventricle resulted in a significant (≥30%) reduction in RVSW associated with an increase (6-25%) in CVP and reduction (8-18%) in pulmonary artery pressure (PAP) despite unchanged PVR, all reflecting the failing right ventricle. There was also a significant drop in CO (14-22%) despite unchanged LAP indicating lessened transpulmonary delivery of left ventricular preload due to the failing right ventricle causing the haemodynamic compromise rather than left ventricular failure. Supraventricular and ventricular arrhythmias occurred in three and two out of seven pigs, respectively-all of which except one were successfully resuscitated with cardioversion and/or defibrillation. This novel open-chest porcine model of induced ischaemia of the right ventricular free wall resulted in significant haemodynamic compromise confirmed using standard haemodynamic measurements making it useful for further research on acute, ischaemic isolated right ventricular failure.

History of erectile dysfunction as a predictor of poor physical performance after an acute myocardial infarction.

PubMed

Compostella, Leonida; Compostella, Caterina; Truong, Li Van Stella; Russo, Nicola; Setzu, Tiziana; Iliceto, Sabino; Bellotto, Fabio

2017-03-01

Background Erectile dysfunction may predict future cardiovascular events and indicate the severity of coronary artery disease in middle-aged men. The aim of this study was to evaluate whether erectile dysfunction (expression of generalized macro- and micro-vascular pathology) could predict reduced effort tolerance in patients after an acute myocardial infarction. Patients and methods One hundred and thirty-nine male patients (60 ± 12 years old), admitted to intensive cardiac rehabilitation 13 days after a complicated acute myocardial infarction, were evaluated for history of erectile dysfunction using the International Index of Erectile Function questionnaire. Their physical performance was assessed by means of two six-minute walk tests (performed two weeks apart) and by a symptom limited cardiopulmonary exercise test (CPET). Results Patients with erectile dysfunction (57% of cases) demonstrated poorer physical performance, significantly correlated to the degree of erectile dysfunction. After cardiac rehabilitation, they walked shorter distances at the final six-minute walk test (490 ± 119 vs. 564 ± 94 m; p < 0.001); at CPET they sustained lower workload (79 ± 28 vs. 109 ± 34 W; p < 0.001) and reached lower oxygen uptake at peak effort (18 ± 5 vs. 21 ± 5 ml/kg per min; p = 0.003) and at anaerobic threshold (13 ± 3 vs.16 ± 4 ml/kg per min; p = 0.001). The positive predictive value of presence of erectile dysfunction was 0.71 for low peak oxygen uptake (<20 ml/kg per min) and 0.69 for reduced effort capacity (W-max <100 W). Conclusions As indicators of generalized underlying vascular pathology, presence and degree of erectile dysfunction may predict the severity of deterioration of effort tolerance in post-acute myocardial infarction patients. In the attempt to reduce the possibly associated long-term risk, an optimization of type, intensity and duration of cardiac rehabilitation should be

Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation.

PubMed

Matt, Stephanie M; Johnson, Rodney W

2016-02-01

Microglia, the resident immune cells of the brain, are at the center of communication between the central nervous system and immune system. While these brain-immune interactions are balanced in healthy adulthood, the ability to maintain homeostasis during aging is impaired. Microglia develop a loss of integrated regulatory networks including aberrant signaling from other brain cells, immune sensors, and epigenetic modifiers. The low-grade chronic neuroinflammation associated with this dysfunctional activity likely contributes to cognitive deficits and susceptibility to age-related pathologies. A better understanding of the underlying mechanisms responsible for neuro-immune dysregulation with age is crucial for providing targeted therapeutic strategies to support brain repair and healthy aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

CD40-CD40 Ligand Pathway is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis.

PubMed

Michels, Monique; Danieslki, Lucinéia Gainski; Vieira, Andriele; Florentino, Drielly; Dall'Igna, Dhébora; Galant, Letícia; Sonai, Beatriz; Vuolo, Francieli; Mina, Franciele; Pescador, Bruna; Dominguini, Diogo; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Petronilho, Fabrícia

2015-03-26

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.

Effects of disease severity and necrosis on pancreatic dysfunction after acute pancreatitis.

PubMed

Garip, Gokhan; Sarandöl, Emre; Kaya, Ekrem

2013-11-28

To evaluate the effects of disease severity and necrosis on organ dysfunctions in acute pancreatitis (AP). One hundred and nine patients treated as AP between March 2003 and September 2007 with at least 6 mo follow-up were included. Patients were classified according to severity of the disease, necrosis ratio and localization. Subjective clinical evaluation and fecal pancreatic elastase-I (FPE-I) were used for exocrine dysfunction evaluation, and oral glucose tolerance test was completed for endocrine dysfunction. The correlation of disease severity, necrosis ratio and localization with exocrine and endocrine dysfunction were investigated. There were 58 male and 51 female patients, and mean age was 56.5 ± 15.7. Of the patients, 35.8% had severe AP (SAP) and 27.5% had pancreatic necrosis. Exocrine dysfunction was identified in 13.7% of the patients [17.9% were in SAP, 11.4% were in mild AP (MAP)] and 34.7% of all of the patients had endocrine dysfunction (56.4% in SAP and 23.2% in MAP). In patients with SAP and necrotizing AP (NAP), FPE-Ilevels were lower than the others (P < 0.05 and 0.001 respectively) and in patients having pancreatic head necrosis or near total necrosis, FPE-1 levels were lower than 200 μg/g stool. Forty percent of the patients who had undergone necrosectomy developed exocrine dysfunction. Endocrine dysfunction was more significant in patients with SAP and NAP (P < 0.001). All of the patients in the necrosectomy group had endocrine dysfunction. Patients with SAP, NAP, pancreatic head necrosis and necrosectomy should be followed for pancreatic functions.

Incidence of pituitary dysfunction following traumatic brain injury: A prospective study from a regional neurosurgical centre.

PubMed

Alavi, Seyed Alireza; Tan, Chin Lik; Menon, David K; Simpson, Helen L; Hutchinson, Peter J

2016-06-01

Patients with traumatic brain injury (TBI) may develop pituitary dysfunction. Although, there is now increasing awareness of and investigations into such post-traumatic hypopituitarism (PTHP), the exact prevalence and incidence remain uncertain. Here, we aim to identify the incidence of PTHP in a selected population of TBI patients deemed at risk of PTHP at a regional neurosurgical centre in the UK. A total of 105 patients have been assessed in two cohorts: (i) 58 patients in serial cohort and (ii) 47 patients in cross-sectional late cohort. We found that in serial cohort, 10.3% (6/58) of TBI patients had abnormalities of the pituitary-adrenal axis in the acute phase (Day 0-7 post injury). In comparison, in cross-sectional late cohort, 21.3% (10/47) of the patients developed dysfunction in at least one of their pituitary axes at 6 months or more post-TBI, with hypogonadotrophic hypogonadism being the most common. Twenty-two patients from these two cohorts had their growth hormone assessment at 12 months or more post-TBI and 9.1% (2/22) were found to have growth hormone deficiency. Our results suggest that PTHP is a common condition amongst sufferers of TBI, and appropriate measures should be taken to detect and manage it.

Role of Interleukin-10 in Acute Brain Injuries

PubMed Central

Garcia, Joshua M.; Stillings, Stephanie A.; Leclerc, Jenna L.; Phillips, Harrison; Edwards, Nancy J.; Robicsek, Steven A.; Hoh, Brian L.; Blackburn, Spiros; Doré, Sylvain

2017-01-01

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation. PMID:28659854

Brain structural network topological alterations of the left prefrontal and limbic cortex in psychogenic erectile dysfunction.

PubMed

Chen, Jianhuai; Chen, Yun; Gao, Qingqiang; Chen, Guotao; Dai, Yutian; Yao, Zhijian; Lu, Qing

2018-05-01

Despite increasing understanding of the cerebral functional changes and structural abnormalities in erectile dysfunction, alterations in the topological organization of brain networks underlying psychogenic erectile dysfunction remain unclear. Here, based on the diffusion tensor image data of 25 patients and 26 healthy controls, we investigated the topological organization of brain structural networks and its correlations with the clinical variables using the graph theoretical analysis. Patients displayed a preserved overall small-world organization and exhibited a less connectivity strength in the left inferior frontal gyrus, amygdale and the right inferior temporal gyrus. Moreover, an abnormal hub pattern was observed in patients, which might disturb the information interactions of the remaining brain network. Additionally, the clustering coefficient of the left hippocampus was positively correlated with the duration of patients and the normalized betweenness centrality of the right anterior cingulate gyrus and the left calcarine fissure were negatively correlated with the sum scores of the 17-item Hamilton Depression Rating Scale. These findings suggested that the damaged white matter and the abnormal hub distribution of the left prefrontal and limbic cortex might contribute to the pathogenesis of psychogenic erectile dysfunction and provided new insights into the understanding of the pathophysiological mechanisms of psychogenic erectile dysfunction.

Impact of acute lung injury and acute respiratory distress syndrome after traumatic brain injury in the United States.

PubMed

Rincon, Fred; Ghosh, Sayantani; Dey, Saugat; Maltenfort, Mitchell; Vibbert, Matthew; Urtecho, Jacqueline; McBride, William; Moussouttas, Michael; Bell, Rodney; Ratliff, John K; Jallo, Jack

2012-10-01

Traumatic brain injury (TBI) is a major cause of disability, morbidity, and mortality. The effect of the acute respiratory distress syndrome and acute lung injury (ARDS/ALI) on in-hospital mortality after TBI remains controversial. To determine the epidemiology of ARDS/ALI, the prevalence of risk factors, and impact on in-hospital mortality after TBI in the United States. Retrospective cohort study of admissions of adult patients>18 years with a diagnosis of TBI and ARDS/ALI from 1988 to 2008 identified through the Nationwide Inpatient Sample. During the 20-year study period, the prevalence of ARDS/ALI increased from 2% (95% confidence interval [CI], 2.1%-2.4%) in 1988 to 22% (95% CI, 21%-22%) in 2008 (P<.001). ARDS/ALI was more common in younger age; males; white race; later year of admission; in conjunction with comorbidities such as congestive heart failure, hypertension, chronic obstructive pulmonary disease, chronic renal and liver failure, sepsis, multiorgan dysfunction; and nonrural, medium/large hospitals, located in the Midwest, South, and West continental US location. Mortality after TBI decreased from 13% (95% CI, 12%-14%) in 1988 to 9% (95% CI, 9%-10%) in 2008 (P<.001). ARDS/ALI-related mortality after TBI decreased from 33% (95% CI, 33%-34%) in 1988 to 28% (95% CI, 28%-29%) in 2008 (P<.001). Predictors of in-hospital mortality after TBI were older age, male sex, white race, cancer, chronic kidney disease, hypertension, chronic liver disease, congestive heart failure, ARDS/ALI, and organ dysfunctions. Our analysis demonstrates that ARDS/ALI is common after TBI. Despite an overall reduction of in-hospital mortality, ARDS/ALI carries a higher risk of in-hospital death after TBI.

[Experimental study of acute brain swelling under acute intracranial hypertension (author's transl)].

PubMed

Shigemori, M; Watanabe, M; Kuramoto, S

1976-12-01

There are many problems about the cause, pathophysiology and treatment of acute brain swelling under intracranial hypertension frequently encountered in the neurosurgical clinics. Generally, rapid increase of the cerebral vasoparesis caused by unknown etiology is thought to be the main cause of acute brain swelling under intracranial hypertension. Moreover, disturbance of the cerebral venous circulatory system is discussed recently by many authors. But, research from the point of systemic respiration and hemodynamics is necessary for resolving these problems. This experiment was designed to study the effects of respiration and hemodynamics on the cerebral vasoparesis. Using 22 adult dogs, acute intracranial hypertension was produced by epidural balloon inflation sustained at the level of 300 - 400 mmH2O. Simultaneously with measurement of intracranial pressure at the epidural space, superior sagittal sinus pressure, respirogram, systemic blood pressure (femoral artery), central venous pressure, common carotid blood flow, EKG and bipolar lead EEG were monitored continuously. The experimental group was divided by the respiratory loading into 5 groups as follows: control (6 cases), 10% CO2 hypercapnia (4 cases), 10% O2 hypoxia (4 cases), stenosis of airway (5 cases), 100% O2-controled respiration (3 cases). 1) Cerebral vasoparesis under acute intracranial hypertension took place earlier and showed more rapid progression in groups of stenosis of airway, hypercapnia and hypoxia than control group of spontaneous respiration in room air. No occurrence of cerebral vasoparesis was found out in a group of 100% O2 controlled respiration. It is proved that increased airway resistance or asphyxia, hypercapnia and hypoxia have strictly reference to the occurrence and progression of cerebral vasoparesis and for the prevention of cerebral vasoparesis, correct 100% O2 cont rolled respiration is effective. 2) From the hemodynamic change, the progression of rapid increase of cerebral

Neuropsychiatric Subsyndromes and Brain Metabolic Network Dysfunctions in Early Onset Alzheimer’s Disease

PubMed Central

Tommaso, Ballarini; Leonardo, Iaccarino; Giuseppe, Magnani; Nagehan, Ayakta; Bruce L, Miller; William J, Jagust; Luisa, Gorno-Tempini Maria; Gil D, Rabinovici; Daniela, Perani

2017-01-01

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer’s disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective and psychotic SSy). 85% of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N=51) and Healthy Controls (N=57). The apathetic, hyperactivity and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. PMID:27412866

Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.

PubMed

Zhou, Ting; Zhao, Lei; Zhan, Rui; He, Qihua; Tong, Yawei; Tian, Xiaosheng; Wang, Hecheng; Zhang, Tao; Fu, Yaoyun; Sun, Yang; Xu, Feng; Guo, Xiangyang; Fan, Dongsheng; Han, Hongbin; Chui, Dehua

2014-10-24

Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase.

PubMed

Villalba, Nuria; Sackheim, Adrian M; Nunez, Ivette A; Hill-Eubanks, David C; Nelson, Mark T; Wellman, George C; Freeman, Kalev

2017-01-01

Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial-dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production. The activity of arginase, which competes with endothelial NO synthase (eNOS) for the common substrate l-arginine, were also significantly increased in arteries, suggesting that arginase-mediated depletion of l-arginine underlies diminished NO production. Consistent with this, substrate restoration by exogenous application of l-arginine or inhibition of arginase recovered endothelial function. Moreover, evidence for increased reactive oxygen species production, a consequence of l-arginine starvation-dependent eNOS uncoupling, was detected in endothelium and plasma. Collectively, our findings demonstrate endothelial dysfunction in a remote vascular bed after TBI, manifesting as impaired endothelial-dependent vasodilation, with increased arginase activity, decreased generation of NO, and increased O 2 - production. We conclude that blood vessels have a "molecular memory" of neurotrauma, 24 h after injury, because of functional changes in vascular endothelial cells; these effects are pertinent to understanding the systemic inflammatory response that occurs after TBI even in the absence of polytrauma.

Concurrent Vision Dysfunctions in Convergence Insufficiency with Traumatic Brain Injury

PubMed Central

Alvarez, Tara L.; Kim, Eun H.; Vicci, Vincent R.; Dhar, Sunil K.; Biswal, Bharat B.; Barrett, A. M.

2012-01-01

Purpose This study assessed the prevalence of convergence insufficiency (CI) with and without simultaneous vision dysfunctions within the traumatic brain injury (TBI) sample population because although CI is commonly reported with TBI, the prevalence of concurrent visual dysfunctions with CI in TBI is unknown. Methods A retrospective analysis of 557 medical records from TBI civilian patients was conducted. Patients were all evaluated by a single optometrist. Visual acuity, oculomotor, binocular vision function, accommodation, visual fields, ocular health and vestibular function were assessed. Statistical comparisons between the CI and non-CI, as well as in-patient and out-patient subgroups, were conducted using chi-squared and Z-tests. Results Approximately 9% of the TBI sample had CI without the following simultaneous diagnoses: saccade or pursuit dysfunction; 3rd, 4th, or 6th nerve palsy; visual field deficit; visual spatial inattention/neglect; vestibular dysfunction or nystagmus. Photophobia with CI was observed in 16.3% (N=21/130) and vestibular dysfunction with CI was observed in 18.5% (N=24/130) of the CI subgroup. CI and cranial nerve palsies were common and yielded prevalence rates of 23.3% (N=130/557) and 26.9% (N=150/557), respectively, within the TBI sample. Accommodative dysfunction was common within the non-presbyopic TBI sample with a prevalence of 24.4% (N=76/314). Visual field deficits or unilateral visual spatial inattention/neglect were observed within 29.6% (N=80/270) of the TBI in-patient subgroup and were significantly more prevalent compared to the out-patient subgroup (p<0.001). Most TBI patients had visual acuities of 20/60 or better in the TBI sample (85%;N=473/557). Conclusions CI without simultaneous visual or vestibular dysfunctions was observed in about 9% of the visually symptomatic TBI civilian population studied. A thorough visual and vestibular examination is recommended for all TBI patients. PMID:23190716

Transient Retinal Dysfunctions after Acute Cannabis Use.

PubMed

Schwitzer, Thomas; Robert, Matthieu P; Giersch, Anne; Angioi-Duprez, Karine; Ingster-Moati, Isabelle; Pon-Monnier, Amandine; Schwan, Raymund; Laprevote, Vincent

2016-01-01

Although cannabis is very widespread worldwide, the impact of cannabis on visual function remains poorly understood. This is partly due to numerous difficulties met in developing clinical studies in cannabis users. Here, we report the first documented case of neuroretinal dysfunction after acute cannabis smoking. This observation was favored by the need of an annual ophthalmic evaluation in the context of a chloroquine intake for a systemic lupus erythematosus in a 47-year-old heavy cannabis user. A complete ophthalmic evaluation including visual acuity tests, intraocular pressure, fundoscopic examination, automated 10° central visual field, full-field electroretinogram (ERG) and multifocal ERG was performed twice - 30 min and 5 h after cannabis smoking. A strong decrease (up to 48%) in the a-wave amplitude of the full-field ERG was measured 30 min after cannabis smoking for all scotopic responses compared with the responses 5 h after smoking. Other tests showed reproducible results between the 2 series of measurements. This clinical case suggests that acute inhalation of cannabis affects the photoreceptors functioning. This rare situation suggests further investigations are required on the impact of cannabis on retinal processing, especially since cannabis has been incriminated in car injuries. © 2016 S. Karger AG, Basel.

Protective effect of hydroxytyrosol in arsenic-induced mitochondrial dysfunction in rat brain.

PubMed

Soni, Manisha; Prakash, Chandra; Sehwag, Sfurti; Kumar, Vijay

2017-07-01

The present study was planned to investigate the protective effect of hydroxytyrosol (HT) against arsenic (As)-induced mitochondrial dysfunction in rat brain. Rats exposed to sodium arsenite (25 ppm for 8 weeks) showed decreased mitochondrial complexes (I, II, IV) activities, mitochondrial superoxide dismutase (MnSOD), and catalase activities in brain mitochondria. As-treated rats showed reduced mRNA expression of complex I (ND-1, ND-2), IV (COX-1, COX-4) subunits, and uncoupling protein-2 (UCP-2). In addition to this, As exposure downregulated the protein expression of MnSOD. Administration of HT with As restored the enzymatic activities of mitochondrial complexes, MnSOD and catalase, increased the mRNA levels of complexes subunits and UCP-2 as well as proteins level of MnSOD. These results suggest that HT efficiently restores mitochondrial dysfunction in As neurotoxicity and might be used as potential mitoprotective agent in future. © 2017 Wiley Periodicals, Inc.

Occurrence of pituitary dysfunction following traumatic brain injury.

PubMed

Bondanelli, Marta; De Marinis, Laura; Ambrosio, Maria Rosaria; Monesi, Marcello; Valle, Domenico; Zatelli, Maria Chiara; Fusco, Alessandra; Bianchi, Antonio; Farneti, Marco; degli Uberti, Ettore C I

2004-06-01

Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects

Bacterial infection causes stress-induced memory dysfunction in mice.

PubMed

Gareau, Mélanie G; Wine, Eytan; Rodrigues, David M; Cho, Joon Ho; Whary, Mark T; Philpott, Dana J; Macqueen, Glenda; Sherman, Philip M

2011-03-01

The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.

A mathematical model of aging-related and cortisol induced hippocampal dysfunction

PubMed Central

McAuley, Mark T; Kenny, Rose Anne; Kirkwood, Thomas BL; Wilkinson, Darren J; Jones, Janette JL; Miller, Veronica M

2009-01-01

Background The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated. Results The in silicoSBML model reflected the in vivoaging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA), increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation. Conclusion Both acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitroand in vivostudies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people. PMID:19320982

Pathophysiology and Treatment of Memory Dysfunction after Traumatic Brain Injury

PubMed Central

Paterno, Rosalia; Folweiler, Kaitlin A.; Cohen, Akiva S.

2018-01-01

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI are alterations in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase i.e., encoding, maintenance or retrieval is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury. PMID:28500417

Postoperative Structural Brain Changes and Cognitive Dysfunction in Patients with Breast Cancer.

PubMed

Sato, Chiho; Sekiguchi, Atsushi; Kawai, Masaaki; Kotozaki, Yuka; Nouchi, Rui; Tada, Hiroshi; Takeuchi, Hikaru; Ishida, Takanori; Taki, Yasuyuki; Kawashima, Ryuta; Ohuchi, Noriaki

2015-01-01

The primary purpose of this study was to clarify the influence of the early response to surgery on brain structure and cognitive function in patients with breast cancer. It was hypothesized that the structure of the thalamus would change during the early response after surgery due to the effects of anesthesia and would represent one aspect of an intermediate phenotype of postoperative cognitive dysfunction (POCD). We examined 32 postmenopausal females with breast cancer and 20 age-matched controls. We assessed their cognitive function (attention, memory, and executive function), and performed brain structural MRI 1.5 ± 0.5 days before and 5.6 ± 1.2 days after surgery. We found a significant interaction between regional grey matter volume (rGMV) in the thalamus (P < 0.05, familywise error (FWE), small volume correction (SVC)) and one attention domain subtest (P = 0.001, Bonferroni correction) after surgery in the patient group compared with the control group. Furthermore, the changes in attention were significantly associated with sevoflurane anesthetic dose (r2 = 0.247, β = ‒0.471, P = 0.032) and marginally associated with rGMV changes in the thalamus (P = 0.07, FWE, SVC) in the Pt group. Our findings suggest that alterations in brain structure, particularly in the thalamus, may occur shortly after surgery and may be associated with attentional dysfunction. This early postoperative response to anesthesia may represent an intermediate phenotype of POCD. It was assumed that patients experiencing other risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments, would develop clinical POCD with broad and multiple types of cognitive dysfunction.

Intersection between metabolic dysfunction, high fat diet consumption, and brain aging.

PubMed

Uranga, Romina M; Bruce-Keller, Annadora J; Morrison, Christopher D; Fernandez-Kim, Sun Ok; Ebenezer, Philip J; Zhang, Le; Dasuri, Kalavathi; Keller, Jeffrey N

2010-07-01

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high-fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high-fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.

Fluid Intake Related to Brain Edema in Acute Middle Cerebral Artery Infarction.

PubMed

Dharmasaroja, Pornpatr A

2016-02-01

Evidence of the appropriate amount of fluid intake during the first few days after acute stroke was scarce. Concerns were raised in patients with acute malignant middle cerebral infarction, who tended to have malignant brain edema later. The purpose of the study was to evaluate the effect of fluid intake on the occurrence of malignant brain edema in patients with acute middle cerebral artery infarction. Patients with acute middle cerebral artery infarction who had National Institute of Health Stroke Scale (NIHSS) score of at least 15 were included. Baseline characteristics and amount of fluid intake during the first few days were compared in patients with and without malignant brain edema. One hundred ninety-three patients were studied. Mean NIHSS score was 20. Malignant brain edema occurred in 69 patients (36%). Higher amount of fluid intake (>1650 ml or >28 ml/kg/day or >93% of daily maintenance fluid) showed a significant association with malignant brain edema (OR = 13.86, 95% CI 5.11-37.60, p value <0.001). Decompressive surgery was performed in 35 patients (18%). With mean follow-up of 12 months, 49 patients (49/184, 27%) had favorable outcomes (modified Rankin scale (mRS) 0-2) at final follow-up. Seventy-nine patients (79/184, 43%) died. In the subgroup of patients with malignant brain edema, 39 patients (39/65, 60%) died and only 11% (7/65 patients) had favorable outcome. High amount of fluid intake in the first few days of acute middle cerebral infarction was related to the occurrence of malignant brain edema.

Prevalence of hypothalamo pituitary dysfunction in patients of traumatic brain injury.

PubMed

Hari Kumar, K V S; Swamy, M N; Khan, M A

2016-01-01

Traumatic brain injury (TBI) is common in young soldiers of armed forces leading to significant morbidity and mortality. We studied the prevalence of hypopituitarism following TBI and its association with trauma severity. We conducted a 12-month prospective study of 56 TBI patients for the presence of hormonal dysfunction. Hormonal parameters were estimated during the early phase (0-10 days posttraumatically) and after 6 and 12 months. Dynamic testing was done when required, and the results were analyzed by appropriate statistical methods. Hormonal dysfunction was seen in 39 of the 56 (70%) patients at initial assessment. Persisting pituitary deficiencies are seen in 7 and 8 patients at the end of 6 months and 12 months, respectively. Hypogonadotropic hypogonadism, hypothyroidism, and growth hormone deficiency are the most common diagnoses. Initial severe TBI and plurihormonal involvement predicted the long-term hypopituitarism. Early hypopituitarism was common in severe TBI, but recovers in majority. Evaluation for the occult pituitary dysfunction is required during the rehabilitation of TBI patients.

Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity?

PubMed

Tanriverdi, F; De Bellis, A; Teksahin, H; Alp, E; Bizzarro, A; Sinisi, A A; Bellastella, G; Paglionico, V A; Bellastella, A; Unluhizarci, K; Doganay, M; Kelestimur, F

2012-12-01

Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean ± SD age 40.9 ± 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months

Exertional heat stroke and acute liver failure: a late dysfunction

PubMed Central

Carvalho, Ana Sofia; Rodeia, Simão C; Silvestre, Joana; Póvoa, Pedro

2016-01-01

Heat stroke (HS) is defined as a severe elevation of core body temperature along with central nervous system dysfunction. Exertional heat stroke (EHS) with acute liver failure (ALF) is a rare condition. The authors report the case of a 25-year-old man with a history of cognitive enhancers’ intake who developed hyperthermia and neurological impairment while running an outdoor marathon. The patient was cooled and returned to normal body temperature after 6 h. He subsequently developed ALF and was transferred to the intensive care unit. Over-the-counter drug intake may have been related to heat intolerance and contributed to the event. The patient was successfully treated with conservative measures. In the presence of EHS, it is crucial to act promptly with aggressive total body cooling, in order to prevent progression of the clinical syndrome. Liver function must also be monitored, since it can be a late organ dysfunction. PMID:26969359

[Brainstem auditory evoked potentials in neurophysiological assessment of brain stem dysfunction in patients with atherostenosis of vertebral arteries].

PubMed

Maksimova, M Yu; Sermagambetova, Zh N; Skrylev, S I; Fedin, P A; Koshcheev, A Yu; Shchipakin, V L; Sinicyn, I A

To assess brain stem dysfunction in patients with hemodynamically significant stenosis of vertebral arteries (VA) using short latency brainstem auditory evoked potentials (BAEP). The study group included 50 patients (mean age 64±6 years) with hemodynamically significant extracranial VA stenosis. Patients with hemodynamically significant extracranial VA stenosis had BAEP abnormalities including the elongation of interpeak intervals I-V and peak V latency as well as the reduction of peak I amplitude. After transluminal balloon angioplasty with stenting of VA stenoses, there was a shortening of peak V latency compared to the preoperative period that reflected the improvement of brain stem conductive functions. Atherostenosis of vertebral arteries is characterized by the signs of brain stem dysfunction, predominantly in the pontomesencephal brain stem. After transluminal balloon angioplasty with stenting of VA, the improvement of brain stem conductive functions was observed.

Intracranial pancreatic islet transplantation increases islet hormone expression in the rat brain and attenuates behavioral dysfunctions induced by MK-801 (dizocilpine).

PubMed

Bloch, Konstantin; Gil-Ad, Irit; Tarasenko, Igor; Vanichkin, Alexey; Taler, Michal; Hornfeld, Shay Henry; Vardi, Pnina; Weizman, Abraham

2015-06-01

The treatment of rodents with non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, MK-801 (dizocilpine), induces symptoms of psychosis, deficits in spatial memory and impairment of synaptic plasticity. Recent studies have suggested that insulin administration might attenuate the cognitive dysfunctions through the modulatory effect on the expression of NMDA receptors and on the brain insulin signaling. Intrahepatic pancreatic islet transplantation is known as an efficient tool for correcting impaired insulin signaling. We examined the capacity of syngeneic islets grafted into the cranial subarachnoid cavity to attenuate behavioral dysfunctions in rats exposed to MK-801. Animals were examined in the open field (OF) and the Morris Water Maze (MWM) tests following acute or subchronic administration of MK-801. We found well-vascularized grafted islets expressing insulin, glucagon and somatostatin onto the olfactory bulb and prefrontal cortex. Significantly higher levels of insulin were detected in the hippocampus and prefrontal cortex of transplanted animals compared to the non-transplanted rats. All animals expressed normal peripheral glucose homeostasis for two months after transplantation. OF tests revealed that rats exposed to MK-801 treatment, showed hyper-responsiveness in motility parameters and augmented center field exploration compared to intact controls and these effects were attenuated by the grafted islets. Moreover, in the MWM, the rats treated with MK-801 showed impairment of spatial memory that were partially corrected by the grafted islets. In conclusion, intracranial islet transplantation leads to the expression of islet hormones in the brain and attenuates behavioral and cognitive dysfunctions in rats exposed to MK-801 administration without altering the peripheral glucose homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.

Expanding the pool of kidney donors: use of kidneys with acute renal dysfunction

PubMed Central

de Matos, Ana Cristina Carvalho; Requião-Moura, Lúcio Roberto; Clarizia, Gabriela; Durão, Marcelino de Souza; Tonato, Eduardo José; Chinen, Rogério; de Arruda, Érika Ferraz; Filiponi, Thiago Corsi; Pires, Luciana Mello de Mello Barros; Bertocchi, Ana Paula Fernandes; Pacheco-Silva, Alvaro

2015-01-01

ABSTRACT Given the shortage of organs transplantation, some strategies have been adopted by the transplant community to increase the supply of organs. One strategy is the use of expanded criteria for donors, that is, donors aged >60 years or 50 and 59 years, and meeting two or more of the following criteria: history of hypertension, terminal serum creatinine >1.5mg/dL, and stroke as the donor´s cause of death. In this review, emphasis was placed on the use of donors with acute renal failure, a condition considered by many as a contraindication for organ acceptance and therefore one of the main causes for kidney discard. Since these are well-selected donors and with no chronic diseases, such as hypertension, renal disease, or diabetes, many studies showed that the use of donors with acute renal failure should be encouraged, because, in general, acute renal dysfunction is reversible. Although most studies demonstrated these grafts have more delayed function, the results of graft and patient survival after transplant are very similar to those with the use of standard donors. Clinical and morphological findings of donors, the use of machine perfusion, and analysis of its parameters, especially intrarenal resistance, are important tools to support decision-making when considering the supply of organs with renal dysfunction. PMID:26154553

CD40–CD40 Ligand Pathway Is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis

PubMed Central

Michels, Monique; Danieslki, Lucinéia Gainski; Vieira, Andriele; Florentino, Drielly; Dall’Igna, Dhébora; Galant, Letícia; Sonai, Beatriz; Vuolo, Francieli; Mina, Franciele; Pescador, Bruna; Dominguini, Diogo; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Petronilho, Fabrícia

2015-01-01

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40–CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40–CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40–CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40–CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis. PMID:25822797

Hypertonic sodium lactate reverses brain oxygenation and metabolism dysfunction after traumatic brain injury.

PubMed

Millet, A; Cuisinier, A; Bouzat, P; Batandier, C; Lemasson, B; Stupar, V; Pernet-Gallay, K; Crespy, T; Barbier, E L; Payen, J F

2018-06-01

The mechanisms by which hypertonic sodium lactate (HSL) solution act in injured brain are unclear. We investigated the effects of HSL on brain metabolism, oxygenation, and perfusion in a rodent model of diffuse traumatic brain injury (TBI). Thirty minutes after trauma, anaesthetised adult rats were randomly assigned to receive a 3 h infusion of either a saline solution (TBI-saline group) or HSL (TBI-HSL group). The sham-saline and sham-HSL groups received no insult. Three series of experiments were conducted up to 4 h after TBI (or equivalent) to investigate: 1) brain oedema using diffusion-weighted magnetic resonance imaging and brain metabolism using localized 1 H-magnetic resonance spectroscopy (n = 10 rats per group). The respiratory control ratio was then determined using oxygraphic analysis of extracted mitochondria, 2) brain oxygenation and perfusion using quantitative blood-oxygenation-level-dependent magnetic resonance approach (n = 10 rats per group), and 3) mitochondrial ultrastructural changes (n = 1 rat per group). Compared with the TBI-saline group, the TBI-HSL and the sham-operated groups had reduced brain oedema. Concomitantly, the TBI-HSL group had lower intracellular lactate/creatine ratio [0.049 (0.047-0.098) vs 0.097 (0.079-0.157); P < 0.05], higher mitochondrial respiratory control ratio, higher tissue oxygen saturation [77% (71-79) vs 66% (55-73); P < 0.05], and reduced mitochondrial cristae thickness in astrocytes [27.5 (22.5-38.4) nm vs 38.4 (31.0-47.5) nm; P < 0.01] compared with the TBI-saline group. Serum sodium and lactate concentrations and serum osmolality were higher in the TBI-HSL than in the TBI-saline group. These findings indicate that the hypertonic sodium lactate solution can reverse brain oxygenation and metabolism dysfunction after traumatic brain injury through vasodilatory, mitochondrial, and anti-oedema effects. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

The role of autophagy in acute brain injury: A state of flux?

PubMed

Wolf, Michael S; Bayır, Hülya; Kochanek, Patrick M; Clark, Robert S B

2018-04-26

It is established that increased autophagy is readily detectable after various types of acute brain injury, including trauma, focal and global cerebral ischemia. What remains controversial, however, is whether this heightened detection of autophagy in brain represents a homeostatic or pathologic process, or an epiphenomenon. The ultimate role of autophagy after acute brain injury likely depends upon: 1) the degree of brain injury and the overall autophagic burden; 2) the capacity of individual cell types to ramp up autophagic flux; 3) the local redox state and signaling of parallel cell death pathways; 4) the capacity to eliminate damage associated molecular patterns and toxic proteins and metabolites both intra- and extracellularly; and 5) the timing of the pro- or anti-autophagic intervention. In this review, we attempt to reconcile conflicting studies that support both a beneficial and detrimental role for autophagy in models of acute brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Immune dysfunction in cirrhosis

PubMed Central

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-01-01

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID:24627592

Immune dysfunction in cirrhosis.

PubMed

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-03-14

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.

Pituitary dysfunction following traumatic brain injury: clinical perspectives

PubMed Central

Tanriverdi, Fatih; Kelestimur, Fahrettin

2015-01-01

Traumatic brain injury (TBI) is a well recognized public health problem worldwide. TBI has previously been considered as a rare cause of hypopituitarism, but an increased prevalence of neuroendocrine dysfunction in patients with TBI has been reported during the last 15 years in most of the retrospective and prospective studies. Based on data in the current literature, approximately 15%–20% of TBI patients develop chronic hypopituitarism, which clearly suggests that TBI-induced hypopituitarism is frequent in contrast with previous assumptions. This review summarizes the current data on TBI-induced hypopituitarism and briefly discusses some clinical perspectives on post-traumatic anterior pituitary hormone deficiency. PMID:26251600

The consequence of spatial visual processing dysfunction caused by traumatic brain injury (TBI).

PubMed

Padula, William V; Capo-Aponte, Jose E; Padula, William V; Singman, Eric L; Jenness, Jonathan

2017-01-01

A bi-modal visual processing model is supported by research to affect dysfunction following a traumatic brain injury (TBI). TBI causes dysfunction of visual processing affecting binocularity, spatial orientation, posture and balance. Research demonstrates that prescription of prisms influence the plasticity between spatial visual processing and motor-sensory systems improving visual processing and reducing symptoms following a TBI. The rationale demonstrates that visual processing underlies the functional aspects of binocularity, balance and posture. The bi-modal visual process maintains plasticity for efficiency. Compromise causes Post Trauma Vision Syndrome (PTVS) and Visual Midline Shift Syndrome (VMSS). Rehabilitation through use of lenses, prisms and sectoral occlusion has inter-professional implications in rehabilitation affecting the plasticity of the bi-modal visual process, thereby improving binocularity, spatial orientation, posture and balance Main outcomes: This review provides an opportunity to create a new perspective of the consequences of TBI on visual processing and the symptoms that are often caused by trauma. It also serves to provide a perspective of visual processing dysfunction that has potential for developing new approaches of rehabilitation. Understanding vision as a bi-modal process facilitates a new perspective of visual processing and the potentials for rehabilitation following a concussion, brain injury or other neurological events.

Systems biomarkers as acute diagnostics and chronic monitoring tools for traumatic brain injury

NASA Astrophysics Data System (ADS)

Wang, Kevin K. W.; Moghieb, Ahmed; Yang, Zhihui; Zhang, Zhiqun

2013-05-01

Traumatic brain injury (TBI) is a significant biomedical problem among military personnel and civilians. There exists an urgent need to develop and refine biological measures of acute brain injury and chronic recovery after brain injury. Such measures "biomarkers" can assist clinicians in helping to define and refine the recovery process and developing treatment paradigms for the acutely injured to reduce secondary injury processes. Recent biomarker studies in the acute phase of TBI have highlighted the importance and feasibilities of identifying clinically useful biomarkers. However, much less is known about the subacute and chronic phases of TBI. We propose here that for a complex biological problem such as TBI, multiple biomarker types might be needed to harness the wide range of pathological and systemic perturbations following injuries, including acute neuronal death, neuroinflammation, neurodegeneration and neuroregeneration to systemic responses. In terms of biomarker types, they range from brain-specific proteins, microRNA, genetic polymorphism, inflammatory cytokines and autoimmune markers and neuro-endocrine hormones. Furthermore, systems biology-driven biomarkers integration can help present a holistic approach to understanding scenarios and complexity pathways involved in brain injury.

A new look on brain mechanisms of acute illness anorexia.

PubMed

Asarian, Lori; Langhans, Wolfgang

2010-07-14

Bacterial lipopolysaccharide (LPS) and other microbial substances trigger the organism's acute phase response and cause acute illness anorexia. Pro-inflammatory cytokines are major endogenous mediators of acute illness anorexia, but how LPS or cytokines stimulate the brain to inhibit eating is not fully resolved. One emerging mechanism involves the activation of the enzyme cyclooxygenase-2 (COX-2) in blood-brain barrier endothelial cells and the subsequent release of prostaglandin E2 (PGE2). Serotonin neurons in the midbrain raphe are targets of PGE2, and serotonergic projections from the midbrain raphe to the hypothalamus appear to be crucial for LPS anorexia. That is, raphe projections activate (1) the corticotrophin-releasing hormone neurons in the paraventricular nucleus which then elicit the stress response and (2) the pro-opiomelanocortin neurons in the arcuate nucleus which then release alphaMSH and elicit anorexia. Here we review available data to support a role for this brain mechanism in acute illness anorexia by center staging PGE2 signaling pathways that converge on central neural circuits that control normal eating. In addition, we review interactions between gonadal hormones and immune function that lead to sex differences in acute illness anorexia. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. 2010 Elsevier Inc. All rights reserved.

Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults.

PubMed

Krahulik, David; Zapletalova, Jirina; Frysak, Zdenek; Vaverka, Miroslav

2010-09-01

Traumatic brain injury (TBI) is a major cause of serious morbidity and mortality. The incidence is 100-500/100,000 inhabitants/year. Chronic pituitary dysfunction is increasingly recognized after TBI. To define the incidence of endocrine dysfunction and risk factors, the authors describe a prospectively assessed group of patients in whom they documented hormonal functions, early diagnosis, and treatment of neuroendocrine dysfunction after TBI. Patients aged 18-65 years were prospectively observed from the time of injury to 1 year postinjury; the Glasgow Coma Scale score ranged from 3 to 14. Patients underwent evaluation of hormonal function at the time of injury and at 3, 6, and 12 months postinjury. Magnetic resonance imaging was also conducted at 1 year postinjury. During the study period, 89 patients were observed. The mean age of the patients was 36 years, there were 23 women, and the median Glasgow Coma Scale score was 7. Nineteen patients (21%) had primary hormonal dysfunction. Major deficits included growth hormone dysfunction, hypogonadism, and diabetes insipidus. Patients in whom the deficiency was major had a worse Glasgow Outcome Scale score, and MR imaging demonstrated empty sella syndrome more often than in patients without a deficit. To the authors' knowledge, this is the third largest study of its kind worldwide. The incidence of chronic hypopituitarism after TBI was higher than the authors expected. After TBI, patients are usually observed on the neurological and rehabilitative wards, and endocrine dysfunction can be overlooked. This dysfunction can be life threatening and other clinical symptoms can worsen the neurological deficit, extend the duration of physiotherapy, and lead to mental illness. The authors recommend routine pituitary hormone testing after moderate or severe TBI within 6 months and 1 year of injury.

Prevalence of hypothalamo pituitary dysfunction in patients of traumatic brain injury

PubMed Central

Hari Kumar, K. V. S.; Swamy, M. N.; Khan, M. A.

2016-01-01

Background: Traumatic brain injury (TBI) is common in young soldiers of armed forces leading to significant morbidity and mortality. We studied the prevalence of hypopituitarism following TBI and its association with trauma severity. Materials and Methods: We conducted a 12-month prospective study of 56 TBI patients for the presence of hormonal dysfunction. Hormonal parameters were estimated during the early phase (0–10 days posttraumatically) and after 6 and 12 months. Dynamic testing was done when required, and the results were analyzed by appropriate statistical methods. Results: Hormonal dysfunction was seen in 39 of the 56 (70%) patients at initial assessment. Persisting pituitary deficiencies are seen in 7 and 8 patients at the end of 6 months and 12 months, respectively. Hypogonadotropic hypogonadism, hypothyroidism, and growth hormone deficiency are the most common diagnoses. Initial severe TBI and plurihormonal involvement predicted the long-term hypopituitarism. Conclusion: Early hypopituitarism was common in severe TBI, but recovers in majority. Evaluation for the occult pituitary dysfunction is required during the rehabilitation of TBI patients. PMID:27867878

Executive dysfunction, brain aging, and political leadership.

PubMed

Fisher, Mark; Franklin, David L; Post, Jerrold M

2014-01-01

Decision-making is an essential component of executive function, and a critical skill of political leadership. Neuroanatomic localization studies have established the prefrontal cortex as the critical brain site for executive function. In addition to the prefrontal cortex, white matter tracts as well as subcortical brain structures are crucial for optimal executive function. Executive function shows a significant decline beginning at age 60, and this is associated with age-related atrophy of prefrontal cortex, cerebral white matter disease, and cerebral microbleeds. Notably, age-related decline in executive function appears to be a relatively selective cognitive deterioration, generally sparing language and memory function. While an individual may appear to be functioning normally with regard to relatively obvious cognitive functions such as language and memory, that same individual may lack the capacity to integrate these cognitive functions to achieve normal decision-making. From a historical perspective, global decline in cognitive function of political leaders has been alternatively described as a catastrophic event, a slowly progressive deterioration, or a relatively episodic phenomenon. Selective loss of executive function in political leaders is less appreciated, but increased utilization of highly sensitive brain imaging techniques will likely bring greater appreciation to this phenomenon. Former Israeli Prime Minister Ariel Sharon was an example of a political leader with a well-described neurodegenerative condition (cerebral amyloid angiopathy) that creates a neuropathological substrate for executive dysfunction. Based on the known neuroanatomical and neuropathological changes that occur with aging, we should probably assume that a significant proportion of political leaders over the age of 65 have impairment of executive function.

Acute and chronic changes in brain activity with deep brain stimulation for refractory depression.

PubMed

Conen, Silke; Matthews, Julian C; Patel, Nikunj K; Anton-Rodriguez, José; Talbot, Peter S

2018-04-01

Deep brain stimulation is a potential option for patients with treatment-refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery-Asberg Depression Rating Scale score from baseline of ≥50%, and remission as a Montgomery-Asberg Depression Rating Scale score ≤8. Changes in regional cerebral blood flow were assessed using [ 15 O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non-remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response.

[Oliguria and acute renal dysfunction in a six-month-old infant].

PubMed

Cui, Ya-Jie; Song, Chun-Lan; Cheng, Yi-Bing

2017-02-01

The infant (a girl aged 6 months) was admitted to the hospital because of oliguria and acute renal dysfunction. The laboratory examination results showed serious metabolic acidosis and increased blood urea nitrogen and serum creatinine levels. The patient continued to be anuric after 10 days of treatment with continuous renal replacement therapy (CRRT). she died a day later. The family history showed that the patient's sister died of acute renal failure 6 months after birth. The genomic sequencing results showed AGXT mutation in the patient and confirmed the diagnosis of primary hyperoxaluria type 1 (PH1). Her parents were heterozygous carriers. PH1 should be considered when the children have abnormal renal function or recurrent renal calculi or have a family history of these symptoms. AGXT gene analysis is an important method for PH1 diagnosis.

SOD1 overexpression prevents acute hyperglycemia-induced cerebral myogenic dysfunction: relevance to contralateral hemisphere and stroke outcomes

PubMed Central

Coucha, Maha; Li, Weiguo; Hafez, Sherif; Abdelsaid, Mohammed; Johnson, Maribeth H.; Fagan, Susan C.

2014-01-01

Admission hyperglycemia (HG) amplifies vascular injury and neurological deficits in acute ischemic stroke, but the mechanisms remain controversial. We recently reported that ischemia-reperfusion (I/R) injury impairs the myogenic response in both hemispheres via increased nitration. However, whether HG amplifies contralateral myogenic dysfunction and whether loss of tone in the contralateral hemisphere contributes to stroke outcomes remain to be determined. Our hypothesis was that contralateral myogenic dysfunction worsens stroke outcomes after acute hyperglycemic stroke in an oxidative stress-dependent manner. Male wild-type or SOD1 transgenic rats were injected with saline or 40% glucose solution 10 min before surgery and then subjected to 30 min of ischemia/45 min or 24 h of reperfusion. In another set of animals (n = 5), SOD1 was overexpressed only in the contralateral hemisphere by stereotaxic adenovirus injection 2–3 wk before I/R. Myogenic tone and neurovascular outcomes were determined. HG exacerbated myogenic dysfunction in contralateral side only, which was associated with infarct size expansion, increased edema, and more pronounced neurological deficit. Global and selective SOD1 overexpression restored myogenic reactivity in ipsilateral and contralateral sides, respectively, and enhanced neurovascular outcomes. In conclusion, our results show that SOD1 overexpression nullified the detrimental effects of HG on myogenic tone and stroke outcomes and that the contralateral hemisphere may be a novel target for the management of acute hyperglycemic stroke. PMID:25552308

Acute stress promotes post-injury brain regeneration in fish.

PubMed

Sinyakov, Michael S; Haimovich, Amihai; Avtalion, Ramy R

2017-12-01

The central nervous system and the immune system, the two major players in homeostasis, operate in the ongoing bidirectional interaction. Stress is the third player that exerts strong effect on these two 'supersystems'; yet, its impact is studied much less. In this work employing carp model, we studied the influence of preliminary stress on neural and immune networks involved in post-injury brain regeneration. The relevant in vivo models of air-exposure stress and precisely directed cerebellum injury have been developed. Neuronal regeneration was evaluated by using specific tracers of cell proliferation and differentiation. Involvement of immune networks was accessed by monitoring the expression of selected T cells markers. Contrast difference between acute and chronic stress manifested in the fact that chronically stressed fish did not survive the brain injury. Neuronal regeneration appeared as a biphasic process whereas involvement of immune system proceeded as a monophasic route. In stressed fish, immune response was fast and accompanied or even preceded neuronal regeneration. In unstressed subjects, immune response took place on the second phase of neuronal regeneration. These findings imply an intrinsic regulatory impact of acute stress on neuronal and immune factors involved in post-injury brain regeneration. Stress activates both neuronal and immune defense mechanisms and thus contributes to faster regeneration. In this context, paradoxically, acute preliminary stress might be considered a distinct asset in speeding up the following post-injury brain regeneration. Copyright © 2017 Elsevier B.V. All rights reserved.

Developing Interventions for Cancer-Related Cognitive Dysfunction in Childhood Cancer Survivors

PubMed Central

Ullrich, Nicole J.; Whelen, Megan J.; Lange, Beverly J.

2014-01-01

Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes. PMID:25080574

Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

PubMed Central

Back, Adam; Tupper, Kelsey Y.; Bai, Tao; Chiranand, Paulpoj; Goldenberg, Fernando D.; Frank, Jeffrey I.; Brorson, James R.

2013-01-01

Objectives Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in acute liver failure is incompletely understood. In vitro models of the cerebral effects of acute liver failure have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in acute liver failure. Methods We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. Results Ammonia exposure at 1–10 mM produced swelling of immunochemically-identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. Discussion Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an in vitro model of cerebral effects of conditions relevant to acute liver failure, applicable to pathophysiological investigations. PMID:22196764

Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia.

PubMed

Daulatzai, Mak Adam

2015-01-01

The non-celiac gluten sensitivity (NCGS) is a chronic functional gastrointestinal disorder which is very common world wide. The human gut harbors microbiota which has a wide variety of microbial organisms; they are mainly symbiotic and important for well being. However, "dysbiosis" - i.e. an alteration in normal commensal gut microbiome with an increase in pathogenic microbes, impacts homeostasis/health. Dysbiosis in NCGS causes gut inflammation, diarrhea, constipation, visceral hypersensitivity, abdominal pain, dysfunctional metabolic state, and peripheral immune and neuro-immune communication. Thus, immune-mediated gut and extra-gut dysfunctions, due to gluten sensitivity with comorbid diarrhea, may last for decades. A significant proportion of NCGS patients may chronically consume alcohol, non-steroidal anti-inflammatory drugs, and fatty diet, as well as suffer from various comorbid disorders. The above pathophysiological substrate and dysbiosis are underpinned by dysfunctional bidirectional "Gut-Brain Axis" pathway. Pathogenic gut microbiota is known to upregulate gut- and systemic inflammation (due to lipopolysaccharide from pathogenic bacteria and synthesis of pro-inflammatory cytokines); they enhance energy harvest, cause obesity, insulin resistance, and dysfunctional vago-vagal gut-brain axis. Conceivably, the above cascade of pathology may promote various pathophysiological mechanisms, neuroinflammation, and cognitive dysfunction. Hence, dysbiosis, gut inflammation, and chronic dyshomeostasis are of great clinical relevance. It is argued here that we need to be aware of NCGS and its chronic pathophysiological impact. Therapeutic measures including probiotics, vagus nerve stimulation, antioxidants, alpha 7 nicotinic receptor agonists, and corticotropin-releasing factor receptor 1 antagonist may ameliorate neuroinflammation and oxidative stress in NCGS; they may therefore, prevent cognitive dysfunction and vulnerability to Alzheimer's disease.

Post-operative cognitive dysfunction after knee arthroplasty: a diagnostic dilemma

PubMed Central

Yap, Kiryu K.; Joyner, Peter

2014-01-01

Post-operative cognitive dysfunction (POCD) is common in the elderly, and significantly impacts their recovery. We present an unusual diagnostic challenge where a 65-year-old male presented 4-week post-total knee arthroplasty with acute cognitive dysfunction lasting 19 days. Curiously, there were no findings uncovering a specific cause, but during investigation underlying predisposing factors such as depression, mild memory deficits and generalized brain volume loss were identified. The impression after psychogeriatric review was that of an organic brain syndrome with overlay of depression, with a complex presentation as POCD. After escalation of behavioural disturbance, he was commenced on anti-psychotic/depressant, with immediate response. We emphasize the importance of pre-operative evaluation of cognitive function and risk factors in all geriatric patients undergoing elective surgery, and the need for further characterization of POCD, as well as experimental research elucidating the underlying mechanisms to better identify and treat this important post-surgical phenomenon. PMID:25988029

Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically.

PubMed

Agrawal, Sonal; Fox, Julia; Thyagarajan, Baskaran; Fox, Jonathan H

2018-05-20

Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 μM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective. Copyright © 2018 Elsevier Inc. All rights reserved.

Brain imaging and cognitive dysfunctions in Huntington's disease

PubMed Central

Montoya, Alonso; Price, Bruce H.; Menear, Matthew; Lepage, Martin

2006-01-01

Recent decades have seen tremendous growth in our understanding of the cognitive dysfunctions observed in Huntington's disease (HD). Advances in neuroimaging have contributed greatly to this growth. We reviewed the role that structural and functional neuroimaging techniques have played in elucidating the cerebral bases of the cognitive deficits associated with HD. We conducted a computer-based search using PubMed and PsycINFO databases to retrieve studies of patients with HD published between 1965 and December 2004 that reported measures on cognitive tasks and used neuroimaging techniques. Structural neuroimaging has provided important evidence of morphological brain changes in HD. Striatal and cortical atrophy are the most common findings, and they correlate with cognitive deficits in attention, working memory and executive functions. Functional studies have also demonstrated correlations between striatal dysfunction and cognitive performance. Striatal hypoperfusion and decreased glucose utilization correlate with executive dysfunction. Hypometabolism also occurs throughout the cerebral cortex and correlates with performance on recognition memory, language and perceptual tests. Measures of presynaptic and postsynaptic dopamine biochemistry have also correlated with measurements of episodic memory, speed of processing and executive functioning. Aided by the results of numerous neuroimaging studies, it is becoming increasingly clear that cognitive deficits in HD involve abnormal connectivity between the basal ganglia and cortical areas. In the future, neuroimaging techniques may shed the most light on the pathophysiology of HD by defining neurodegenerative disease phenotypes as a valuable tool for knowing when patients become “symptomatic,” having been in a gene-positive presymptomatic state, and as a biomarker in following the disease, thereby providing a prospect for improved patient care. PMID:16496032

Organ dysfunction, injury and failure in acute heart failure: from pathophysiology to diagnosis and management. A review on behalf of the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

PubMed

Harjola, Veli-Pekka; Mullens, Wilfried; Banaszewski, Marek; Bauersachs, Johann; Brunner-La Rocca, Hans-Peter; Chioncel, Ovidiu; Collins, Sean P; Doehner, Wolfram; Filippatos, Gerasimos S; Flammer, Andreas J; Fuhrmann, Valentin; Lainscak, Mitja; Lassus, Johan; Legrand, Matthieu; Masip, Josep; Mueller, Christian; Papp, Zoltán; Parissis, John; Platz, Elke; Rudiger, Alain; Ruschitzka, Frank; Schäfer, Andreas; Seferovic, Petar M; Skouri, Hadi; Yilmaz, Mehmet Birhan; Mebazaa, Alexandre

2017-07-01

Organ injury and impairment are commonly observed in patients with acute heart failure (AHF), and congestion is an essential pathophysiological mechanism of impaired organ function. Congestion is the predominant clinical profile in most patients with AHF; a smaller proportion presents with peripheral hypoperfusion or cardiogenic shock. Hypoperfusion further deteriorates organ function. The injury and dysfunction of target organs (i.e. heart, lungs, kidneys, liver, intestine, brain) in the setting of AHF are associated with increased risk for mortality. Improvement in organ function after decongestive therapies has been associated with a lower risk for post-discharge mortality. Thus, the prevention and correction of organ dysfunction represent a therapeutic target of interest in AHF and should be evaluated in clinical trials. Treatment strategies that specifically prevent, reduce or reverse organ dysfunction remain to be identified and evaluated to determine if such interventions impact mortality, morbidity and patient-centred outcomes. This paper reflects current understanding among experts of the presentation and management of organ impairment in AHF and suggests priorities for future research to advance the field. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

[Sacroiliac joint dysfunction presented with acute low back pain: three case reports].

PubMed

Hamauchi, Shuji; Morimoto, Daijiro; Isu, Toyohiko; Sugawara, Atsushi; Kim, Kyongsong; Shimoda, Yusuke; Motegi, Hiroaki; Matsumoto, Ryoji; Isobe, Masanori

2010-07-01

Sacroiliac joint (SIJ) can cause low back pain when its joint capsule and ligamentous tissue are damaged. We report our experience in treating three SIJ dysfunction patients presenting with acute low back pain (a 38 year-old male, a 24 year-old male, and a 32 year-old female). SIJ dysfunction was diagnosed using the one-finger test, the modified Newton test, and SIJ injection. In all three patients, lumbar MRI demonstrated slightly degenerated lumbar lesions (lumbar canal stenosis, lumbar disc hernia). Two patients had paresthesia or pain in the leg and all three patients showed iliac muscle tenderness in the groin, which was thought to be a referred symptom because of improvement after SIJ injection. The two male patients returned to work and the problems have not recurred. Although our female patient resumed daily life as a housewife, her condition recurred at intervals of 2-3 months and she required regular SIJ injections. The prevalence of SIJ dysfunction of low back pain is about 10%, so it should be considered as a differential diagnosis when treating low back pain and designing treatment for lumbar spinal disorders.

Evaluation of the effects of Eserine and JWH-133 on brain dysfunction associated with experimental endotoxemia.

PubMed

Gamal, Maha; Moawad, Jackline; Rashed, Laila; El-Eraky, Wafaa; Saleh, Dalia; Lehmann, Christian; Sharawy, Nivin

2015-04-15

Sepsis is associated with neuronal damage and cognitive impairment, with the participation of pro-inflammatory cytokines and oxidative-nitrous stress. It is known that activated microglia plays a vital role in neuro-inflammation and neuro-degeneration. Thus, the objective of this study was to evaluate therapeutic roles of two microglia regulating agents, JWH-133 and Eserine, on the neuroinflammatory associated brain dysfunctions. To achieve our aim, we used control rats or submitted rats to lipopolysaccharide (LPS) challenge. 30 min after LPS challenge, the animals received either saline, Eserine, JWH-133 or Eserine+JWH-133. After 24h, animals were submitted to the habituation to T maze, Rotarod and activity cage tests. The rats were killed after and were evaluated for central and peripheral inflammatory and oxidative parameters. We observed that the use of Eserine, JWH-133 or Eserine + JWH-133 reverted the increases in the inflammatory markers [interleukin 6 (IL6), vascular cell adhesion molecule 1(VCAM-1) and Eselectin] and oxidative-nitrous stress MDM, and that the anti-inflammatory, antioxidant properties of both JWH-133 and Eserine successfully improve the LPS induced brain dysfunction. The results observed in this study reinforce the role of microglia activation regulating agents, in particular, JWH-133 and Eserine, in the brain dysfunction associated with endotoxemia. Copyright © 2015 Elsevier B.V. All rights reserved.

2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells.

PubMed

Bernhart, Eva; Kogelnik, Nora; Prasch, Jürgen; Gottschalk, Benjamin; Goeritzer, Madeleine; Depaoli, Maria Rosa; Reicher, Helga; Nusshold, Christoph; Plastira, Ioanna; Hammer, Astrid; Fauler, Günter; Malli, Roland; Graier, Wolfgang F; Malle, Ernst; Sattler, Wolfgang

2018-05-01

Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H 2 O 2 -chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a 'clickable' alkyne derivative (2-ClHyA) that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2-ClHyA in the endoplasmic reticulum (ER) and mitochondria of human BMVEC (hCMEC/D3 cell line). 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL)-6 as well as IL-8. 2-ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Corticosterone and dehydroepiandrosterone in songbird plasma and brain: effects of season and acute stress

PubMed Central

Newman, Amy E. M.; Soma, Kiran K.

2010-01-01

Prolonged increases in plasma glucocorticoids can exacerbate neurodegeneration. In rats, these neurodegenerative effects can be reduced by dehydroepiandrosterone (DHEA), an androgen precursor with anti-glucocorticoid actions. In song sparrows, season and acute restraint stress affect circulating levels of corticosterone and DHEA, and the effects of stress differ in plasma collected from the brachial and jugular veins. Jugular plasma is an indirect index of the neural steroidal milieu. Here, we directly measured corticosterone and DHEA in several brain regions and jugular plasma, and examined the effects of season and acute restraint stress (30 min) (n = 571 samples). Corticosterone levels were up to 10× lower in brain than in jugular plasma. In contrast, DHEA levels were up to 5× higher in brain than in jugular plasma and were highest in the hippocampus. Corticosterone and DHEA concentrations were strongly seasonally regulated in plasma but, surprisingly, not seasonally regulated in brain. Acute stress increased corticosterone levels in plasma and brain, except during the molt, when stress unexpectedly decreased corticosterone levels in the hippocampus. Acute stress increased DHEA levels in plasma during the molt but had no effects on DHEA levels in brain. This is the first study to measure (i) corticosterone or DHEA levels in the brain of adult songbirds and (ii) seasonal changes in corticosterone or DHEA levels in the brain of any species. These results highlight several critical differences between systemic and local steroid concentrations and the difficulty of using circulating steroid levels to infer local steroid levels within the brain. PMID:19473242

A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

NASA Astrophysics Data System (ADS)

Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

2016-06-01

Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.

Brain Microstructural Correlates of Cognitive Dysfunction in Clinically and Biochemically Normal Hepatitis C Virus Infection.

PubMed

Kumar, Ajay; Deep, Amar; Gupta, Rakesh K; Atam, Virendra; Mohindra, Samir

2017-09-01

This study examined correlates of the brain's neurocognitive performance among clinically and biochemically normal adult patient with hepatitis C virus (HCV). We hypothesized that anti-HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using diffusion tensor tractrography (DTT) metrics. Anti-HCV positive patient ( n  = 40), and healthy controls ( n  = 31), fulfilling inclusion criteria (incidentally detected anti-HCV positive) and able to provide informed consent were screened and recruited for the study. All these subjects and controls underwent subjective assessment of their quality of life related symptoms, neuropsychometric tests (NPT) and magnetic resonance imaging. The patients were subjected to neuroimaging as well as psychological testing. There was no significant difference in basic laboratory parameters in these two groups. Independent t -test reveals significantly lower neuropsychological functioning as compared to healthy control. A significantly decreased FA values and myoinsitol were observed in HCV subjects on sensory, inferior longitudinal fascicules, and STR fiber bundles as compared to healthy control. Bivariate correlation analysis reveals that neuropsychological scores are significantly positive. Our result show that HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using DTT metrics.

Telerehabilitation for addressing executive dysfunction after traumatic brain injury.

PubMed

Ng, Edith M W; Polatajko, Helene J; Marziali, Elsa; Hunt, Anne; Dawson, Deirdre R

2013-01-01

To investigate the feasibility of implementing the Cognitive Orientation to daily Occupational Performance approach (CO-OP) in a telerehabilitation format and to examine its impact on community integration and executive dysfunction for adults with traumatic brain injury (TBI). A pilot series of three case studies with 3-month follow-up was conducted. Three adults (all males, >10 years post-TBI) and their significant others were recruited. The CO-OP intervention, a meta-cognitive approach, was delivered through videoconferencing via Internet to train three of five participant-identified goals. Two goals were not trained to allow examination of transfer. Outcome measures included the Canadian Occupational Performance Measure, the Mayo-Portland Adaptability Inventory-4 Participation Index, and the Dysexecutive Questionnaire. Descriptive statistical analysis was used. The CO-OP approach administered in a telerehabilitation format was found to be feasible. All participants indicated self-reported improvement in both trained and untrained goals. Trends toward fewer symptoms of executive dysfunction and greater community integration were demonstrated. All participants expressed satisfaction with the Internet delivery method. Telerehabilitation shows promise as a way to deliver the CO-OP approach and may help promote community integration of individuals living with TBI. Further study is warranted.

Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury

PubMed Central

Thom, Vivien; Arumugam, Thiruma V.; Magnus, Tim; Gelderblom, Mathias

2017-01-01

Acute ischemic and traumatic injury of the central nervous system (CNS) is known to induce a cascade of inflammatory events that lead to secondary tissue damage. In particular, the sterile inflammatory response in stroke has been intensively investigated in the last decade, and numerous experimental studies demonstrated the neuroprotective potential of a targeted modulation of the immune system. Among the investigated immunomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial therapeutic potential in experimental stroke as well as several other experimental models of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and various mechanisms of action have been proposed. Only recently, several experimental studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and suggested that the immune system as well as neuronal cells can directly be targeted by IVIg. This review gives further insight into the role of secondary inflammation in acute brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg. PMID:28824617

Effects of the Acute and Chronic Ethanol Intoxication on Acetate Metabolism and Kinetics in the Rat Brain.

PubMed

Hsieh, Ya-Ju; Wu, Liang-Chih; Ke, Chien-Chih; Chang, Chi-Wei; Kuo, Jung-Wen; Huang, Wen-Sheng; Chen, Fu-Du; Yang, Bang-Hung; Tai, Hsiao-Ting; Chen, Sharon Chia-Ju; Liu, Ren-Shyan

2018-02-01

Ethanol (EtOH) intoxication inhibits glucose transport and decreases overall brain glucose metabolism; however, humans with long-term EtOH consumption were found to have a significant increase in [1- 11 C]-acetate uptake in the brain. The relationship between the cause and effect of [1- 11 C]-acetate kinetics and acute/chronic EtOH intoxication, however, is still unclear. [1- 11 C]-acetate positron emission tomography (PET) with dynamic measurement of K 1 and k 2 rate constants was used to investigate the changes in acetate metabolism in different brain regions of rats with acute or chronic EtOH intoxication. PET imaging demonstrated decreased [1- 11 C]-acetate uptake in rat brain with acute EtOH intoxication, but this increased with chronic EtOH intoxication. Tracer uptake rate constant K 1 and clearance rate constant k 2 were decreased in acutely intoxicated rats. No significant change was noted in K 1 and k 2 in chronic EtOH intoxication, although 6 of 7 brain regions showed slightly higher k 2 than baseline. These results indicate that acute EtOH intoxication accelerated acetate transport and metabolism in the rat brain, whereas chronic EtOH intoxication status showed no significant effect. In vivo PET study confirmed the modulatory role of EtOH, administered acutely or chronically, in [1- 11 C]-acetate kinetics and metabolism in the rat brain. Acute EtOH intoxication may inhibit the transport and metabolism of acetate in the brain, whereas chronic EtOH exposure may lead to the adaptation of the rat brain to EtOH in acetate utilization. [1- 11 C]-acetate PET imaging is a feasible approach to study the effect of EtOH on acetate metabolism in rat brain. Copyright © 2017 by the Research Society on Alcoholism.

Imaging Sex Differences in Regional Brain Metabolism during Acute Opioid Withdrawal

PubMed Central

Santoro, Giovanni C; Carrion, Joseph; Dewey, Stephen L

2017-01-01

The rate of opioid overdose continues to rise, necessitating improved treatment options. Current therapeutic approaches rely on administration of either a blocking agent, such as naloxone, or chronic treatment with replacement drugs, including methadone and/or buprenorphine. Recent findings suggest that males and females respond to these treatments uniquely. In an effort to better understand this sex-specific variation in treatment efficacy, we investigated the effects of acute opioid withdrawal in male and female rats using 18FDG and microPET. These data demonstrate that acute opioid withdrawal produces metabolic alterations in brain regions associated with reward and drug dependence, namely corpus striatum, thalamic nuclei, septum, and frontal cortex. Furthermore, certain changes are unique to males. Specifically, males demonstrated increased metabolism in the anterior cingulate cortex and the ventral hippocampus (CA3) following acute opioid withdrawal. If males and females exhibit sex-specific changes in regional brain metabolism following acute opioid withdrawal, then perhaps it is not surprising that they respond to treatment differently. PMID:29046888

Function and Dysfunction of Prefrontal Brain Circuitry in Alcoholic Korsakoff’s Syndrome

PubMed Central

Oscar-Berman, Marlene

2013-01-01

The signature symptom of alcohol-induced persisting amnestic disorder, more commonly referred to as alcoholic Korsakoff’s syndrome (KS), is anterograde amnesia, or memory loss for recent events, and until the mid 20th Century, the putative brain damage was considered to be in diencephalic and medial temporal lobe structures. Overall intelligence, as measured by standardized IQ tests, usually remains intact. Preservation of IQ occurs because memories formed before the onset of prolonged heavy drinking — the types of information and abilities tapped by intelligence tests — remain relatively well preserved compared with memories recently acquired. However, clinical and experimental evidence has shown that neurobehavioral dysfunction in alcoholic patients with KS does include nonmnemonic abilities, and further brain damage involves extensive frontal and limbic circuitries. Among the abnormalities are confabulation, disruption of elements of executive functioning and cognitive control, and emotional impairments. Here, we discuss the relationship between neurobehavioral impairments in KS and alcoholism-related brain damage. More specifically, we examine the role of damage to prefrontal brain systems in the neuropsychological profile of alcoholic KS. PMID:22538385

Assessment of the usefulness of magnetic resonance brain imaging in patients presenting with acute seizures.

PubMed

Olszewska, D A; Costello, D J

2014-12-01

Magnetic Resonance Imaging (MRI) is increasingly available as a tool for assessment of patients presenting to acute services with seizures. We set out to prospectively determine the usefulness of early MRI brain in a cohort of patients presenting with acute seizures. We examined the MR imaging studies performed in patients admitted solely because of acute seizures to Cork University Hospital over a 12-month period. The main aim of the study was to determine if the MRI established the proximate cause for the patient's recent seizure. We identified 91 patients who underwent MRI brain within 48 h of admission for seizures. Of the 91 studies, 51 were normal (56 %). The remaining 40 studies were abnormal as follows: microvascular disease (usually moderate/severe) (n = 19), post-traumatic gliosis (n = 7), remote symptomatic lesion (n = 6), primary brain tumour (n = 5), venous sinus thrombosis (n = 3), developmental lesion (n = 3), post-surgical gliosis (n = 3) and single cases of demyelination, unilateral hippocampal sclerosis, lobar haemorrhage and metastatic malignant melanoma. Abnormalities in diffusion-weighted sequences that were attributable to prolonged ictal activity were seen in nine patients, all of who had significant ongoing clinical deficits, most commonly delirium. Of the 40 patients with abnormal MRI studies, seven patients had unremarkable CT brain. MR brain imaging revealed the underlying cause for acute seizures in 44 % of patients. CT brain imaging failed to detect the cause of the acute seizures in 19 % of patients in whom subsequent MRI established the cause. This study emphasises the importance of obtaining optimal imaging in people admitted with acute seizures.

Prospective investigation of anterior pituitary function in the acute phase and 12 months after pediatric traumatic brain injury.

PubMed

Ulutabanca, Halil; Hatipoglu, Nihal; Tanriverdi, Fatih; Gökoglu, Abdülkerim; Keskin, Mehmet; Selcuklu, Ahmet; Kurtoglu, Selim; Kelestimur, Fahrettin

2014-06-01

Although head trauma is common in childhood, there is no enough prospective study investigating both acute phase and 12 months after injury. Therefore, a prospective clinical trial was planned to evaluate the pituitary function in childhood in the acute and chronic phase after traumatic brain injury (TBI). Forty-one children (27 boys and 14 girls, mean age 7 ± 4.3), who were admitted to neurosurgery intensive care unit due to head trauma, were included. Twenty-one (51.2 %) patients had mild, 10 (24.4 %) had moderate, and 10 (24.4 %) had severe TBI. Twenty-two of them were reevaluated 12 months after TBI. Basal pituitary hormone levels were measured during acute (first 24 h) and chronic phase of TBI. Additionally, in the chronic phase, GHRH-arginine test was used for the diagnosis of growth hormone (GH) deficiency. In the acute phase, 10 patients (24.4 %) had ACTH deficiency, and the overall 44.3 % of patients had at least one pituitary hormone dysfunction. All the pituitary hormone deficiencies during the acute phase were recovered after 12 months. Two patients (9.1 %) had new-onset GH deficiency in the chronic phase, and in one of them, ACTH deficiency was also present. Present prospective data clearly demonstrated that most of the hormonal changes in the early acute phase were transient, suggesting an adaptive response, and these changes did not predict the hormone deficiencies after 1 year. In the chronic phase, although GH deficiency was present, the frequency of TBI-induced hypopituitarism was clearly lower than the adult patients.

[Cyclic vomiting with ketosis as a cause of acute kidney dysfunction: own clinical experience].

PubMed

Ostrowska-Nawarycz, L; Rapacka, E; Baszczyński, J; Górski, P; Czajka, J; Makowski, M; Kudzin, A

2000-04-01

The aim of the study was to evaluate renal activity during cyclic vomiting with ketosis. The clinical material was obtained from 50 cases of children hospitalized in Department of Pediatrics Military Medical University within 1993-1999 what makes about 1% of all patients. The examined group consisted of 26 boys (52%) and 24 girls (48%). Three of the children were repeatedly hospitalized (3 to 8 times) because of acetonemic vomiting. The special attention during the laboratory studies was paid to evaluation of renal activity. Vomiting with ketosis were associated with temporary kidneys acute dysfunction in 46% of cases. In 98% of cases the parenteral hydration was necessary. Ketonemic vomiting with kidneys dysfunction was observed mainly with the children in pre-school age.

Combined Therapy of Iron Chelator and Antioxidant Completely Restores Brain Dysfunction Induced by Iron Toxicity

PubMed Central

Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

2014-01-01

Background Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied. Methodology Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results. Conclusion In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload. PMID:24400127

Chronic Neuropsychological Sequelae of Cholinesterase Inhibitors in the Absence of Structural Brain Damage: Two Cases of Acute Poisoning

PubMed Central

Roldán-Tapia, Lola; Leyva, Antonia; Laynez, Francisco; Santed, Fernando Sánchez

2005-01-01

Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers. PMID:15929901

Brain MRI findings in acute hepatic encephalopathy in liver transplant recipients.

PubMed

Guo, Ruo-Mi; Li, Qing-Ling; Zhong, Li-Ru; Guo, Yu; Jiao, Ju; Chen, Shao-Qiong; Wang, Jin; Zhang, Yong

2018-06-01

Acute hepatic encephalopathy has significant morbidity and mortality in liver transplant recipients unless it is promptly treated. We evaluated the brain magnetic resonance (MR) imaging findings associated with acute hepatic encephalopathy in transplant recipients. We retrospectively reviewed the clinical and imaging data and outcomes of twenty-five liver transplant patients (16 male; mean age, 49.3 years) with clinically diagnosed acute hepatic encephalopathy and forty liver transplant patients (20 males; mean age, 45.5 years) without neurological symptoms suggestive of hepatic encephalopathy at our institution. Bilateral symmetric hyperintensities of the insular cortex and cingulate gyrus were observed in twenty-one patients (84.00%), bilateral symmetric extensive increased cortical signal intensity (involving two or more regions) was observed in 72.00% of the patients, leptomeningeal enhancement in 73.68%, and visualization of prominent venules in 52.00%. The most common symptom at diagnosis was rigidity (n = 14), and the plasma ammonia levels ranged from 68.63 to 192.16 μmol/L. After active treatment, 17 patients gradually recovered, four patients suffered from mild or moderate neurologic deficits, and four patients with widespread brain edema died. The specific brain MR imaging features were bilateral symmetric increased cortical signal intensity, especially in the insular cortex and cingulate gyrus, leptomeningeal enhancement, visualization of the prominent venules, and widespread brain edema. These features may indicate poor prognosis and should alert radiologists to the possibility of acute hepatic encephalopathy in liver transplant recipients and encourage clinicians to prepare appropriate treatment in advance.

[Stress adaptive effects after traumatic brain injury].

PubMed

Teryaeva, N B; Moshkin, A V

Neuroendocrine dysfunction, in particular impaired synthesis of anterior pituitary hormones, is a common complication of traumatic brain injury. Deficiency of tropic pituitary hormones entails a hypofunction of the related peripheral endocrine glands and can be accompanied by persistent endocrine and metabolic disorders. In particular, the hypophyseal mechanisms are the key ones in implementation of most stress effects. Adequate implementation of these mechanisms largely determines a favorable outcome in the acute stage of disease. Traumatic brain injury (as well as any significant injury) initiates a stress response that can not develop in full in the case of pituitary gland failure. It is logical to suppose that the course of the acute phase of stress in the presence of hypopituitarism is different to a certain extent from the typical course, which inevitably affects certain adaptation elements. In this review, we analyzed the adaptive effects of stress after traumatic brain injury.

Thrombocytopenia and Platelet Dysfunction in Acute Tropical Infectious Diseases.

PubMed

Hapsari Putri, Indri; Tunjungputri, Rahajeng N; De Groot, Philip G; van der Ven, Andre J; de Mast, Quirijn

2018-06-18

Thrombocytopenia is a well-known manifestation of acute tropical infectious diseases. The role of platelets in infections has received much attention recently because of their emerging activities in modulation of inflammatory responses, host defense, and vascular integrity. However, while many studies have addressed thrombocytopenia in tropical infections, abnormalities in platelet function have been largely overlooked. This is an important research gap, as platelet dysfunction may contribute to the bleeding tendency that characterizes some tropical infections. The development of novel platelet function assays that can be used in thrombocytopenic conditions (e.g., flow cytometry assays) has contributed to important new insights in recent years. In this review, the importance of platelets in tropical infections is discussed with special emphasis on the underlying mechanisms and consequences of thrombocytopenia and platelet dysfunction in these infections. Special attention is paid to malaria, a disease characterized by microvascular obstruction in which bleeding is rare, and to infections in which bleeding is common, such as dengue, other viral hemorrhagic fevers, and the bacterial infection leptospirosis. Given the importance of platelet function abnormalities in these infections, the development of affordable assays for monitoring of platelet function in low-resource countries, as well as pharmacologic interventions to prevent or reverse platelet function abnormalities, might improve clinical care and the prognosis of these infections. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

In situ rat brain and liver spontaneous chemiluminescence after acute ethanol intake.

PubMed

Boveris, A; Llesuy, S; Azzalis, L A; Giavarotti, L; Simon, K A; Junqueira, V B; Porta, E A; Videla, L A; Lissi, E A

1997-09-19

The influence of acute ethanol administration on the oxidative stress status of rat brain and liver was assessed by in situ spontaneous organ chemiluminescence (CL). Brain and liver CL was significantly increased after acute ethanol administration to fed rats, a response that is time-dependent and evidenced at doses higher than 1 g/kg. Ethanol-induced CL development is faster in liver compared with brain probably due to the greater ethanol metabolic capacity of the liver, whereas the net enhancement in brain light emission at 3 h after ethanol treatment is higher than that of the liver, which could reflect the greater susceptibility of brain to oxidative stress. The effect of ethanol on brain and liver CL seems to be mediated by acetaldehyde, due to its abolishment by the alcohol dehydrogenase inhibitor 4-methylpyrazole and exacerbation by the aldehyde dehydrogenase inhibitor disulfiram. In brain, these findings were observed in the absence of changes in the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase. However, the content of brain glutathione was significantly decreased by 31%, by ethanol, thus establishing an enhanced oxidative stress in this tissue.

Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.

PubMed

Chen, Horng H; Anstrom, Kevin J; Givertz, Michael M; Stevenson, Lynne W; Semigran, Marc J; Goldsmith, Steven R; Bart, Bradley A; Bull, David A; Stehlik, Josef; LeWinter, Martin M; Konstam, Marvin A; Huggins, Gordon S; Rouleau, Jean L; O'Meara, Eileen; Tang, W H Wilson; Starling, Randall C; Butler, Javed; Deswal, Anita; Felker, G Michael; O'Connor, Christopher M; Bonita, Raphael E; Margulies, Kenneth B; Cappola, Thomas P; Ofili, Elizabeth O; Mann, Douglas L; Dávila-Román, Víctor G; McNulty, Steven E; Borlaug, Barry A; Velazquez, Eric J; Lee, Kerry L; Shah, Monica R; Hernandez, Adrian F; Braunwald, Eugene; Redfield, Margaret M

2013-12-18

Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo

Multimodal brain monitoring in fulminant hepatic failure

PubMed Central

Paschoal Jr, Fernando Mendes; Nogueira, Ricardo Carvalho; Ronconi, Karla De Almeida Lins; de Lima Oliveira, Marcelo; Teixeira, Manoel Jacobsen; Bor-Seng-Shu, Edson

2016-01-01

Acute liver failure, also known as fulminant hepatic failure (FHF), embraces a spectrum of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction, and hepatic encephalopathy. Cerebral edema and intracranial hypertension are common causes of mortality in patients with FHF. The management of patients who present acute liver failure starts with determining the cause and an initial evaluation of prognosis. Regardless of whether or not patients are listed for liver transplantation, they should still be monitored for recovery, death, or transplantation. In the past, neuromonitoring was restricted to serial clinical neurologic examination and, in some cases, intracranial pressure monitoring. Over the years, this monitoring has proven insufficient, as brain abnormalities were detected at late and irreversible stages. The need for real-time monitoring of brain functions to favor prompt treatment and avert irreversible brain injuries led to the concepts of multimodal monitoring and neurophysiological decision support. New monitoring techniques, such as brain tissue oxygen tension, continuous electroencephalogram, transcranial Doppler, and cerebral microdialysis, have been developed. These techniques enable early diagnosis of brain hemodynamic, electrical, and biochemical changes, allow brain anatomical and physiological monitoring-guided therapy, and have improved patient survival rates. The purpose of this review is to discuss the multimodality methods available for monitoring patients with FHF in the neurocritical care setting. PMID:27574545

Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8.

PubMed

Eckert, Gunter P; Schiborr, Christina; Hagl, Stephanie; Abdel-Kader, Reham; Müller, Walter E; Rimbach, Gerald; Frank, Jan

2013-04-01

The aging brain suffers mitochondrial dysfunction and a reduced availability of energy in the form of ATP, which in turn may cause or promote the decline in cognitive, sensory, and motor function observed with advancing age. There is a need for animal models that display some of the pathological features of human brain aging in order to study their prevention by e.g. dietary factors. We thus investigated the suitability of the fast-aging senescence-accelerated mouse-prone 8 (SAMP8) strain and its normally aging control senescence-accelerated mouse-resistant 1 (SAMR1) as a model for the age-dependent changes in mitochondrial function in the brain. To this end, 2-months old male SAMR1 (n=10) and SAMP8 mice (n=7) were fed a Western type diet (control groups) for 5months and one group of SAMP8 mice (n=6) was fed an identical diet fortified with 500mg curcumin per kg. Dissociated brain cells and brain tissue homogenates were analyzed for malondialdehyde, heme oxygenase-1 mRNA, mitochondrial membrane potential (MMP), ATP concentrations, protein levels of mitochondrial marker proteins for mitochondrial membranes (TIMM, TOMM), the mitochondrial permeability transition pore (ANT1, VDAC1, TSPO), respiration complexes, and fission and fusion (Fis, Opa1, Mfn1, Drp1). Dissociated brain cells isolated from SAMP8 mice showed significantly reduced MMP and ATP levels, probably due to significantly diminished complex V protein expression, and increased expression of TSPO. Fission and fusion marker proteins indicate enhanced mitochondrial fission in brains of SAMP8 mice. Treatment of SAMP8 mice with curcumin improved MMP and ATP and restored mitochondrial fusion, probably by up-regulating nuclear factor PGC1α protein expression. In conclusion, SAMP8 compared to SAMR1 mice are a suitable model to study age-dependent changes in mitochondrial function and curcumin emerges as a promising nutraceutical for the prevention of neurodegenerative diseases that are accompanied or caused by

Blood-brain Barrier Disruption Leads to Postoperative Cognitive Dysfunction.

PubMed

Wang, Bin; Li, Siyuan; Cao, Xipeng; Dou, Xinghui; Li, Jingzhu; Wang, Ling; Wang, Mingshan; Bi, Yanlin

2017-01-01

Postoperative Cognitive Dysfunction (POCD) has received considerable attention as one of the main postoperative complications. The underlying mechanism of POCD in elderly subjects has not been fully elucidated to date. The Central Nervous System (CNS) is isolated from the bloodstream by the Blood Brain Barrier (BBB) that consists of endothelial cells, capillary blood vessels and tight junctions. The tight junctions carry out significant biological functions that are associated with the CNS and blood circulation. In this review, I present a hypothesis that blood-brain barrier disruption leads to postoperative cognitive dysfunction. A total of 81 healthy male Wistar rats were used for the present study. All the experimental animals were randomly divided into 3 groups: normal control group, isoflurane group and splenectomy group. The control group was not subjected to any form of treatment. The rats in isoflurane group were given 1.5-2% isoflurane under intubation and mechanical ventilation. The rats in splenectomy group underwent splenectomy under the same anesthesia as the isoflurane group. The Morris water maze was used to examine the learning and memory ability of the animals. The expression of the Tight Junctions Proteins (TJPs) in the hippocampus was analyzed using Western blotting. The concentration of Evans Blue (EB) in the supernatant was analyzed using UV spectroscopy. Ultrastructure changes in the basal laminas, the Tight Junctions (TJs), mitochondria and the endoplasmic reticulum surrounding the capillaries were assessed by Transmission Electron Microscopy (TEM). Following splenectomy, the rats displayed concomitant significant cognitive deficits in the Morris water maze test. Taken together, the results indicate that the expression levels of occludin (65KD) following splenectomy were reduced on days one and three in aged rats. No significant difference was noted in the expression levels of claudin-5, except for a reduction after surgery on day one. The

Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.

PubMed

Cotman, Carl W; Head, Elizabeth; Muggenburg, Bruce A; Zicker, S; Milgram, Norton W

2002-01-01

Animal models that simulate various aspects of human brain aging are an essential step in the development of interventions to manage cognitive dysfunction in the elderly. Over the past several years we have been studying cognition and neuropathology in the aged-canine (dog). Like humans, canines naturally accumulate deposits of beta-amyloid (Abeta) in the brain with age. Further, canines and humans share the same Abeta sequence and also first show deposits of the longer Abeta1-42 species followed by the deposition of Abeta1-40. Aged canines like humans also show increased oxidative damage. As a function of age, canines show impaired learning and memory on tasks similar to those used in aged primates and humans. The extent of Abeta deposition correlates with the severity of cognitive dysfunction in canines. To test the hypothesis that a cascade of mechanisms centered on oxidative damage and Abeta results in cognitive dysfunction we have evaluated the cognitive effects of an antioxidant diet in aged canines. The diet resulted in a significant improvement in the ability of aged but not young animals to acquire progressively more difficult learning tasks (e.g. oddity discrimination learning). The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies. Copyright 2002 Elsevier Science Inc.

Neuropsychological factors related to returning to work in patients with higher brain dysfunction.

PubMed

Kai, Akiko; Hashimoto, Manabu; Okazaki, Tetsuya; Hachisuka, Kenji

2008-12-01

We conducted neuropsychological tests of patients with higher brain dysfunction to examine the characteristics of barriers to employment. We tested 92 patients with higher brain dysfunction (average age of 36.3 +/- 13.8 years old, ranging between 16 and 63 years old, with an average post-injury period of 35.6 +/- 67.8 months) who were hospitalized at the university hospital between February 2002 and June 2007 for further neuropsychological evaluation, conducting the Wechsler Adult Intelligence Scale-Revised (WAIS-R), Wechsler Memory Scale-Revised (WMS-R), the Rivermead Behavioral Memory Test (RBMT), Frontal Assessment Battery (FAB) and Behavioral Assessment of Dysexecutive Syndrome (BADS). The outcomes after discharge were classified between competitive employment, sheltered employment and non-employment, and the three groups were compared using one-way analysis of variance and the Scheffe test. The WAIS-R subtests were mutually compared based on the standard values of significant differences described in the WAIS-R manual. Verbal performance and full scale Intelligence Quotient (IQ) of WAIS-R were 87.7 +/- 15.6 (mean +/- standard deviation), 78.5 +/- 18.1 and 81.0 +/- 17.2, respectively, and verbal memory, visual memory, general memory, attention/concentration and delayed recall were 74.6 +/- 20.0, 76.6 +/- 21.4, 72.0 +/- 20.4, 89.0 +/- 16.5 and 65.2 +/- 20.8, respectively. The competitive employment group showed significantly higher scores in performance IQ and full IQ on the WAIS-R and verbal memory, visual memory, general memory and delayed recall on the WMS-R and RBMT than the non-employment group. The sheltered employment group showed a significantly higher score in delayed recall than the non-employment group. No difference was observed in the FAB or BADS between the three groups. In the subtests of the WAIS-R, the score for Digit Symbol-Coding was significantly lower than almost all the other subtests. For patients with higher brain dysfunction, IQ (full

Adolescent Depression: Stress and Reward Dysfunction

PubMed Central

Auerbach, Randy P.; Admon, Roee; Pizzagalli, Diego A.

2014-01-01

Adolescence is a peak period for the onset of depression, and it is also a time marked by substantial stress as well as neural development within the brain reward circuitry. In the current review, we provide a selective overview of current animal and human research investigating the relationship among reward processes, stress, and depression. Three separate, but related, etiological models examine the differential roles that stress may play with regard to reward dysfunction and adolescent depression. First, the reward mediation model suggests that acute and chronic stress contribute to reward deficits, which in turn, potentiate depressive symptoms and/or increase the risk for depression. Second, in line with the stress generation perspective, it is plausible that premorbid reward-related dysfunction generates stress, in particular interpersonal stress, which then leads to the manifestation of depressive symptoms. Last, consistent with a diathesis-stress model, the interaction between stress and premorbid reward dysfunction may contribute to the onset of depression. Given the equifinal nature of depression, these models could shed important light on different etiological pathways during adolescence, particularly as they may relate to understanding the heterogeneity of depression. To highlight the translational potential of these insights, a hypothetical case study is provided as means of demonstrating the importance of targeting reward dysfunction in both assessment and treatment of adolescent depression. PMID:24704785

Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

PubMed

Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

2017-12-01

Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

WAIS Digit Span-Based Indicators of Malingered Neurocognitive Dysfunction: Classification Accuracy in Traumatic Brain Injury

ERIC Educational Resources Information Center

Heinly, Matthew T.; Greve, Kevin W.; Bianchini, Kevin J.; Love, Jeffrey M.; Brennan, Adrianne

2005-01-01

The present study determined specificity and sensitivity to malingered neurocognitive dysfunction (MND) in traumatic brain injury (TBI) for several Wechsler Adult Intelligence Scale (WAIS) Digit Span scores. TBI patients (n = 344) were categorized into one of five groups: no incentive, incentive only, suspect, probable MND, and definite MND.…

Luteinizing Hormone and Testosterone Levels during Acute Phase of Severe Traumatic Brain Injury: Prognostic Implications for Adult Male Patients

PubMed Central

Hohl, Alexandre; Zanela, Fernando Areas; Ghisi, Gabriela; Ronsoni, Marcelo Fernando; Diaz, Alexandre Paim; Schwarzbold, Marcelo Liborio; Dafre, Alcir Luiz; Reddi, Benjamin; Lin, Kátia; Pizzol, Felipe Dal; Walz, Roger

2018-01-01

Traumatic brain injury (TBI) is a worldwide core public health problem affecting mostly young male subjects. An alarming increase in incidence has turned TBI into a leading cause of morbidity and mortality in young adults as well as a tremendous resource burden on the health and welfare sector. Hormone dysfunction is highly prevalent during the acute phase of severe TBI. In particular, investigation of the luteinizing hormone (LH) and testosterone levels during the acute phase of severe TBI in male has identified a high incidence of low testosterone levels in male patients (36.5–100%) but the prognostic significance of which remains controversial. Two independent studies showed that normal or elevated levels of LH levels earlier during hospitalization are significantly associated with higher mortality/morbidity. The association between LH levels and prognosis was independent of other predictive variables such as neuroimaging, admission Glasgow coma scale, and pupillary reaction. The possible mechanisms underlying this association and further research directions in this field are discussed. Overall, current data suggest that LH levels during the acute phase of TBI might contribute to accurate prognostication and further prospective multicentric studies are required to develop more sophisticated predictive models incorporating biomarkers such as LH in the quest for accurate outcome prediction following TBI. Moreover, the potential therapeutic benefits of modulating LH during the acute phase of TBI warrant investigation. PMID:29487565

Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms.

PubMed

Miksys, Sharon; Wadji, Fariba Baghai; Tolledo, Edgor Cole; Remington, Gary; Nobrega, Jose N; Tyndale, Rachel F

2017-08-01

Risk for side-effects after acute (e.g. parkinsonism) or chronic (e.g. tardive dyskinesia) treatment with antipsychotics, including haloperidol, varies substantially among people. CYP2D can metabolize many antipsychotics and variable brain CYP2D metabolism can influence local drug and metabolite levels sufficiently to alter behavioral responses. Here we investigated a role for brain CYP2D in acutely and chronically administered haloperidol levels and side-effects in a rat model. Rat brain, but not liver, CYP2D activity was irreversibly inhibited with intracerebral propranolol and/or induced by seven days of subcutaneous nicotine pre-treatment. The role of variable brain CYP2D was investigated in rat models of acute (catalepsy) and chronic (vacuous chewing movements, VCMs) haloperidol side-effects. Selective inhibition and induction of brain, but not liver, CYP2D decreased and increased catalepsy after acute haloperidol, respectively. Catalepsy correlated with brain, but not hepatic, CYP2D enzyme activity. Inhibition of brain CYP2D increased VCMs after chronic haloperidol; VCMs correlated with brain, but not hepatic, CYP2D activity, haloperidol levels and lipid peroxidation. Baseline measures, hepatic CYP2D activity and plasma haloperidol levels were unchanged by brain CYP2D manipulations. Variable rat brain CYP2D alters side-effects from acute and chronic haloperidol in opposite directions; catalepsy appears to be enhanced by a brain CYP2D-derived metabolite while the parent haloperidol likely causes VCMs. These data provide novel mechanistic evidence for brain CYP2D altering side-effects of haloperidol and other antipsychotics metabolized by CYP2D, suggesting that variation in human brain CYP2D may be a risk factor for antipsychotic side-effects. Copyright © 2017 Elsevier Inc. All rights reserved.

Cognitive dysfunction in patients with brain metastases: influences on caregiver resilience and coping.

PubMed

Saria, Marlon Garzo; Courchesne, Natasia; Evangelista, Lorraine; Carter, Joshua; MacManus, Daniel A; Gorman, Mary Kay; Nyamathi, Adeline M; Phillips, Linda R; Piccioni, David; Kesari, Santosh; Maliski, Sally

2017-04-01

Neurologic deficits that may be manifested as cognitive impairment contribute to the challenges faced by caregivers of patients with brain metastases. To better address their needs, we examined how caregivers respond to these challenges and explore the relationship between the patient's cognitive impairment and caregiver resilience and coping. We conducted a descriptive, cross-sectional study using self-reported data from 56 caregivers of patients with brain metastases. Study participants from a comprehensive cancer center were asked to complete a series of instruments that measured their perception of the patient's cognitive dysfunction (revised memory and behavior problems checklist, RMBC), their own personal resilience (Resilience Scale, RS), and their utilization of a broad range of coping responses (COPE inventory and Emotional-Approach Coping scale). Caregivers reported that memory-related problems occurred more frequently in the patients they cared for compared to depression and disruptive behavior (mean scores 3.52 vs 2.34 vs. 1.32, respectively). Coping strategies most frequently used by caregivers were acceptance (3.28), planning (3.08), and positive reinterpretation and growth (2.95). Most caregivers scored moderate to high on the RS (77%). The coping strategy acceptance correlated significantly with the memory and disruptive behavior subscales of the RMBC. Given the protective effect of problem-focused coping and the high rate of caregivers utilizing less effective coping strategies in instances of worsening cognitive dysfunction, healthcare professionals need to systematically assess the coping strategies of caregivers and deliver a more personalized approach to enhance effective coping among caregivers of patients with brain metastases.

Electroencephalographic inverse localization of brain activity in acute traumatic brain injury as a guide to surgery, monitoring and treatment

PubMed Central

Irimia, Andrei; Goh, S.-Y. Matthew; Torgerson, Carinna M.; Stein, Nathan R.; Chambers, Micah C.; Vespa, Paul M.; Van Horn, John D.

2013-01-01

Objective To inverse-localize epileptiform cortical electrical activity recorded from severe traumatic brain injury (TBI) patients using electroencephalography (EEG). Methods Three acute TBI cases were imaged using computed tomography (CT) and multimodal magnetic resonance imaging (MRI). Semi-automatic segmentation was performed to partition the complete TBI head into 25 distinct tissue types, including 6 tissue types accounting for pathology. Segmentations were employed to generate a finite element method model of the head, and EEG activity generators were modeled as dipolar currents distributed over the cortical surface. Results We demonstrate anatomically faithful localization of EEG generators responsible for epileptiform discharges in severe TBI. By accounting for injury-related tissue conductivity changes, our work offers the most realistic implementation currently available for the inverse estimation of cortical activity in TBI. Conclusion Whereas standard localization techniques are available for electrical activity mapping in uninjured brains, they are rarely applied to acute TBI. Modern models of TBI-induced pathology can inform the localization of epileptogenic foci, improve surgical efficacy, contribute to the improvement of critical care monitoring and provide guidance for patient-tailored treatment. With approaches such as this, neurosurgeons and neurologists can study brain activity in acute TBI and obtain insights regarding injury effects upon brain metabolism and clinical outcome. PMID:24011495

Electroencephalographic inverse localization of brain activity in acute traumatic brain injury as a guide to surgery, monitoring and treatment.

PubMed

Irimia, Andrei; Goh, S-Y Matthew; Torgerson, Carinna M; Stein, Nathan R; Chambers, Micah C; Vespa, Paul M; Van Horn, John D

2013-10-01

To inverse-localize epileptiform cortical electrical activity recorded from severe traumatic brain injury (TBI) patients using electroencephalography (EEG). Three acute TBI cases were imaged using computed tomography (CT) and multimodal magnetic resonance imaging (MRI). Semi-automatic segmentation was performed to partition the complete TBI head into 25 distinct tissue types, including 6 tissue types accounting for pathology. Segmentations were employed to generate a finite element method model of the head, and EEG activity generators were modeled as dipolar currents distributed over the cortical surface. We demonstrate anatomically faithful localization of EEG generators responsible for epileptiform discharges in severe TBI. By accounting for injury-related tissue conductivity changes, our work offers the most realistic implementation currently available for the inverse estimation of cortical activity in TBI. Whereas standard localization techniques are available for electrical activity mapping in uninjured brains, they are rarely applied to acute TBI. Modern models of TBI-induced pathology can inform the localization of epileptogenic foci, improve surgical efficacy, contribute to the improvement of critical care monitoring and provide guidance for patient-tailored treatment. With approaches such as this, neurosurgeons and neurologists can study brain activity in acute TBI and obtain insights regarding injury effects upon brain metabolism and clinical outcome. Published by Elsevier B.V.

Endotoxin-induced lung alveolar cell injury causes brain cell damage.

PubMed

Rodríguez-González, Raquel; Ramos-Nuez, Ángela; Martín-Barrasa, José Luis; López-Aguilar, Josefina; Baluja, Aurora; Álvarez, Julián; Rocco, Patricia R M; Pelosi, Paolo; Villar, Jesús

2015-01-01

Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome. © 2014 by the Society for Experimental Biology and Medicine.

Memory Function Before and After Whole Brain Radiotherapy in Patients With and Without Brain Metastases

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

Welzel, Grit; Fleckenstein, Katharina; Department of Radiation Oncology, Duke University Medical Center, Durham, NC

2008-12-01

Purpose: To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. Methods and Materials: Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. Results: Before therapy,more » prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. Conclusions: The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.« less

[Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

PubMed

Ichikawa, Hiroo

2016-02-01

Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.

Role of brain iron accumulation in cognitive dysfunction: evidence from animal models and human studies.

PubMed

Schröder, Nadja; Figueiredo, Luciana Silva; de Lima, Maria Noêmia Martins

2013-01-01

Over the last decades, studies from our laboratory and other groups using animal models have shown that iron overload, resulting in iron accumulation in the brain, produces significant cognitive deficits. Iron accumulation in the hippocampus and the basal ganglia has been related to impairments in spatial memory, aversive memory, and recognition memory in rodents. These results are corroborated by studies showing that the administration of iron chelators attenuates cognitive deficits in a variety of animal models of cognitive dysfunction, including aging and Alzheimer's disease models. Remarkably, recent human studies using magnetic resonance image techniques have also shown a consistent correlation between cognitive dysfunction and iron deposition, mostly in the hippocampus, cortical areas, and basal ganglia. These findings may have relevant implications in the light of the knowledge that iron accumulates in brain regions of patients suffering from neurodegenerative diseases. A better understanding of the functional consequences of iron dysregulation in aging and neurological diseases may help to identify novel targets for treating memory problems that afflict a growing aging population.

Central diabetes insipidus in children with acute brain insult.

PubMed

Yang, Yun-Hsuan; Lin, Jainn-Jim; Hsia, Shao-Hsuan; Wu, Chang-Teng; Wang, Huei-Shyong; Hung, Po-Cheng; Chou, Min-Liang; Hsieh, Meng-Ying; Lin, Kuang-Lin

2011-12-01

Central diabetes insipidus occurs in patients with overwhelming central nervous system injuries, and may be associated with brain death. The clinical picture of children with acquired central diabetes insipidus after acute brain insult is seldom reported. We retrospectively reviewed cases dating from January 2000-February 2008 at a tertiary pediatric intensive care unit. Fifty-four patients (28 girls, 26 boys), aged 3 months to 18 years, were enrolled. Etiologies included severe central nervous system infection (35.2%), hypoxic-ischemic events (31.5%), head injury (18.5%), and vascular lesions (14.8%). In 39 (72.2%) patients, diabetes insipidus was diagnosed during the first 2 days after acute central nervous system injury, and 40 (74.0%) developed maximum serum sodium concentrations of >160 mEq/L. In 16, sequential cerebral salt wasting syndrome developed after their initial diabetes insipidus presentation. Overall mortality at 2 months after admission was 77.8%. Our results demonstrate that patients who develop central diabetes insipidus after acute central nervous system injury manifest high mortality. Development of central diabetes insipidus within the first 2 days and a maximum plasma sodium >160 mEq/L were significant predictors of outcomes. Copyright © 2011 Elsevier Inc. All rights reserved.

Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection.

PubMed

Sailasuta, Napapon; Ross, William; Ananworanich, Jintanat; Chalermchai, Thep; DeGruttola, Victor; Lerdlum, Sukalaya; Pothisri, Mantana; Busovaca, Edgar; Ratto-Kim, Silvia; Jagodzinski, Linda; Spudich, Serena; Michael, Nelson; Kim, Jerome H; Valcour, Victor

2012-01-01

Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART). Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART. After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months. We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury.

Contrasting Acute and Slow-Growing Lesions: A New Door to Brain Plasticity

ERIC Educational Resources Information Center

Desmurget, Michel; Bonnetblanc, FranCois; Duffau, Hugues

2007-01-01

The concept of plasticity describes the mechanisms that rearrange cerebral organization following a brain injury. During the last century, plasticity has been mainly investigated in humans with acute strokes. It was then shown: (i) that the brain is organized into highly specialized functional areas, often designated "eloquent" areas and (ii) that…

Concussive Brain Trauma in the Mouse Results in Acute Cognitive Deficits and Sustained Impairment of Axonal Function

PubMed Central

Creed, Jennifer A.; DiLeonardi, Ann Mae; Fox, Douglas P.; Tessler, Alan R.

2011-01-01

Abstract Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function. PMID:21299360

CD147/basigin reflects renal dysfunction in patients with acute kidney injury.

PubMed

Nagaya, Hiroshi; Kosugi, Tomoki; Maeda-Hori, Mayuko; Maeda, Kayaho; Sato, Yuka; Kojima, Hiroshi; Hayashi, Hiroki; Kato, Noritoshi; Ishimoto, Takuji; Sato, Waichi; Yuzawa, Yukio; Matsuo, Seiichi; Kadomatsu, Kenji; Maruyama, Shoichi

2014-10-01

Acute tubular necrosis (ATN) describes a form of intrinsic acute kidney injury (AKI) that results from persistent hypoperfusion and subsequent activation of the immune system. A glycosylated transmembrane protein, CD147/basigin, is involved in the pathogenesis of renal ischemia and fibrosis. The present study investigated whether CD147 can reflect pathological features and renal dysfunction in patients with AKI. Plasma and spot urine samples were collected from 24 patients (12 controls and 12 with ATN) who underwent renal biopsy between 2008 and 2012. In another study, patients undergoing open surgery to treat abdominal aortic aneurysms (AAAs) were enrolled in 2004. We collected urine and plasma samples from seven patients with AKI and 33 patients without AKI, respectively. In these experiments, plasma and urinary CD147, and urinary L-fatty acid-binding protein (L-FABP) levels were measured, and the former expression in kidneys was examined by immunostaining. In biopsy tissues of ATN with severe histological features, CD147 induction was strikingly present in inflammatory cells such as macrophages and lymphocytes in the injured interstitium, but not in damaged tubules representing atrophy. Both plasma and urinary CD147 levels were strikingly increased in ATN patients; both values showed greater correlations with renal dysfunction compared to urinary L-FABP. In patients who had undergone open AAA surgery, urinary and plasma CD147 values in AKI patients were significantly higher than in non-AKI patients at post-operative day 1, similar to the profile of urinary L-FABP. CD147 was prominent in its ability to detect AKI and may allow the start of preemptive medication.

Caffeine restores regional brain activation in acute hypoglycaemia in healthy volunteers.

PubMed

Rosenthal, M J; Smith, D; Yaguez, L; Giampietro, V; Kerr, D; Bullmore, E; Brammer, M; Williams, S C R; Amiel, S A

2007-07-01

Caffeine enhances counterregulatory responses to acute hypoglycaemia. Our aim was to explore its effects on cortical function, which are not known at present. Regional brain activation during performance of the four-choice reaction time (4CRT) at different levels of complexity was measured using functional magnetic resonance imaging (fMRI) at euglycaemia (5 mmol/l) and hypoglycaemia (2.6 mmol/l) in the presence and absence of caffeine in six healthy right-handed men. During hypoglycaemia, caffeine enhanced adrenaline responses to hypoglycaemia (2.5 +/- 0.7 nmol/l to 4.0 +/- 1.0 nmol/l, P = 0.01) and restored the brain activation response to the non-cued 4CRT, the linear increases in regional brain activation associated with increased task complexity and the ability to respond to a cue that were lost in hypoglycaemia alone. Caffeine can sustain regional brain activation patterns lost in acute hypoglycaemia, with some restoration of cortical function and enhanced adrenaline responsiveness. A methodology has been established that may help in the development of therapies to protect against severe hypoglycaemia in insulin therapy for patients with diabetes and problematic hypoglycaemia.

Brain Basics: Know Your Brain

MedlinePlus

... free mailed brochure Table of Contents Introduction The Architecture of the Brain The Geography of Thought The ... brain is diseased or dysfunctional. Image 1 The Architecture of the Brain The brain is like a ...

Nonlinear Dynamic Theory of Acute Cell Injuries and Brain Ischemia

NASA Astrophysics Data System (ADS)

Taha, Doaa; Anggraini, Fika; Degracia, Donald; Huang, Zhi-Feng

2015-03-01

Cerebral ischemia in the form of stroke and cardiac arrest brain damage affect over 1 million people per year in the USA alone. In spite of close to 200 clinical trials and decades of research, there are no treatments to stop post-ischemic neuron death. We have argued that a major weakness of current brain ischemia research is lack of a deductive theoretical framework of acute cell injury to guide empirical studies. A previously published autonomous model based on the concept of nonlinear dynamic network was shown to capture important facets of cell injury, linking the concept of therapeutic to bistable dynamics. Here we present an improved, non-autonomous formulation of the nonlinear dynamic model of cell injury that allows multiple acute injuries over time, thereby allowing simulations of both therapeutic treatment and preconditioning. Our results are connected to the experimental data of gene expression and proteomics of neuron cells. Importantly, this new model may be construed as a novel approach to pharmacodynamics of acute cell injury. The model makes explicit that any pro-survival therapy is always a form of sub-lethal injury. This insight is expected to widely influence treatment of acute injury conditions that have defied successful treatment to date. This work is supported by NIH NINDS (NS081347) and Wayne State University President's Research Enhancement Award.

[Relationship between the Expression of α-syn and Neuronal Apoptosis in Brain Cortex of Acute Alcoholism Rats].

PubMed

Li, F; Zhang, Y; Ma, S L

2016-12-01

To observe the changes of expression of α-synuclein （α-syn） and neuronal apoptosis in brain cortex of acute alcoholism rats and to explore the mechanism of the damage caused by ethanol to the neurons. The model of acute alcoholism rat was established by 50% alcohol gavage. The α-syn and caspase-3 were detected by immunohistochemical staining and imaging analysis at 1 h, 3 h, 6 h and 12 h after acute alcoholism. The number of positive cell and mean of optical density were detected and the trend change was analyzed. The variance analysis and t -test were also performed. The number of α-syn positive cell and average optical density in brain cortex of acute alcoholism rat increased significantly and peaked at 6 hour with a following slight decrease at 12 h, but still higher than the groups at 1 h and 3 h. Within 12 hours after poisoning, the number of caspase-3 positive cell and average optical density in brain cortex of rats gradually increased. The abnormal aggregation of α-syn caused by brain edema and hypoxia may participate the early stage of neuronal apoptosis in brain cortex after acute alcoholism. Copyright© by the Editorial Department of Journal of Forensic Medicine

Acute and delayed neuroinflammatory response following experimental penetrating ballistic brain injury in the rat

PubMed Central

Williams, Anthony J; Wei, Hans H; Dave, Jitendra R; Tortella, Frank C

2007-01-01

Background Neuroinflammation following acute brain trauma is considered to play a prominent role in both the pathological and reconstructive response of the brain to injury. Here we characterize and contrast both an acute and delayed phase of inflammation following experimental penetrating ballistic brain injury (PBBI) in rats out to 7 days post-injury. Methods Quantitative real time PCR (QRT-PCR) was used to evaluate changes in inflammatory gene expression from the brain tissue of rats exposed to a unilateral frontal PBBI. Brain histopathology was assessed using hematoxylin and eosin (H&E), silver staining, and immunoreactivity for astrocytes (GFAP), microglia (OX-18) and the inflammatory proteins IL-1β and ICAM-1. Results Time course analysis of gene expression levels using QRT-PCR indicated a peak increase during the acute phase of the injury between 3–6 h for the cytokines TNF-α (8–11 fold), IL-1β (11–13 fold), and IL-6 (40–74 fold) as well as the cellular adhesion molecules VCAM (2–3 fold), ICAM-1 (7–15 fold), and E-selectin (11–13 fold). Consistent with the upregulation of pro-inflammatory genes, peripheral blood cell infiltration was a prominent post-injury event with peak levels of infiltrating neutrophils (24 h) and macrophages (72 h) observed throughout the core lesion. In regions of the forebrain immediately surrounding the lesion, strong immunoreactivity for activated astrocytes (GFAP) was observed as early as 6 h post-injury followed by prominent microglial reactivity (OX-18) at 72 h and resolution of both cell types in cortical brain regions by day 7. Delayed thalamic inflammation (remote from the primary lesion) was also observed as indicated by both microglial and astrocyte reactivity (72 h to 7 days) concomitant with the presence of fiber degeneration (silver staining). Conclusion In summary, PBBI induces both an acute and delayed neuroinflammatory response occurring in distinct brain regions, which may provide useful diagnostic

Irritant vocal cord dysfunction at first misdiagnosed as reactive airway dysfunction syndrome.

PubMed

Galdi, Eugenia; Perfetti, Luca; Pagella, Fabio; Bertino, Giulia; Ferrari, Massimo; Moscato, Gianna

2005-06-01

This report describes a case of vocal cord dysfunction at first misdiagnosed as reactive airway dysfunction syndrome (RADS). A woman developed recurrent episodes of cough, dyspnea, and wheezing unresponsive to asthma therapy after irritant exposure to glutaraldehyde. Direct laryngoscopy was performed immediately after the induction of symptoms. Laryngoscopy showed a paradoxical adduction of the vocal cord on inspiration. Vocal cord dysfunction was diagnosed. A case of vocal cord dysfunction occurred after exposure to glutaraldhyde in a person with a history highly suggestive of RADS. Vocal cord dysfunction should always be considered in the differential diagnosis of patients with acute respiratory symptoms after exposure to irritants and with asthma-like symptoms that fail to respond to conventional asthma therapy.

Brain natriuretic peptide and right heart dysfunction after heart transplantation.

PubMed

Talha, Samy; Charloux, Anne; Piquard, François; Geny, Bernard

2017-06-01

Heart transplantation (HT) should normalize cardiac endocrine function, but brain natriuretic peptide (BNP) levels remain elevated after HT, even in the absence of left ventricular hemodynamic disturbance or allograft rejection. Right ventricle (RV) abnormalities are common in HT recipients (HTx), as a result of engraftment process, tricuspid insufficiency, and/or repeated inflammation due to iterative endomyocardial biopsies. RV function follow-up is vital for patient management as RV dysfunction is a recognized cause of in-hospital death and is responsible for a worse prognosis. Interestingly, few and controversial data are available concerning the relationship between plasma BNP levels and RV functional impairment in HTx. This suggests that infra-clinical modifications, such as subtle immune system disorders or hypoxic conditions, might influence BNP expression. Nevertheless, due to other altered circulating molecular forms of BNP, a lack of specificity of BNP assays is described in heart failure patients. This phenomenon could exist in HT population and could explain elevated BNP plasmatic levels despite a normal RV function. In clinical practice, intra-individual change in BNP over time, rather than absolute BNP values, might be more helpful in detecting right cardiac dysfunction in HTx. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Identifying the brain regions associated with acute spasticity in patients diagnosed with an ischemic stroke.

PubMed

Barlow, Susan J

2016-06-01

Spasticity is a common impairment found in patients that have been diagnosed with a stroke. Little is known about the pathophysiology of spasticity at the level of the brain. This retrospective study was performed to identify an association between the area of the brain affected by an ischemic stroke and the presence of acute spasticity. Physical and occupational therapy assessments from all patients (n = 441) that had suffered a stroke and were admitted into a local hospital over a 4-year period were screened for inclusion in this study. Subjects that fit the inclusion criteria were grouped according to the presence (n = 42) or absence (n = 129) of acute spasticity by the Modified Ashworth Scale score given during the hospital admission assessment. Magnetic resonance images from 20 subjects in the spasticity group and 52 from the control group were then compared using lesion density plots and voxel-based lesion-symptom mapping. An association of acute spasticity with the gray matter regions of the insula, basal ganglia, and thalamus was found in this study. White matter tracts including the pontine crossing tract, corticospinal tract, internal capsule, corona radiata, external capsule, and the superior fronto-occipital fasciculus were also found to be significantly associated with acute spasticity. This is the first study to describe an association between a region of the brain affected by an infarct and the presence of acute spasticity. Understanding the regions associated with acute spasticity will aid in understanding the pathophysiology of this musculoskeletal impairment at the level of the brain.

Change in Brain Magnetic Resonance Spectroscopy after Treatment during Acute HIV Infection

PubMed Central

Sailasuta, Napapon; Ross, William; Ananworanich, Jintanat; Chalermchai, Thep; DeGruttola, Victor; Lerdlum, Sukalaya; Pothisri, Mantana; Busovaca, Edgar; Ratto-Kim, Silvia; Jagodzinski, Linda; Spudich, Serena; Michael, Nelson; Kim, Jerome H.; Valcour, Victor

2012-01-01

Objective Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART). Methods Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART. Results After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months. Interpretation We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury. PMID:23229129

Do acute phase markers explain body temperature and brain temperature after ischemic stroke?

PubMed Central

Whiteley, William N.; Thomas, Ralph; Lowe, Gordon; Rumley, Ann; Karaszewski, Bartosz; Armitage, Paul; Marshall, Ian; Lymer, Katherine; Dennis, Martin

2012-01-01

Objective: Both brain and body temperature rise after stroke but the cause of each is uncertain. We investigated the relationship between circulating markers of inflammation with brain and body temperature after stroke. Methods: We recruited patients with acute ischemic stroke and measured brain temperature at hospital admission and 5 days after stroke with multivoxel magnetic resonance spectroscopic imaging in normal brain and the acute ischemic lesion (defined by diffusion-weighted imaging [DWI]). We measured body temperature with digital aural thermometers 4-hourly and drew blood daily to measure interleukin-6, C-reactive protein, and fibrinogen, for 5 days after stroke. Results: In 44 stroke patients, the mean temperature in DWI-ischemic brain soon after admission was 38.4°C (95% confidence interval [CI] 38.2–38.6), in DWI-normal brain was 37.7°C (95% CI 37.6–37.7), and mean body temperature was 36.6°C (95% CI 36.3–37.0). Higher mean levels of interleukin-6, C-reactive protein, and fibrinogen were associated with higher temperature in DWI-normal brain at admission and 5 days, and higher overall mean body temperature, but only with higher temperature in DWI-ischemic brain on admission. Conclusions: Systemic inflammation after stroke is associated with elevated temperature in normal brain and the body but not with later ischemic brain temperature. Elevated brain temperature is a potential mechanism for the poorer outcome observed in stroke patients with higher levels of circulating inflammatory markers. PMID:22744672

[Obsessive-compulsive disorder, a new model of basal ganglia dysfunction? Elements from deep brain stimulation studies].

PubMed

Haynes, W I A; Millet, B; Mallet, L

2012-01-01

Deep brain stimulation was first developed for movement disorders but is now being offered as a therapeutic alternative in severe psychiatric disorders after the failure of conventional therapies. One of such pathologies is obsessive-compulsive disorder. This disorder which associates intrusive thoughts (obsessions) and repetitive irrepressible rituals (compulsions) is characterized by a dysfunction of a cortico-subcortical loop. After having reviewed the pathophysiological evidence to show why deep brain stimulation was an interesting path to take for severe and resistant cases of obsessive-compulsive disorder, we will present the results of the different clinical trials. Finally, we will provide possible mechanisms for the effects of deep brain stimulation in this pathology. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

[Levels of unified metabolites and thyroid hormones in blood and oral fluid of children with minimal brain dysfunction].

PubMed

Gil'miiarova, F N; Pervova, Iu V; Radomskaia, V M; Gergel', N I; Tarasova, S V

2004-01-01

Minimal brain dysfunctions in children with various perinatal complications are accompanied by metabolic imbalance manifested by decreased total protein content, the tendency to reduced triglycerides, increased cholesterol concentrations in the oral fluid, the trend to hypoproteinaemia, hypoglycaemia, hypotriglyceridaemia. The most significant changes in the redox systems alpha-ketoglutarate-glutamate, oxaloacetate-malate, pyruvate-lactate, dioxyacetone phosphate-alpha-glycerophosphate in biological fluids were revealed in cases of antenatal alcoholisation. A certain correlation was found between anemia in pregnant women and hypothyroidal background in children. In addition, a high level of free and total thyroxine, that of total triiodthyronine were found in the oral fluid. Hypophysis--thyroid dysregulation in children with minimal brain dysfunction associated with gestosis in their mothers during pregnancy, was manifested by decreased content of total and free T4 and T3 in blood serum and increased level of the thyroid-stimulating hormone.

CT Perfusion in Acute Stroke: "Black Holes" on Time-to-Peak Image Maps Indicate Unsalvageable Brain.

PubMed

Meagher, Ruairi; Shankar, Jai Jai Shiva

2016-11-01

CT perfusion is becoming important in acute stroke imaging to determine optimal patient-management strategies. The purpose of this study was to examine the predictive value of time-to-peak image maps and, specifically, a phenomenon coined a "black hole" for assessing infarcted brain tissue at the time of scan. Acute stroke patients were screened for the presence of black holes and their follow-up imaging (noncontrast CT or MR) was reviewed to assess for infarcted brain tissue. Of the 23 patients with signs of acute ischemia on CT perfusion, all had black holes. The black holes corresponded with areas of infarcted brain on follow-up imaging (specificity 100%). Black holes demonstrated significantly lower cerebral blood volumes (P < .001) and cerebral blood flow (P < .001) compared to immediately adjacent tissue. Black holes on time-to-peak image maps represent areas of unsalvageable brain. Copyright © 2016 by the American Society of Neuroimaging.

Remote Traumatic Brain Injury Is Associated with Motor Dysfunction in Older Military Veterans.

PubMed

Gardner, Raquel C; Peltz, Carrie B; Kenney, Kimbra; Covinsky, Kenneth E; Diaz-Arrastia, Ramon; Yaffe, Kristine

2017-09-01

Traumatic brain injury (TBI) has been identified as a risk factor for Parkinson's disease (PD). Motor dysfunction among TBI-exposed elders without PD has not been well characterized. We sought to determine whether remote TBI is a risk factor for motor dysfunction on exam and functionally relevant motor dysfunction in day-to-day life among independently living elders without PD. This is a cross-sectional cohort study of independently living retired military veterans aged 50 or older with (n = 78) and without (n = 85) prior TBI-all without diagnosed PD. To characterize multidimensional aspects of motor function on exam, the Unified Parkinson's Disease Rating Scale (UPDRS) Motor Examination was performed by a board-certified neurologist and used to calculate a modified UPDRS (mUPDRS) global motor score and four domain scores (tremor, rigidity, bradykinesia, and posture/gait). Functionally relevant motor dysfunction was assessed via self-report of falls within the past year. In analyses adjusted for demographics and comorbidities that differed between groups, compared with veterans without TBI, those with moderate-to-severe TBI were more likely to have fallen in past year (33% vs. 14%, risk ratio 2.5 [95% confidence interval 1.1-5.4]), had higher (worse) mUPDRS global motor (p = .03) and posture/gait scores (p = .02), but not higher tremor (p = .70), rigidity (p = .21), or bradykinesia scores (p = .22). Mild TBI was not associated with worse motor function. Remote moderate-to-severe TBI is a risk factor for motor dysfunction-defined as recent falls and impaired posture/gait-among older veterans. TBI-exposed older adults may be ideal candidates for aggressive fall-screening and prevention strategies. © The Author 2017. 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.

Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis.

PubMed

Weiss, Nicolas; Rosselli, Matteo; Mouri, Sarah; Galanaud, Damien; Puybasset, Louis; Agarwal, Banwari; Thabut, Dominique; Jalan, Rajiv

2017-04-01

Although hepatic encephalopathy (HE) on the background of acute on chronic liver failure (ACLF) is associated with high mortality rates, it is unknown whether this is due to increased blood-brain barrier permeability. Specific gravity of cerebrospinal fluid measured by CT is able to estimate blood-cerebrospinal fluid-barrier permeability. This study aimed to assess cerebrospinal fluid specific gravity in acutely decompensated cirrhosis and to compare it in patients with or without ACLF and with or without hepatic encephalopathy. We identified all the patients admitted for acute decompensation of cirrhosis who underwent a brain CT-scan. Those patients could present acute decompensation with or without ACLF. The presence of hepatic encephalopathy was noted. They were compared to a group of stable cirrhotic patients and healthy controls. Quantitative brain CT analysis used the Brainview software that gives the weight, the volume and the specific gravity of each determined brain regions. Results are given as median and interquartile ranges and as relative variation compared to the control/baseline group. 36 patients presented an acute decompensation of cirrhosis. Among them, 25 presented with ACLF and 11 without ACLF; 20 presented with hepatic encephalopathy grade ≥ 2. They were compared to 31 stable cirrhosis patients and 61 healthy controls. Cirrhotic patients had increased cerebrospinal fluid specific gravity (CSF-SG) compared to healthy controls (+0.4 %, p < 0.0001). Cirrhotic patients with ACLF have decreased CSF-SG as compared to cirrhotic patients without ACLF (-0.2 %, p = 0.0030) that remained higher than in healthy controls. The presence of hepatic encephalopathy did not modify CSF-SG (-0.09 %, p = 0.1757). Specific gravity did not differ between different brain regions according to the presence or absence of either ACLF or HE. In patients with acute decompensation of cirrhosis, and those with ACLF, CSF specific gravity is modified compared to

[Expression of aquaporin-4 during brain edema in rats with thioacetamide-induced acute encephalopathy].

PubMed

Wang, Li-Qing; Zhu, Sheng-Mei; Zhou, Heng-Jun; Pan, Cai-Fei

2011-09-27

To investigate the expression of aquaporin-4 (AQP4) during brain edema in rats with thioacetamide-induced acute liver failure and encephalopathy. The rat model of acute hepatic failure and encephalopathy was induced by intraperitoneal injection of thioacetamide (TAA) at a 24-hour interval for 2 consecutive days. Thirty-two SD rats were randomly divided into the model group (n = 24) and the control group (normal saline, n = 8). And then the model group was further divided into 3 subgroups by the timepoint of decapitation: 24 h (n = 8), 48 h (n = 8) and 60 h (n = 8). Then we observed their clinical symptoms and stages of HE, indices of liver function and ammonia, liver histology and brain water content. The expression of AQP4 protein in brain tissues was measured with Western blot and the expression of AQP4mRNA with RT-PCR (reverse transcription-polymerase chain reaction). Typical clinical manifestations of hepatic encephalopathy occurred in all TAA-administrated rats. The model rats showed the higher indices of ALT (alanine aminotransferase), AST (aspartate aminotransferase), TBIL (total bilirubin) and ammonia than the control rats (P < 0.05). The brain water content was significantly elevated in TAA-administrated rats compared with the control (P < 0.05). The expressions of AQP4 protein and mRNA in brain tissues significantly increased in TAA-administrated rats (P < 0.05). In addition, the expressions of AQP4 protein and mRNA were positively correlated with brain water content (r = 0.536, P < 0.01; r = 0.566, P = 0.01). The high expression of AQP4 in rats with TAA-induced acute liver failure and encephalopathy plays a significant role during brain edema. AQP4 is one of the molecular mechanisms for the occurrence of brain edema in hepatic encephalopathy.

Brain networks during free viewing of complex erotic movie: new insights on psychogenic erectile dysfunction.

PubMed

Cera, Nicoletta; Di Pierro, Ezio Domenico; Ferretti, Antonio; Tartaro, Armando; Romani, Gian Luca; Perrucci, Mauro Gianni

2014-01-01

Psychogenic erectile dysfunction (ED) is defined as a male sexual dysfunction characterized by a persistent or recurrent inability to attain adequate penile erection due predominantly or exclusively to psychological or interpersonal factors. Previous fMRI studies were based on the common occurrence in the male sexual behaviour represented by the sexual arousal and penile erection related to viewing of erotic movies. However, there is no experimental evidence of altered brain networks in psychogenic ED patients (EDp). Some studies showed that fMRI activity collected during non sexual movie viewing can be analyzed in a reliable manner with independent component analysis (ICA) and that the resulting brain networks are consistent with previous resting state neuroimaging studies. In the present study, we investigated the modification of the brain networks in EDp compared to healthy controls (HC), using whole-brain fMRI during free viewing of an erotic video clip. Sixteen EDp and nineteen HC were recruited after RigiScan evaluation, psychiatric, and general medical evaluations. The performed ICA showed that visual network (VN), default-mode network (DMN), fronto-parietal network (FPN) and salience network (SN) were spatially consistent across EDp and HC. However, between-group differences in functional connectivity were observed in the DMN and in the SN. In the DMN, EDp showed decreased connectivity values in the inferior parietal lobes, posterior cingulate cortex and medial prefrontal cortex, whereas in the SN decreased and increased connectivity was observed in the right insula and in the anterior cingulate cortex respectively. The decreased levels of intrinsic functional connectivity principally involved the subsystem of DMN relevant for the self relevant mental simulation that concerns remembering of past experiences, thinking to the future and conceiving the viewpoint of the other's actions. Moreover, the between group differences in the SN nodes suggested a

Brain Networks during Free Viewing of Complex Erotic Movie: New Insights on Psychogenic Erectile Dysfunction

PubMed Central

Cera, Nicoletta; Di Pierro, Ezio Domenico; Ferretti, Antonio; Tartaro, Armando; Romani, Gian Luca; Perrucci, Mauro Gianni

2014-01-01

Psychogenic erectile dysfunction (ED) is defined as a male sexual dysfunction characterized by a persistent or recurrent inability to attain adequate penile erection due predominantly or exclusively to psychological or interpersonal factors. Previous fMRI studies were based on the common occurrence in the male sexual behaviour represented by the sexual arousal and penile erection related to viewing of erotic movies. However, there is no experimental evidence of altered brain networks in psychogenic ED patients (EDp). Some studies showed that fMRI activity collected during non sexual movie viewing can be analyzed in a reliable manner with independent component analysis (ICA) and that the resulting brain networks are consistent with previous resting state neuroimaging studies. In the present study, we investigated the modification of the brain networks in EDp compared to healthy controls (HC), using whole-brain fMRI during free viewing of an erotic video clip. Sixteen EDp and nineteen HC were recruited after RigiScan evaluation, psychiatric, and general medical evaluations. The performed ICA showed that visual network (VN), default-mode network (DMN), fronto-parietal network (FPN) and salience network (SN) were spatially consistent across EDp and HC. However, between-group differences in functional connectivity were observed in the DMN and in the SN. In the DMN, EDp showed decreased connectivity values in the inferior parietal lobes, posterior cingulate cortex and medial prefrontal cortex, whereas in the SN decreased and increased connectivity was observed in the right insula and in the anterior cingulate cortex respectively. The decreased levels of intrinsic functional connectivity principally involved the subsystem of DMN relevant for the self relevant mental simulation that concerns remembering of past experiences, thinking to the future and conceiving the viewpoint of the other’s actions. Moreover, the between group differences in the SN nodes suggested a

Mobile Phone Application for Supporting Persons with Higher Brain Dysfunctions

NASA Astrophysics Data System (ADS)

Nakayama, Tsuyoshi; Miyaji, Yuka; Kato, Seishi; Sakurada, Nobuhisa; Ueda, Noriyuki; Nomura, Takayuki; Okaya, Kazunori; Uematsu, Hiroshi; Kimura, Eiji

This paper shows a mobile phone application for supporting persons with higher brain dysfunction (HBD) such as a cognitive disorder, a memory disorder, and an attention-deficit disorder. This application serves them as a schedule manager, an alarm and an instructor of work sequences. The development concept of this application is easy handling and simple display, because persons with HBD are easily bewildered by complex procedures in the work. Five persons with HBD participated in the experiments for assessing the application at the vocational training place. The use of the application resulted in the drastic decrease of the number of errors and the increase of the System Usability Score, indicating that the developed application is useful for persons with HBD especially in performing vocational training tasks such as the use of database software on PC.

Acute restraint stress induces endothelial dysfunction: role of vasoconstrictor prostanoids and oxidative stress.

PubMed

Carda, Ana P P; Marchi, Katia C; Rizzi, Elen; Mecawi, André S; Antunes-Rodrigues, José; Padovan, Claudia M; Tirapelli, Carlos R

2015-01-01

We hypothesized that acute stress would induce endothelial dysfunction. Male Wistar rats were restrained for 2 h within wire mesh. Functional and biochemical analyses were conducted 24 h after the 2-h period of restraint. Stressed rats showed decreased exploration on the open arms of an elevated-plus maze (EPM) and increased plasma corticosterone concentration. Acute restraint stress did not alter systolic blood pressure, whereas it increased the in vitro contractile response to phenylephrine and serotonin in endothelium-intact rat aortas. NG-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase, NOS, inhibitor) did not alter the contraction induced by phenylephrine in aortic rings from stressed rats. Tiron, indomethacin and SQ29548 reversed the increase in the contractile response to phenylephrine induced by restraint stress. Increased systemic and vascular oxidative stress was evident in stressed rats. Restraint stress decreased plasma and vascular nitrate/nitrite (NOx) concentration and increased aortic expression of inducible (i) NOS, but not endothelial (e) NOS. Reduced expression of cyclooxygenase (COX)-1, but not COX-2, was observed in aortas from stressed rats. Restraint stress increased thromboxane (TX)B(2) (stable TXA(2) metabolite) concentration but did not affect prostaglandin (PG)F2α concentration in the aorta. Restraint reduced superoxide dismutase (SOD) activity, whereas concentrations of hydrogen peroxide (H(2)O(2)) and reduced glutathione (GSH) were not affected. The major new finding of our study is that restraint stress increases vascular contraction by an endothelium-dependent mechanism that involves increased oxidative stress and the generation of COX-derived vasoconstrictor prostanoids. Such stress-induced endothelial dysfunction could predispose to the development of cardiovascular diseases.

Nerve growth factor metabolic dysfunction in Down’s syndrome brains

PubMed Central

Iulita, M. Florencia; Do Carmo, Sonia; Ower, Alison K.; Fortress, Ashley M.; Aguilar, Lisi Flores; Hanna, Michael; Wisniewski, Thomas; Granholm, Ann-Charlotte; Buhusi, Mona; Busciglio, Jorge

2014-01-01

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer’s disease and Down’s syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer’s disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF’s extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down’s syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down’s syndrome and age-matched controls (age range 31–68 years). We further examined primary cultures of human foetal Down’s syndrome cortex (17–21 gestational age weeks) and brains from Ts65Dn mice (12–22 months), a widely used animal model of Down’s syndrome. We report a significant increase in proNGF levels in human and mouse Down’s syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down’s syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down’s syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic

Impact of mild traumatic brain injury on auditory brain stem dysfunction in mouse model.

PubMed

Amanipour, Reza M; Frisina, Robert D; Cresoe, Samantha A; Parsons, Teresa J; Xiaoxia Zhu; Borlongan, Cesario V; Walton, Joseph P

2016-08-01

The auditory brainstem response (ABR) is an electrophysiological test that examines the functionality of the auditory nerve and brainstem. Traumatic brain injury (TBI) can be detected if prolonged peak latency is observed in ABR measurements, since latency measures the neural conduction time in the brainstem, and an increase in latency can be a sign of pathological lesion at the auditory brainstem level. The ABR is elicited by brief sounds that can be used to measure hearing sensitivity as well as temporal processing. Reduction in peak amplitudes and increases in latency are indicative of dysfunction in the auditory nerve and/or central auditory pathways. In this study we used sixteen young adult mice that were divided into two groups: sham and mild traumatic brain injury (mTBI), with ABR measurements obtained prior to, and at 2, 6, and 14 weeks after injury. Abnormal ABRs were observed for the nine TBI cases as early as two weeks after injury and the deficits lasted for fourteen weeks after injury. Results indicated a significant reduction in the Peak 1 (P1) and Peak 4 (P4) amplitudes to the first noise burst, as well as an increase in latency response for P1 and P4 following mTBI. These results are the first to demonstrate auditory sound processing deficits in a rodent model of mild TBI.

Cerebral Metabolism and the Role of Glucose Control in Acute Traumatic Brain Injury.

PubMed

Buitrago Blanco, Manuel M; Prashant, Giyarpuram N; Vespa, Paul M

2016-10-01

This article reviews key concepts of cerebral glucose metabolism, neurologic outcomes in clinical trials, the biology of the neurovascular unit and its involvement in secondary brain injury after traumatic brain insults, and current scientific and clinical data that demonstrate a better understanding of the biology of metabolic dysfunction in the brain, a concept now known as cerebral metabolic energy crisis. The use of neuromonitoring techniques to better understand the pathophysiology of the metabolic crisis is reviewed and a model that summarizes the triphasic view of cerebral metabolic disturbance supported by existing scientific data is outlined. The evidence is summarized and a template for future research provided. Copyright © 2016 Elsevier Inc. All rights reserved.

Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis.

PubMed

Markwardt, Daniel; Holdt, Lesca; Steib, Christian; Benesic, Andreas; Bendtsen, Flemming; Bernardi, Mauro; Moreau, Richard; Teupser, Daniel; Wendon, Julia; Nevens, Frederik; Trebicka, Jonel; Garcia, Elisabet; Pavesi, Marco; Arroyo, Vicente; Gerbes, Alexander L

2017-10-01

The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241). © 2017 by the American Association for the Study of Liver Diseases.

Plasma copeptin level predicts acute traumatic coagulopathy and progressive hemorrhagic injury after traumatic brain injury.

PubMed

Yang, Ding-Bo; Yu, Wen-Hua; Dong, Xiao-Qiao; Du, Quan; Shen, Yong-Feng; Zhang, Zu-Yong; Zhu, Qiang; Che, Zhi-Hao; Liu, Qun-Jie; Wang, Hao; Jiang, Li; Du, Yuan-Feng

2014-08-01

Higher plasma copeptin levels correlate with poor clinical outcomes after traumatic brain injury. Nevertheless, their links with acute traumatic coagulopathy and progressive hemorrhagic injury are unknown. Therefore, we aimed to investigate the relationship between plasma copeptin levels, acute traumatic coagulopathy and progressive hemorrhagic injury in patients with severe traumatic brain injury. We prospectively studied 100 consecutive patients presenting within 6h from head trauma. Progressive hemorrhagic injury was present when the follow-up computerized tomography scan reported any increase in size or number of the hemorrhagic lesion, including newly developed ones. Acute traumatic coagulopathy was defined as an activated partial thromboplastic time greater than 40s and/or international normalized ratio greater than 1.2 and/or a platelet count less than 120×10(9)/L. We measured plasma copeptin levels on admission using an enzyme-linked immunosorbent assay in a blinded fashion. In multivariate logistic regression analysis, plasma copeptin level emerged as an independent predictor of progressive hemorrhagic injury and acute traumatic coagulopathy. Using receiver operating characteristic curves, we calculated areas under the curve for progressive hemorrhagic injury and acute traumatic coagulopathy. The predictive performance of copeptin was similar to that of Glasgow Coma Scale score. However, copeptin did not obviously improve the predictive value of Glasgow Coma Scale score. Thus, copeptin may help in the prediction of progressive hemorrhagic injury and acute traumatic coagulopathy after traumatic brain injury. Copyright © 2014 Elsevier Inc. All rights reserved.

Altered brain function in new onset childhood acute lymphoblastic leukemia before chemotherapy: A resting-state fMRI study.

PubMed

Hu, Zhanqi; Zou, Dongfang; Mai, Huirong; Yuan, Xiuli; Wang, Lihong; Li, Yue; Liao, Jianxiang; Liu, Liwei; Liu, Guosheng; Zeng, Hongwu; Wen, Feiqiu

2017-10-01

Cognitive impairments had been reported in childhood acute lymphoblastic leukemia, what caused the impairments needed to be demonstrated, chemotherapy-related or the disease itself. The primary aim of this exploratory investigation was to determine if there were changes in brain function of children with acute lymphoblastic leukemia before chemotherapy. In this study, we advanced a measure named regional homogeneity to evaluate the resting-state brain activities, intelligence quotient test was performed at same time. Using regional homogeneity, we first investigated the resting state brain function in patients with new onset childhood acute lymphoblastic leukemia before chemotherapy, healthy children as control. The decreased ReHo values were mainly founded in the default mode network and left frontal lobe, bilateral inferior parietal lobule, bilateral temporal lobe, bilateral occipital lobe, precentral gyrus, bilateral cerebellum in the newly diagnosed acute lymphoblastic leukemia patients compared with the healthy control. While in contrast, increased ReHo values were mainly shown in the right frontal lobe (language area), superior frontal gyrus-R, middle frontal gyrus-R and inferior parietal lobule-R for acute lymphoblastic leukemia patients group. There were no significant differences for intelligence quotient measurements between the acute lymphoblastic leukemia patient group and the healthy control in performance intelligence quotient, verbal intelligence quotient, total intelligence quotient. The altered brain functions are associated with cognitive change and language, it is suggested that there may be cognition impairment before the chemotherapy. Regional homogeneity by functional magnetic resonance image is a sensitive way for early detection on brain damage in childhood acute lymphoblastic leukemia. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

The differential effects of acute right- vs. left-sided vestibular failure on brain metabolism.

PubMed

Becker-Bense, Sandra; Dieterich, Marianne; Buchholz, Hans-Georg; Bartenstein, Peter; Schreckenberger, Mathias; Brandt, Thomas

2014-07-01

The human vestibular system is represented in the brain bilaterally, but it has functional asymmetries, i.e., a dominance of ipsilateral pathways and of the right hemisphere in right-handers. To determine if acute right- or left-sided unilateral vestibular neuritis (VN) is associated with differential patterns of brain metabolism in areas representing the vestibular network and the visual-vestibular interaction, patients with acute VN (right n = 9; left n = 13) underwent resting state (18)F-FDG PET once in the acute phase and once 3 months later after central vestibular compensation. The contrast acute vs. chronic phase showed signal differences in contralateral vestibular areas and the inverse contrast in visual cortex areas, both more pronounced in VN right. In VN left additional regions were found in the cerebellar hemispheres and vermis bilaterally, accentuated in severe cases. In general, signal changes appeared more pronounced in patients with more severe vestibular deficits. Acute phase PET data of patients compared to that of age-matched healthy controls disclosed similarities to these patterns, thus permitting the interpretation that the signal changes in vestibular temporo-parietal areas reflect signal increases, and in visual areas, signal decreases. These data imply that brain activity in the acute phase of right- and left-sided VN exhibits different compensatory patterns, i.e., the dominant ascending input is shifted from the ipsilateral to the contralateral pathways, presumably due to the missing ipsilateral vestibular input. The visual-vestibular interaction patterns were preserved, but were of different prominence in each hemisphere and more pronounced in patients with right-sided failure and more severe vestibular deficits.

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

PubMed Central

2013-01-01

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches. PMID:24289502

Establishment of a canine model of acute pulmonary embolism with definite right ventricular dysfunction through introduced autologous blood clots.

PubMed

Zhao, Lin-Bo; Jia, Zhen-Yu; Lu, Guang-Dong; Zhu, Yin-Su; Jing, Lei; Shi, Hai-Bin

2015-04-01

To establish a canine model of acute pulmonary embolism (PE) with right ventricular (RV) dysfunction using autologous blood clots and evaluate by echocardiography and contrast-enhanced Computed Tomography (CT). Autologous blood clots formed in vitro were introduced sequentially into the pulmonary arteries of eight healthy mixed-breed dogs while monitoring pulmonary and systemic hemodynamic function. Blood clots were injected until the mean pulmonary artery pressure (MPAP) reached two-three times the baseline pressure, which was maintained up to 1 hour. The RV function was assessed by echocardiography and ECG-gated dual-source contrast CT. All animals survived the imaging procedure. The post-injection pulmonary angiograms showed extensive PE, and MPAP increased from 16.50±2.45 mmHg to 43.13±4.91 mmHg (P<0.001). On echocardiography, the RV fractional area change decreased from 42.06±3.36 to 27.96±3.54 (P<0.001), and the RV myocardial performance increased from 0.20±0.05 to 0.63±0.16 (P<0.001). On CT, the RV end-systolic volume increased from 11.11±1.81 ml to 24.71±4.60 ml (P<0.001), RV end-diastolic volume from 20.73±2.83 ml to 34.63±5.76 ml (P<0.001), and the four-chamber RV/left ventricular diameter ratio from 0.38±0.07 to 0.81±0.14 (P<0.001). Acute PE with RV dysfunction was established in a large animal model through controlled injection of autologous blood clots, which may be useful for developing and evaluating new therapeutic approaches for acute PE with RV dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

PubMed Central

Bleau, Christian; Filliol, Aveline; Samson, Michel

2015-01-01

ABSTRACT Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-β) production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCE Coronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells.

PubMed

Bleau, Christian; Filliol, Aveline; Samson, Michel; Lamontagne, Lucie

2015-10-01

Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-β) production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. Coronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain

Urocortin Treatment Improves Acute Hemodynamic Instability and Reduces Myocardial Damage in Post-Cardiac Arrest Myocardial Dysfunction

PubMed Central

Huang, Chien-Hua; Wang, Chih-Hung; Tsai, Min-Shan; Hsu, Nai-Tan; Chiang, Chih-Yen; Wang, Tzung-Dau; Chang, Wei-Tien; Chen, Huei-Wen; Chen, Wen-Jone

2016-01-01

Aims Hemodynamic instability occurs following cardiac arrest and is associated with high mortality during the post-cardiac period. Urocortin is a novel peptide and a member of the corticotrophin-releasing factor family. Urocortin has the potential to improve acute cardiac dysfunction, as well as to reduce the myocardial damage sustained after ischemia reperfusion injury. The effects of urocortin in post-cardiac arrest myocardial dysfunction remain unclear. Methods and Results We developed a preclinical cardiac arrest model and investigated the effects of urocortin. After cardiac arrest induced by 6.5 min asphyxia, male Wistar rats were resuscitated and randomized to either the urocortin treatment group or the control group. Urocortin (10 μg/kg) was administrated intravenously upon onset of resuscitation in the experimental group. The rate of return of spontaneous circulation (ROSC) was similar between the urocortin group (76%) and the control group (72%) after resuscitation. The left ventricular systolic (dP/dt40) and diastolic (maximal negative dP/dt) functions, and cardiac output, were ameliorated within 4 h after ROSC in the urocortin-treated group compared to the control group (P<0.01). The neurological function of surviving animals was better at 6 h after ROSC in the urocortin-treated group (p = 0.023). The 72-h survival rate was greater in the urocortin-treated group compared to the control group (p = 0.044 by log-rank test). Cardiomyocyte apoptosis was lower in the urocortin-treated group (39.9±8.6 vs. 17.5±4.6% of TUNEL positive nuclei, P<0.05) with significantly increased Akt, ERK and STAT-3 activation and phosphorylation in the myocardium (P<0.05). Conclusions Urocortin treatment can improve acute hemodynamic instability as well as reducing myocardial damage in post-cardiac arrest myocardial dysfunction. PMID:27832152

Mitochondrial dysfunction in brain cortex mitochondria of STZ-diabetic rats: effect of l-Arginine.

PubMed

Ortiz, M Del Carmen; Lores-Arnaiz, Silvia; Albertoni Borghese, M Florencia; Balonga, Sabrina; Lavagna, Agustina; Filipuzzi, Ana Laura; Cicerchia, Daniela; Majowicz, Monica; Bustamante, Juanita

2013-12-01

Mitochondrial dysfunction has been implicated in many diseases, including diabetes. It is well known that oxygen free radical species are produced endogenously by mitochondria, and also nitric oxide (NO) by nitric oxide synthases (NOS) associated to mitochondrial membranes, in consequence these organelles constitute main targets for oxidative damage. The aim of this study was to analyze mitochondrial physiology and NO production in brain cortex mitochondria of streptozotocin (STZ) diabetic rats in an early stage of diabetes and the potential effect of L-arginine administration. The diabetic condition was characterized by a clear hyperglycaemic state with loose of body weight after 4 days of STZ injection. This hyperglycaemic state was associated with mitochondrial dysfunction that was evident by an impairment of the respiratory activity, increased production of superoxide anion and a clear mitochondrial depolarization. In addition, the alteration in mitochondrial physiology was associated with a significant decrease in both NO production and nitric oxide synthase type I (NOS I) expression associated to the mitochondrial membranes. An increased level of thiobarbituric acid-reactive substances (TBARS) in brain cortex homogenates from STZ-diabetic rats indicated the presence of lipid peroxidation. L-arginine treatment to diabetic rats did not change blood glucose levels but significantly ameliorated the oxidative stress evidenced by lower TBARS and a lower level of superoxide anion. This effect was paralleled by improvement of mitochondrial respiratory function and a partial mitochondrial repolarization.In addition, the administration of L-arginine to diabetic rats prevented the decrease in NO production and NOSI expression. These results could indicate that exogenously administered L-arginine may have beneficial effects on mitochondrial function, oxidative stress and NO production in brain cortex mitochondria of STZ-diabetic rats.

Heat stroke induced cerebellar dysfunction: A “forgotten syndrome”

PubMed Central

Kosgallana, Athula D; Mallik, Shreyashee; Patel, Vishal; Beran, Roy G

2013-01-01

We report a case of heat stroke induced acute cerebellar dysfunction, a rare neurological disease characterized by gross cerebellar dysfunction with no acute radiographic changes, in a 61 years old ship captain presenting with slurred speech and gait ataxia. A systematic review of the literature on heat stroke induced cerebellar dysfunction was performed, with a focus on investigations, treatment and outcomes. After review of the literature and detailed patient investigation it was concluded that this patient suffered heat stroke at a temperature less than that quoted in the literature. PMID:24340279

Acute and non-acute effects of cannabis on brain functioning and neuropsychological performance.

PubMed

Gonzalez, Raul

2007-09-01

Cannabis has an ancient history of human use and is currently one of the most commonly used drugs worldwide. Understanding its impact on neurobehavioral functioning is of significant public health concern. In recent decades, substantial progress has been made in understanding the impact of cannabis use on neurobehavioral functioning. This has been fueled, in part, by characterization of an endocannabinoid signaling system in the brain through which cannabis exerts its psychoactive effects. Acute intoxication with cannabis causes marked changes in subjective mental status, brain functioning, and neuropsychological performance. Some of these changes are consistently detected and well characterized, yet others are not. Changes in brain functioning and neuropsychological performance are also reported after abstinence, but appear to be mild, circumscribed, and transient. On the other hand, functional neuroimaging often reveals subtle differences in the brain functioning of abstinent cannabis users compared with controls. The persistence and clinical significance of these differences, however, remains to be determined. Neuropsychological deficits and differences in brain functioning are most consistently observed only among frequent, heavy users, who are those most likely addicted to cannabis. The dire impact of drug addiction on a person's life and everyday functioning suggests that the large number of individuals addicted to cannabis experience substantial negative effects from its use. This manuscript reviews the scientific literature on the aforementioned topics in detail, providing evidence for converging findings, and highlighting areas in need of further investigation.

A novel application of the fluorescent dye bis-ANS for labeling neurons in acute brain slices.

PubMed

Mozes, Emese; Hunya, Akos; Toth, Aniko; Ayaydin, Ferhan; Penke, Botond; Datki, Zsolt L

2011-10-10

The cell-impermeant oligomer-(e.g. beta-amyloid-, or tubulin-) specific fluorescent dye, bis-ANS (4,4'-bis-1-anilinonaphtalene-8-sulfonate), was successfully used for labeling mechanically damaged but still viable neuron bodies, neurites and neurite cross sections in acute brain slices. Acute hippocampal brain slices of rats were co-stained with bis-ANS and the cell-impermeant, DNA-specific dye propidium iodide (PI) and were then analyzed using fluorescence and confocal microscopes. Both the neuron bodies and the neurites were found to exhibit increased fluorescence intensities, suggesting that using this method they can be detected more easily. In addition, bis-ANS showed good region - but not cell specific co-localization with the neuron-specific fluorescent dye Dil (1,1'-Dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). These two dyes label different neuronal structures: Dil binds specifically to intact cell membranes while bis-ANS can enter cells with compromised cell membranes and then stain the microtubules in the cytoplasm. For a quick (10min) staining of acute brain slices with bis-ANS both HEPES and NaHCO(3) were needed in order to achieve high signal intensity. Labeling with bis-ANS fluorescent dye is an easy method for imaging the neuronal structures on the surface of acute brain slices. Copyright © 2011 Elsevier Inc. All rights reserved.

Pathophysiology of hypopituitarism in the setting of brain injury

PubMed Central

Dusick, Joshua R.; Wang, Christina; Cohan, Pejman; Swerdloff, Ronald

2014-01-01

The complex pathophysiology of traumatic brain injury (TBI) involves not only the primary mechanical event but also secondary insults such as hypotension, hypoxia, raised intracranial pressure and changes in cerebral blood flow and metabolism. It is increasingly evident that these initial insults as well as transient events and treatments during the early injury phase can impact hypothalamic-pituitary function both acutely and chronically after injury. In turn, untreated pituitary hormonal dysfunction itself can further hinder recovery from brain injury. Secondary adrenal insufficiency, although typically reversible, occurs in up to 50% of intubated TBI victims and is associated with lower systemic blood pressure. PMID:18481181

Online problem-solving therapy for executive dysfunction after child traumatic brain injury.

PubMed

Kurowski, Brad G; Wade, Shari L; Kirkwood, Michael W; Brown, Tanya M; Stancin, Terry; Taylor, H Gerry

2013-07-01

Executive dysfunction after traumatic brain injury (TBI) in children is common and leads to significant problems in functioning across multiple settings. The objective of this study was to evaluate the efficacy of a web-based counselor-assisted problem solving (CAPS) intervention compared with an Internet resource comparison (IRC) for treatment of executive dysfunction within 12 months after complicated mild to severe TBI in adolescents. We hypothesized that CAPS would significantly improve parent ratings of executive dysfunction compared with an IRC. Participants included 132 adolescents aged 12 to 17 years who sustained a complicated mild to severe TBI within 1 to 6 months before study enrollment. Study design was a multisite, assessor-blinded, randomized controlled trial. Study sites included 3 tertiary pediatric hospitals and 2 tertiary general medical centers. The main outcome measure was primary caregiver Behavioral Rating Inventory of Executive Function Global Executive Composite at baseline and 6-month follow-up. Generalized linear models that controlled for baseline scores were used to compare the CAPS and IRC scores. In older teens, the CAPS group showed significant improvement in executive function behaviors at 6-month follow-up compared with the IRC group (F = 6.74, P = .01, Cohen's d = 0.63). Findings indicate that web-based CAPS improves primary caregiver-rated executive functioning within the first 12 months after TBI in older adolescents. Future research needs to define the optimal timing after injury for delivery of CAPS and characteristics of individuals and families who are most likely to benefit from CAPS.

A neurovascular perspective for long-term changes after brain trauma.

PubMed

Pop, V; Badaut, J

2011-12-01

Traumatic brain injury (TBI) affects all age groups in a population and is an injury generating scientific interest not only as an acute event, but also as a complex brain disease with several underlying neurobehavioral and neuropathological characteristics. We review early and long-term alterations after juvenile and adult TBI with a focus on changes in the neurovascular unit (NVU), including neuronal interactions with glia and blood vessels at the blood-brain barrier (BBB). Post-traumatic changes in cerebral blood-flow, BBB structures and function, as well as mechanistic pathways associated with brain aging and neurodegeneration are presented from clinical and experimental reports. Based on the literature, increased attention on BBB changes should be integrated in studies characterizing TBI outcome and may provide a meaningful therapeutic target to resolve detrimental post-traumatic dysfunction.

Acute and Chronic Altitude-Induced Cognitive Dysfunction in Children and Adolescents.

PubMed

Rimoldi, Stefano F; Rexhaj, Emrush; Duplain, Hervé; Urben, Sébastien; Billieux, Joël; Allemann, Yves; Romero, Catherine; Ayaviri, Alejandro; Salinas, Carlos; Villena, Mercedes; Scherrer, Urs; Sartori, Claudio

2016-02-01

To assess whether exposure to high altitude induces cognitive dysfunction in young healthy European children and adolescents during acute, short-term exposure to an altitude of 3450 m and in an age-matched European population permanently living at this altitude. We tested executive function (inhibition, shifting, and working memory), memory (verbal, short-term visuospatial, and verbal episodic memory), and speed processing ability in: (1) 48 healthy nonacclimatized European children and adolescents, 24 hours after arrival at high altitude and 3 months after return to low altitude; (2) 21 matched European subjects permanently living at high altitude; and (3) a matched control group tested twice at low altitude. Short-term hypoxia significantly impaired all but 2 (visuospatial memory and processing speed) of the neuropsychological abilities that were tested. These impairments were even more severe in the children permanently living at high altitude. Three months after return to low altitude, the neuropsychological performances significantly improved and were comparable with those observed in the control group tested only at low altitude. Acute short-term exposure to an altitude at which major tourist destinations are located induces marked executive and memory deficits in healthy children. These deficits are equally marked or more severe in children permanently living at high altitude and are expected to impair their learning abilities. Copyright © 2016 Elsevier Inc. All rights reserved.

[Possibilities of magnetic-laser therapy in comprehensive treatment of patients with brain concussion in acute period].

PubMed

Zubkova, O V; Samosiuk, I Z; Polishchuk, O V; Shul'ga, N M; Samosiuk, N I

2012-01-01

The efficacy of magnetic-laser therapy used according to the method developed by us was studied in patients having the brain concussion (BC) in an acute period. The study was based on the dynamics of values of the evoked vestibular potentials and the disease clinical course. It was shown that following the magnetic-laser therapy in combination with traditional pharmacotherapy in BC acute period, the statistically significant positive changes were registered in the quantitative characteristics of the evoked vestibular brain potentials that correlated with the dynamics of the disease clinical course. The data obtained substantiate the possibility of using the magnetic-laser therapy in patients with a mild craniocereblal injury in an acute period.

Fractal Dimension of EEG Activity Senses Neuronal Impairment in Acute Stroke

PubMed Central

Zappasodi, Filippo; Olejarczyk, Elzbieta; Marzetti, Laura; Assenza, Giovanni; Pizzella, Vittorio; Tecchio, Franca

2014-01-01

The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal) properties. Under the hypothesis that the fractal dimension (FD) of the electroencephalographic signal (EEG) is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD’s ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4–10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss) was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy) and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105) and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures’ activities in stroke recovery. PMID:24967904

Fractal dimension of EEG activity senses neuronal impairment in acute stroke.

PubMed

Zappasodi, Filippo; Olejarczyk, Elzbieta; Marzetti, Laura; Assenza, Giovanni; Pizzella, Vittorio; Tecchio, Franca

2014-01-01

The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal) properties. Under the hypothesis that the fractal dimension (FD) of the electroencephalographic signal (EEG) is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD's ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4-10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss) was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy) and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105) and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures' activities in stroke recovery.

Practice patterns, outcomes, and end-organ dysfunction for patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension (STAT) registry.

PubMed

Katz, Jason N; Gore, Joel M; Amin, Alpesh; Anderson, Frederick A; Dasta, Joseph F; Ferguson, James J; Kleinschmidt, Kurt; Mayer, Stephan A; Multz, Alan S; Peacock, W Frank; Peterson, Eric; Pollack, Charles; Sung, Gene Yong; Shorr, Andrew; Varon, Joseph; Wyman, Allison; Emery, Leigh A; Granger, Christopher B

2009-10-01

Limited data are available on the care of patients with acute severe hypertension requiring hospitalization. We characterized contemporary practice patterns and outcomes for this population. STAT is a 25-institution, US registry of consecutive patients with acute severe hypertension (>180 mm Hg systolic and/or >110 mm Hg diastolic; >140 and/or >90 for subarachnoid hemorrhage) treated with intravenous therapy in a critical care setting. One thousand five hundred eighty-eight patients were enrolled (January 2007 to April 2008). Median age was 58 years (interquartile range 49-70 years), 779 (49%) were women, and 892 (56%) were African American; 27% (n = 425) had a prior admission for acute hypertension and 486 (31%) had chronic kidney disease. Median qualifying blood pressure (BP) was 200 (186, 220) systolic and 110 (93, 123) mm Hg diastolic. Initial intravenous antihypertensive therapies used to control BP varied, with 1,009 (64%) patients requiring multiple drugs. Median time to achieve a systolic BP <160 mm Hg (<140 mm Hg for subarachnoid hemorrhage) was 4.0 (0.8, 12) hours; 893 (60%) had reelevation to >180 (>140 for subarachnoid hemorrhage) after initial control; and 63 (4.0%) developed iatrogenic hypotension. Hospital mortality was 6.9% (n = 109) with an aggregate 90-day mortality rate of 11% (174/1,588); 59% (n = 943) had acute/worsening end-organ dysfunction during hospitalization. The 90-day readmission rate was 37% (523/1,415), of which one quarter (132/523) was due to recurrent acute severe hypertension. This study highlights heterogeneity in care, BP control, and outcomes of patients hospitalized with acute severe hypertension.

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury.

PubMed

Piro, Justin R; Suidan, Georgette L; Quan, Jie; Pi, YeQing; O'Neill, Sharon M; Ilardi, Marissa; Pozdnyakov, Nikolay; Lanz, Thomas A; Xi, Hualin; Bell, Robert D; Samad, Tarek A

2018-05-14

Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential. Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2. Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the

Acute and Chronic Effects of Ethanol on Learning-Related Synaptic Plasticity

PubMed Central

Zorumski, Charles F.; Mennerick, Steven; Izumi, Yukitoshi

2014-01-01

Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol’s acute and long-term pharmacological consequences. PMID:24447472

Individual responses to methylphenidate and caffeine in children with minimal brain dysfunction.

PubMed Central

Garfinkel, B. D.; Webster, C. D.; Sloman, L.

1975-01-01

Eight children with minimal brain dysfunction were studied for their individual responses to two stimulant medications--methylphenidate hydrochloride and caffeine citrate. Four types of behavioural responses were observed in the double-blind crossover experiment: four children responded favourably to both psychostimulants, one responded to methylphenidate alone and two responded to the placebo. The behaviour of one child deteriorated while he was taking methylphenidate and caffeine. In general, methylphenidate was superior to caffeine in diminishing hyperactive and aggressive behaviour. It is apparent that such stimulant medication exerts its therapeutic effects in these two areas primarily and would therefore be useful as one aspect of a complete treatment program for children with this syndrome. PMID:803184

IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure.

PubMed

Bémeur, Chantal; Qu, Hong; Desjardins, Paul; Butterworth, Roger F

2010-01-01

Previous reports suggested that brain-derived proinflammatory cytokines are involved in the pathogenesis of hepatic encephalopathy (HE) and brain edema in acute liver failure (ALF). To further address this issue, expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were measured in the brains of mice with acute liver failure resulting from exposure to azoxymethane. In addition, time to severe encephalopathy (coma) was assessed in mice lacking genes coding for interferon-gamma, the tumor necrosis factor receptor-1 or the interleukin-1 type 1 receptor. Interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma expression were quantified using RT-PCR. Significant increases in interleukin-1beta and tumor necrosis factor-alpha mRNA were observed in the frontal cortex of azoxymethane-treated wild-type mice at coma stages of encephalopathy. Interferon-gamma, however, could not be detected in the brains of these animals. Onset of severe encephalopathy (coma) and brain edema in ALF mice were significantly delayed in interleukin-1 type 1 receptor or tumor necrosis factor receptor-1 knockout mice. Deletion of the interferon-gamma gene, on the other hand, had no significative effect on the neurological status or brain water content of acute liver failure mice. These results demonstrate that toxic liver injury resulting from exposure to azoxymethane is associated with selective induction of proinflammatory cytokines in the brain and that deletion of tumor necrosis factor receptor-1 or interlukin-1 type 1 receptor delays the onset of coma and brain edema in this model of acute liver failure. These findings further support a role for selective brain-derived cytokines in the pathogenesis of the cerebral complications in acute liver failure and suggest that anti-inflammatory strategies could be beneficial in their prevention. Copyright 2009 Elsevier Ltd. All rights reserved.

Biomarkers in Acute Heart Failure – Cardiac And Kidney

PubMed Central

2015-01-01

Natriuretic peptides (NP) are well-validated aids in the diagnosis of acute decompensated heart failure (ADHF). In acute presentations, both brain natriuretic peptide (BNP) and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) offer high sensitivity (>90 %) and negative predictive values (>95 %) for ruling out ADHF at thresholds of 100 and 300 pg/ml, respectively. Plasma NP rise with age. For added rule-in performance age-adjusted thresholds (450 pg/ml for under 50 years, 900 pg/ml for 50–75 years and 1,800 pg/ml for those >75 years) can be applied to NT-proBNP results. Test performance (specificity and accuracy but not sensitivity) is clearly reduced by renal dysfunction and atrial fibrillation. Obesity offsets the threshold downwards (to ~50 pg/ml for BNP), but overall discrimination is preserved. Reliable markers for impending acute kidney injury in ADHF constitute an unmet need, with candidates, such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, failing to perform sufficiently well, and new possibilities, including the cell cycle markers insulin growth factor binding protein 7 and tissue inhibitor of metalloproteinases type 2, remain the subject of research. PMID:28785442

The brain is a target organ after acute exposure to depleted uranium.

PubMed

Lestaevel, P; Houpert, P; Bussy, C; Dhieux, B; Gourmelon, P; Paquet, F

2005-09-01

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144+/-10 microg DU kg-1 as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6 microg of DU g-1 of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70+/-8 microg DU kg-1), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed.

Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude.

PubMed

Zhu, Hai-tao; Bian, Chen; Yuan, Ji-chao; Liao, Xiao-jun; Liu, Wei; Zhu, Gang; Feng, Hua; Lin, Jiang-kai

2015-06-15

Intracerebral hemorrhage (ICH) at high altitude is not well understood to date. This study investigates the effects of high altitude on ICH, and examines the acute neuroprotection of hyperbaric oxygen (HBO) therapy against high-altitude ICH. Minipigs were placed in a hypobaric chamber for 72 h before the operation. ICH was induced by an infusion of autologous arterial blood (3 ml) into the right basal ganglia. Animals in the high-altitude ICH group received HBO therapy (2.5 ATA for 60 min) 30 min after ICH. Blood gas, blood glucose and brain tissue oxygen partial pressure (PbtO2) were monitored continuously for animals from all groups, as were microdialysis products including glucose, lactate, pyruvate and glutamate in perihematomal tissue from 3 to 12 h post-ICH. High-altitude ICH animals showed significantly lower PbtO2, higher lactate/pyruvate ratio (LPR) and glutamate levels than low-altitude ICH animals. More severe neurological deficits, brain edema and neuronal damage were also observed in high-altitude ICH. After HBO therapy, PbtO2 was significantly increased and LPR and glutamate levels were significantly decreased. Brain edema, neurological deficits and neuronal damage were also ameliorated. The data suggested a more serious disturbance of tissue oxygenation and cerebral metabolism in the acute stage after ICH at high altitude. Early HBO treatment reduced acute brain injury, perhaps through a mechanism involving the amelioration of the derangement of cerebral oxygenation and metabolism following high-altitude ICH.

Acute Frontal Lobe Dysfunction Following Prefrontal Low-Frequency Repetitive Transcranial Magnetic Stimulation in a Patient with Treatment-Resistant Depression

PubMed Central

Carle, Guilhem; Touat, Mehdi; Bruno, Nicolas; Galanaud, Damien; Peretti, Charles-Siegfried; Valero-Cabré, Antoni; Levy, Richard; Azuar, Carole

2017-01-01

The potential of repetitive transcranial magnetic stimulation (rTMS) to treat numerous neurological and psychiatric disorders has been thoroughly studied for the last two decades. Here, we report for the first time, the case of a 65-year-old woman suffering from treatment-resistant depression who developed an acute frontal lobe syndrome following eight sessions of low-frequency rTMS (LF-rTMS) to the right dorsolateral prefrontal cortex while also treated with sertraline and mianserin. The pathophysiological mechanisms underlying such an unexpected acute frontal lobe dysfunction are discussed in relation to the therapeutic use of LF-rTMS in combination with pharmacotherapy in depressed patients. PMID:28611694

Predictors of acute and persisting ischemic brain lesions in patients randomized to carotid stenting or endarterectomy.

PubMed

Rostamzadeh, Ayda; Zumbrunn, Thomas; Jongen, Lisa M; Nederkoorn, Paul J; Macdonald, Sumaira; Lyrer, Philippe A; Kappelle, L Jaap; Mali, Willem P Th M; Brown, Martin M; van der Worp, H Bart; Engelter, Stefan T; Bonati, Leo H

2014-02-01

We investigated predictors for acute and persisting periprocedural ischemic brain lesions among patients with symptomatic carotid stenosis randomized to stenting or endarterectomy in the International Carotid Stenting Study. We assessed acute lesions on diffusion-weighted imaging 1 to 3 days after treatment in 124 stenting and 107 endarterectomy patients and lesions persisting on fluid-attenuated inversion recovery after 1 month in 86 and 75 patients, respectively. Stenting patients had more acute (relative risk, 8.8; 95% confidence interval, 4.4-17.5; P<0.001) and persisting lesions (relative risk, 4.2; 95% confidence interval, 1.6-11.1; P=0.005) than endarterectomy patients. Acute lesion count was associated with age (by trend), male sex, and stroke as the qualifying event in stenting; high systolic blood pressure in endarterectomy; and white matter disease in both groups. The rate of conversion from acute to persisting lesions was lower in the stenting group (relative risk, 0.4; 95% confidence interval, 0.2-0.8; P=0.007), and was only predicted by acute lesion volume. Stenting caused more acute and persisting ischemic brain lesions than endarterectomy. However, the rate of conversion from acute to persisting lesions was lower in the stenting group, most likely attributable to lower acute lesion volumes. Clinical Trial Registration -URL: www.isrctn.org. Unique identifier: ISRCTN25337470.

Traumatic Brain Injury: At the Crossroads of Neuropathology and Common Metabolic Endocrinopathies

PubMed Central

Li, Melanie

2018-01-01

Building on the seminal work by Geoffrey Harris in the 1970s, the neuroendocrinology field, having undergone spectacular growth, has endeavored to understand the mechanisms of hormonal connectivity between the brain and the rest of the body. Given the fundamental role of the brain in the orchestration of endocrine processes through interactions among neurohormones, it is thus not surprising that the structural and/or functional alterations following traumatic brain injury (TBI) can lead to endocrine changes affecting the whole organism. Taking into account that systemic hormones also act on the brain, modifying its structure and biochemistry, and can acutely and chronically affect several neurophysiological endpoints, the question is to what extent preexisting endocrine dysfunction may set the stage for an adverse outcome after TBI. In this review, we provide an overview of some aspects of three common metabolic endocrinopathies, e.g., diabetes mellitus, obesity, and thyroid dysfunction, and how these could be triggered by TBI. In addition, we discuss how the complex endocrine networks are woven into the responses to sudden changes after TBI, as well as some of the potential mechanisms that, separately or synergistically, can influence outcomes after TBI. PMID:29538298

Cognitive activity limitations one year post-trauma in patients admitted to sub-acute rehabilitation after severe traumatic brain injury.

PubMed

Sommer, Jens Bak; Norup, Anne; Poulsen, Ingrid; Morgensen, Jesper

2013-09-01

To examine cognitive activity limitations and predictors of outcome 1 year post-trauma in patients admitted to sub-acute rehabilitation after severe traumatic brain injury. The study included 119 patients with severe traumatic brain injury admitted to centralized sub-acute rehabilitation in the Eastern part of Denmark during a 5-year period from 2005 to 2009. Level of consciousness was assessed consecutively during rehabilitation and at 1 year post-trauma. Severity of traumatic brain injury was classified according to duration of post-traumatic amnesia. The cognitive subscale of Functional Independence MeasureTM (Cog-FIM) was used to assess cognitive activity limitations. Multivariate logistic regression analyses were performed to identify predictors of an independent level of functioning. The majority of patients progressed to a post-confusional level of consciousness during the first year post-trauma. At follow-up 33-58% of patients had achieved functional independence within the cognitive domains on the Cog-FIM. Socio-economic status, duration of acute care and post-traumatic amnesia were significant predictors of outcome. Substantial recovery was documented among patients with severe traumatic brain injury during the first year post-trauma. The results of the current study suggest that absence of consciousness at discharge from acute care should not preclude patients from being referred to specialized sub-acute rehabilitation.

Acute allograft failure in thoracic organ transplantation.

PubMed

Jahania, M S; Mullett, T W; Sanchez, J A; Narayan, P; Lasley, R D; Mentzer, R M

2000-01-01

Thoracic organ transplantation is an effective form of treatment for end-stage heart and lung disease. Despite major advances in the field, transplant patients remain at risk for acute allograft dysfunction, a major cause of early and late mortality. The most common causes of allograft failure include primary graft failure secondary to inadequate heart and lung preservation during cold storage, cellular rejection, and various donor-recipient-related factors. During cold storage and early reperfusion, heart and lung allografts are vulnerable to intracellular calcium overload, acidosis, cell swelling, injury mediated by reactive oxygen species, and the inflammatory response. Brain death itself is associated with a reduction in myocardial contractility, and recipient-related factors such as preexisting pulmonary hypertension can lead to acute right heart failure and the pulmonary reimplantation response. The development of new methods to prevent or treat these various causes of acute graft failure could lead to a marked improvement in short- and long-term survival of patients undergoing thoracic organ transplantation.

Inclusion and definition of acute renal dysfunction in critically ill patients in randomized controlled trials: a systematic review.

PubMed

da Hora Passos, Rogerio; Ramos, Joao Gabriel Rosa; Gobatto, André; Caldas, Juliana; Macedo, Etienne; Batista, Paulo Benigno

2018-04-24

In evidence-based medicine, multicenter, prospective, randomized controlled trials (RCTs) are the gold standard for evaluating treatment benefits and ensuring the effectiveness of interventions. Patient-centered outcomes, such as mortality, are most often the preferred evaluated outcomes. While there is currently agreement on how to classify renal dysfunction in critically ill patients , the application frequency of this new classification system in RCTs has not previously been evaluated. In this study, we aim to assess the definition of renal dysfunction in multicenter RCTs involving critically ill patients that included mortality as a primary endpoint. A comprehensive search was conducted for publications reporting multicenter randomized controlled trials (RCTs) involving adult patients in intensive care units (ICUs) that included mortality as a primary outcome. MEDLINE and PUBMED were queried for relevant articles in core clinical journals published between May 2004 and December 2017. Of 418 articles reviewed, 46 multicenter RCTs with a primary endpoint related to mortality were included. Thirty-six (78.3%) of the trial reports provided information on renal function in the participants. Only seven articles (15.2%) included mean or median serum creatinine levels, mean creatinine clearance or estimated glomerular filtration rates. Sequential organ failure assessment (SOFA) score was the most commonly used definition of renal dysfunction (20 studies; 43.5%). Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria were used in five (10.9%) trials. In thirteen trials (28.3%), no renal dysfunction criteria were reported. Only one trial excluded patients with renal dysfunction, and it used urinary output or need for renal replacement therapy (RRT) as criteria for this diagnosis. The presence of renal dysfunction was included as a baseline patient characteristic in

Psychological Characteristics in Acute Mild Traumatic Brain Injury: An MMPI-2 Study.

PubMed

Gass, Carlton S; Rogers, David; Kinne, Erica

2017-01-01

The psychological characteristics of acute traumatic brain injury (TBI) have received limited research focus, despite empirical evidence of their relevance for subsequent psychological adjustment and early therapeutic intervention. This study addressed a wide range of psychological features in 47 individuals who were hospitalized as a result of acute mild TBI (mTBI). Participants were screened from amongst consecutive TBI admissions for moderate to severe brain injury, and for pre-injury neurological, psychiatric, or substance abuse histories. Clinical and content scale scores on the MMPI-2 were explored in relation to patient gender, age, level of education, and extent of cognitive complaints. The results revealed diverse psychosocial problem areas across the sample, the most common of which were somatic and cognitive complaints, compromised insight, and a naively optimistic self-perception. The mediating roles of injury severity and demographic variables are discussed. Clinical implications and specific recommendations are presented.

Selective Cognitive Dysfunction Is Related to a Specific Pattern of Cerebral Damage in Persons With Severe Traumatic Brain Injury.

PubMed

Di Paola, Margherita; Phillips, Owen; Costa, Alberto; Ciurli, Paola; Bivona, Umberto; Catani, Sheila; Formisano, Rita; Caltagirone, Carlo; Carlesimo, Giovanni Augusto

2015-01-01

Cognitive dysfunction is a common sequela of traumatic brain injury (TBI); indeed, patients show a heterogeneous pattern of cognitive deficits. This study was aimed at investigating whether patients who show selective cognitive dysfunction after TBI present a selective pattern of cerebral damage. Post-Coma Unit, IRCCS Santa Lucia Foundation, Rome, Italy. We collected data from 8 TBI patients with episodic memory disorder and without executive deficits, 7 patients with executive function impairment and preserved episodic memory capacities, and 16 healthy controls. We used 2 complementary analyses: (1) an exploratory and qualitative approach in which we investigated the distribution of lesions in the TBI groups, and (2) a hypothesis-driven and quantitative approach in which we calculated the volume of hippocampi of individuals in the TBI and control groups. Neuropsychological scores and hippocampal volumes. We found that patients with TBI and executive functions impairment presented focal lesions involving the frontal lobes, whereas patients with TBI and episodic memory disorders showed atrophic changes of the mesial temporal structure (hippocampus). The complexity of TBI is due to several heterogeneous factors. Indeed, studying patients with TBI and selective cognitive dysfunction should lead to a better understanding of correlations with specific brain impairment and damage, better follow-up of long-term outcome scenarios, and better planning of selective and focused rehabilitation programs.

Cognitive benefit and cost of acute stress is differentially modulated by individual brain state.

PubMed

Kohn, Nils; Hermans, Erno J; Fernández, Guillén

2017-07-01

Acute stress is associated with beneficial as well as detrimental effects on cognition in different individuals. However, it is not yet known how stress can have such opposing effects. Stroop-like tasks typically show this dissociation: stress diminishes speed, but improves accuracy. We investigated accuracy and speed during a stroop-like task of 120 healthy male subjects after an experimental stress induction or control condition in a randomized, counter-balanced cross-over design; we assessed brain-behavior associations and determined the influence of individual brain connectivity patterns on these associations, which may moderate the effect and help identify stress resilience factors. In the mean, stress was associated to increase in accuracy, but decrease in speed. Accuracy was associated to brain activation in a distributed set of brain regions overlapping with the executive control network (ECN) and speed to temporo-parietal activation. In line with a stress-related large-scale network reconfiguration, individuals showing an upregulation of the salience and down-regulation of the executive-control network under stress displayed increased speed, but decreased performance. In contrast, individuals who upregulate their ECN under stress show improved performance. Our results indicate that the individual large-scale brain network balance under acute stress moderates cognitive consequences of threat. © The Author (2017). Published by Oxford University Press.

Deletion of aquaporin-4 is neuroprotective during the acute stage of micro traumatic brain injury in mice.

PubMed

Liang, Fengyin; Luo, Chuanming; Xu, Guangqing; Su, Fengjuan; He, Xiaofei; Long, Simei; Ren, Huixia; Liu, Yaning; Feng, Yanqing; Pei, Zhong

2015-06-26

Micro traumatic brain injury (TBI) is the most common type of brain injury, but the mechanisms underlying it are poorly understood. Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet, which plays an important role in brain edema. However, little is known about the role of AQP4 in micro TBI. Here, we examined the role of AQP4 in the pathogenesis of micro TBI in a closed-skull brain injury model, using two-photon microscopy. Our results indicate that AQP4 deletion reduced cell death, water content, astrocyte swelling and lesion volume during the acute stage of micro TBI. Our data revealed that astrocyte swelling is a decisive pathophysiological factor in the acute phase of this form of micro brain injury. Thus, treatments that inhibit AQP4 could be used as a neuroprotective strategy for micro TBI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice.

PubMed

Jia, Tingting; Sun, Zhiguo; Lu, Ying; Gao, Jie; Zou, Hao; Xie, Fangyuan; Zhang, Guoqing; Xu, Hao; Sun, Duxin; Yu, Yuan; Zhong, Yanqiang

2016-01-01

Due to the impermeability of the blood-brain barrier and the nonselective distribution of drugs in the brain, the therapeutic access to intractable neurological disorders is challenging. In this study, dual brain-targeting polymersomes (POs) functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) promoted the transportation of curcumin into the brain and provided neuroprotection. The modification of the ligands that bind to the surface of POs was revealed by X-ray photoelectron spectroscopy analysis. The cell uptake of a coculture model of mouse brain capillary endothelial cells with neurons showed that the Tf/Tet-1-POs had significant transportation properties and possessed affinity for neurons. The pharmacokinetic analysis showed that the blood-brain barrier permeability-surface efficiency of the Tf/Tet-1-POs was 0.28 mL/h/g and that the brain tissue uptake rate (% ID/g) was 0.08, which were significant compared with the controls (P<0.05). The curcumin-encapsulated Tf/Tet-1-POs provided neuroprotection and ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice. These results suggest that the dual brain-targeting POs are more capable of drug delivery to the brain that can be exploited as a multiple noninvasive vehicle for targeting therapeutics.

Dysfunctional Attitudes Scale Perfectionism: A Predictor and Partial Mediator of Acute Treatment Outcome among Clinically Depressed Adolescents

PubMed Central

Jacobs, Rachel H.; Silva, Susan G.; Reinecke, Mark A.; Curry, John F.; Ginsburg, Golda S.; Kratochvil, Christopher J.; March, John S.

2009-01-01

The effect of perfectionism on acute treatment outcomes was explored in a randomized controlled trial of 439 clinically depressed adolescents (12–17 years of age) enrolled in the Treatment for Adolescents with Depression Study (TADS) who received cognitive behavior therapy (CBT), fluoxetine, a combination of CBT and FLX, or pill placebo. Measures included the Children’s Depression Rating Scale–Revised, the Suicidal Ideation Questionnaire–Grades 7–9, and the perfectionism subscale from the Dysfunctional Attitudes Scale (DAS). Predictor results indicate that adolescents with higher versus lower DAS perfectionism scores at baseline, regardless of treatment, continued to demonstrate elevated depression scores across the acute treatment period. In the case of suicidality, DAS perfectionism impeded improvement. Treatment outcomes were partially mediated by the change in DAS perfectionism across the 12-week period. PMID:20183664

Sleep-Disordered Breathing in Acute Ischemic Stroke: A Mechanistic Link to Peripheral Endothelial Dysfunction.

PubMed

Scherbakov, Nadja; Sandek, Anja; Ebner, Nicole; Valentova, Miroslava; Nave, Alexander Heinrich; Jankowska, Ewa A; Schefold, Jörg C; von Haehling, Stephan; Anker, Stefan D; Fietze, Ingo; Fiebach, Jochen B; Haeusler, Karl Georg; Doehner, Wolfram

2017-09-11

Sleep-disordered breathing (SDB) after acute ischemic stroke is frequent and may be linked to stroke-induced autonomic imbalance. In the present study, the interaction between SDB and peripheral endothelial dysfunction (ED) was investigated in patients with acute ischemic stroke and at 1-year follow-up. SDB was assessed by transthoracic impedance records in 101 patients with acute ischemic stroke (mean age, 69 years; 61% men; median National Institutes of Health Stroke Scale, 4) while being on the stroke unit. SDB was defined by apnea-hypopnea index ≥5 episodes per hour. Peripheral endothelial function was assessed using peripheral arterial tonometry (EndoPAT-2000). ED was defined by reactive hyperemia index ≤1.8. Forty-one stroke patients underwent 1-year follow-up (390±24 days) after stroke. SDB was observed in 57% patients with acute ischemic stroke. Compared with patients without SDB, ED was more prevalent in patients with SDB (32% versus 64%; P <0.01). After adjustment for multiple confounders, presence of SDB remained independently associated with ED (odds ratio, 3.1; [95% confidence interval, 1.2-7.9]; P <0.05). After 1 year, the prevalence of SDB decreased from 59% to 15% ( P <0.001). Interestingly, peripheral endothelial function improved in stroke patients with normalized SDB, compared with patients with persisting SDB ( P <0.05). SDB was present in more than half of all patients with acute ischemic stroke and was independently associated with peripheral ED. Normalized ED in patients with normalized breathing pattern 1 year after stroke suggests a mechanistic link between SDB and ED. URL: https://drks-neu.uniklinik-freiburg.de. Unique identifier: DRKS00000514. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

PubMed Central

Bales, James W.; Wagner, Amy K.; Kline, Anthony E.; Dixon, C. Edward

2010-01-01

Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study. PMID:19580914

Effects of statin therapy on clinical outcomes after acute myocardial infarction in patients with advanced renal dysfunction: A propensity score-matched analysis.

PubMed

Kim, Jin Sug; Kim, Weon; Park, Ji Yoon; Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyun; Moon, Ju-Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

2017-01-01

Lipid lowering therapy is widely used for the prevention of cardiovascular complications after acute myocardial infarction (AMI). However, some studies show that this benefit is uncertain in patients with renal dysfunction, and the role of statins is based on the severity of renal dysfunction. In this study, we investigated the impact of statin therapy on major adverse cardiac events (MACEs) and all-cause mortality in patients with advanced renal dysfunction undergoing percutaneous coronary intervention (PCI) after AMI. This study was based on the Korea Acute Myocardial Infarction Registry database. We included 861 patients with advanced renal dysfunction from among 33,205 patients who underwent PCI after AMI between November 2005 and July 2012. Patients were divided into two groups: a statin group (n = 537) and a no-statin group (n = 324). We investigated the 12-month MACEs (cardiac death, myocardial infarction, repeated PCI or coronary artery bypass grafting) and all-cause mortality of each group. Subsequently, a propensity score-matched analysis was performed. In the total population studied, no significant differences were observed between the two groups with respect to the rate of recurrent MI, repeated PCI, coronary artery bypass grafting (CABG), or all-cause mortality. However, the cardiac death rate was significantly lower in the statin group (p = 0.009). Propensity score-matched analysis yielded 274 pairs demonstrating, results similar to those obtained from the total population. However, there was no significant difference in the cardiac death rate in the propensity score-matched population (p = 0.103). Cox-regression analysis revealed only left ventricular ejection fraction to be an independent predictor of 12-month MACEs (Hazard ratio [HR] of 0.979, 95% confidence interval [CI], 0962-0.996, p = 0.018). Statin therapy was not significantly associated with a reduction in the 12-month MACEs or all-cause mortality in patients with advanced renal dysfunction

How Acute Total Sleep Loss Affects the Attending Brain: A Meta-Analysis of Neuroimaging Studies

PubMed Central

Ma, Ning; Dinges, David F.; Basner, Mathias; Rao, Hengyi

2015-01-01

Study Objectives: Attention is a cognitive domain that can be severely affected by sleep deprivation. Previous neuroimaging studies have used different attention paradigms and reported both increased and reduced brain activation after sleep deprivation. However, due to large variability in sleep deprivation protocols, task paradigms, experimental designs, characteristics of subject populations, and imaging techniques, there is no consensus regarding the effects of sleep loss on the attending brain. The aim of this meta-analysis was to identify brain activations that are commonly altered by acute total sleep deprivation across different attention tasks. Design: Coordinate-based meta-analysis of neuroimaging studies of performance on attention tasks during experimental sleep deprivation. Methods: The current version of the activation likelihood estimation (ALE) approach was used for meta-analysis. The authors searched published articles and identified 11 sleep deprivation neuroimaging studies using different attention tasks with a total of 185 participants, equaling 81 foci for ALE analysis. Results: The meta-analysis revealed significantly reduced brain activation in multiple regions following sleep deprivation compared to rested wakefulness, including bilateral intraparietal sulcus, bilateral insula, right prefrontal cortex, medial frontal cortex, and right parahippocampal gyrus. Increased activation was found only in bilateral thalamus after sleep deprivation compared to rested wakefulness. Conclusion: Acute total sleep deprivation decreases brain activation in the fronto-parietal attention network (prefrontal cortex and intraparietal sulcus) and in the salience network (insula and medial frontal cortex). Increased thalamic activation after sleep deprivation may reflect a complex interaction between the de-arousing effects of sleep loss and the arousing effects of task performance on thalamic activity. Citation: Ma N, Dinges DF, Basner M, Rao H. How acute total

The impacts of acute carbon monoxide poisoning on the brain: Longitudinal clinical and 99mTc ethyl cysteinate brain SPECT characterization of patients with persistent and delayed neurological sequelae.

PubMed

Tsai, Chung-Fen; Yip, Ping-Keung; Chen, Shao-Yuan; Lin, Jen-Cheng; Yeh, Zai-Ting; Kung, Lan-Yu; Wang, Cheng-Yi; Fan, Yu-Ming

2014-04-01

Acute carbon monoxide (CO) poisoning poses a significant threat to the central nervous system. It can cause brain injury and diverse neurological deficits including persistent neurological sequelae (PNS) and delayed neurological sequelae (DNS). The study aimed to investigate the long-term impacts of acute CO poisoning on brain perfusion and neurological function, and to explore potential differences between PNS and DNS patients. We evaluated brain perfusion using (99m)Tc ethyl cysteinate (ECD) brain single photon emission computed tomography (SPECT) and assessed clinical neurological symptoms and signs one month following acute poisoning. For DNS patients, ECD SPECT and clinical evaluation were performed when their delayed symptoms appeared. All patients had follow-up SPECT imaging, along with clinical assessments six months following poisoning. 12 PNS and 12 DNS patients were recruited between 2007 and 2010. Clinically, the main characteristic presentations were cognitive decline, emotional instability, and gait disturbance. SPECT imaging demonstrated consistent frontal hypoperfusion of varying severities in all patients, which decreased in severity at follow-up imaging. DNS patients usually had more severe symptoms and perfusion defects, along with worse clinical outcomes than the PNS group. These results suggest that acute CO poisoning might lead to long term brain injuries and neurological sequelae, particularly in DNS patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Expression of Bcl-2 and NF-κB in brain tissue after acute renal ischemia-reperfusion in rats.

PubMed

Zhang, Na; Cheng, Gen-Yang; Liu, Xian-Zhi; Zhang, Feng-Jiang

2014-05-01

To investigate the effect of acute renal ischemia reperfusion on brain tissue. Fourty eight rats were randomly divided into four groups (n=12): sham operation group, 30 min ischemia 60 min reperfusion group, 60 min ischemia 60 min reperfusion group, and 120 min ischemia 60 min reperfusion group. The brain tissues were taken after the experiment. TUNEL assay was used to detect the brain cell apoptosis, and western blot was used to detect the expression of apoptosis-related proteins and inflammatory factors. Renal ischemia-reperfusion induced apoptosis of brain tissues, and the apoptosis increased with prolongation of ischemia time. The detection at the molecular level showed decreased Bcl-2 expression, increased Bax expression, upregulated expression of NF-κB and its downstream factor COX-2/PGE2. Acute renal ischemia-reperfusion can cause brain tissue damage, manifested as induced brain tissues apoptosis and inflammation activation. Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Clinical Correlates and Prognostic Significance of Lateralized Periodic Discharges in Patients Without Acute or Progressive Brain Injury: A Case-Control Study.

PubMed

Sainju, Rup K; Manganas, Louis N; Gilmore, Emily J; Petroff, Ognen A; Rampal, Nishi; Hirsch, Lawrence J; Gaspard, Nicolas

2015-12-01

Lateralized periodic discharges (LPDs, also known as periodic lateralized epileptiform discharges) in conjunction with acute brain injuries are known to be associated with worse prognosis but little is known about their importance in absence of such acute injuries. We studied the clinical correlates and outcome of patients with LPDs in the absence of acute or progressive brain injury. This is a case-control study of 74 patients with no acute brain injury undergoing continuous EEG monitoring, half with LPDs and half without, matched for age and etiology of remote brain injury, if any, or history of epilepsy. Lateralized periodic discharges were found in 145/1785 (8.1%) of subjects; 37/145 (26%) had no radiologic evidence of acute or progressive brain injury. Those with LPDs were more likely to have abnormal consciousness (86% vs. 57%; P = 0.005), seizures (70% vs. 24%; P = 0.0002), and functional decline (62% vs. 27%; P = 0.005), and were less likely to be discharged home (24% vs. 62%; P = 0.002). On multivariate analysis, LPDs and status epilepticus were associated with abnormal consciousness (P = 0.009; odds ratio = 5.2, 95% CI = 1.60-20.00 and P = 0.017; odds ratio = 5.0, 95% CI = 1.4-21.4); and LPDs were independently associated with functional decline (P = 0.001; odds ratio = 4.8, 95% CI = 1.6-15.4) and lower likelihood of being discharged home (P = 0.009; odds ratio = 0.2, 95% CI = 0.04-0.6). Despite absence of acute or progressive brain injury, LPDs were independently associated with abnormal consciousness and worse outcome at hospital discharge.

Apoptosis and Acute Brain Ischemia in Ischemic Stroke.

PubMed

Radak, Djordje; Katsiki, Niki; Resanovic, Ivana; Jovanovic, Aleksandra; Sudar-Milovanovic, Emina; Zafirovic, Sonja; Mousad, Shaker A; Isenovic, Esma R

2017-01-01

Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia (ABI), but the underlying mechanisms are still not fully understood. Brain ischemia may lead to stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra. The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core. ABI is characterized by key molecular events that initiate apoptosis in many cells, such as overproduction of free radicals, Ca2+ overload and excitotoxicity. These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Brainstem auditory-evoked potentials as an objective tool for evaluating hearing dysfunction in traumatic brain injury.

PubMed

Lew, Henry L; Lee, Eun Ha; Miyoshi, Yasushi; Chang, Douglas G; Date, Elaine S; Jerger, James F

2004-03-01

Because of the violent nature of traumatic brain injury, traumatic brain injury patients are susceptible to various types of trauma involving the auditory system. We report a case of a 55-yr-old man who presented with communication problems after traumatic brain injury. Initial results from behavioral audiometry and Weber/Rinne tests were not reliable because of poor cooperation. He was transferred to our service for inpatient rehabilitation, where review of the initial head computed tomographic scan showed only left temporal bone fracture. Brainstem auditory-evoked potential was then performed to evaluate his hearing function. The results showed bilateral absence of auditory-evoked responses, which strongly suggested bilateral deafness. This finding led to a follow-up computed tomographic scan, with focus on bilateral temporal bones. A subtle transverse fracture of the right temporal bone was then detected, in addition to the left temporal bone fracture previously identified. Like children with hearing impairment, traumatic brain injury patients may not be able to verbalize their auditory deficits in a timely manner. If hearing loss is suspected in a patient who is unable to participate in traditional behavioral audiometric testing, brainstem auditory-evoked potential may be an option for evaluating hearing dysfunction.

Lack of effect of moderate hypothermia on brain tissue oxygenation after acute intracranial hypertension in pigs.

PubMed

Bao, Ying-Hui; Liang, Yu-Min; Gao, Guo-Yi; Jiang, Ji-Yao

2010-02-01

In this study, we explored the effect of moderate hypothermia on brain tissue oxygenation following acute intracranial hypertension in micropigs. Twenty healthy juvenile micropigs weighting 4-6 kg were randomized into two groups: a normothermia group (n = 10) and a moderate hypothermia group (n = 10). The animals were intravenously anesthetized with propofol (4 mg/kg), an endotracheal tube was inserted, and mechanical ventilation was begun. Autologous arterial blood was injected into the left frontal lobe to establish acute intracerebral hematoma and intracranial hypertension (intracranial pressure [ICP] >40 mm Hg) in all animals. Cooling was initiated at 30 min after injection of the blood, and was achieved via the use of an ice bath and ice packs. In the hypothermia group, the brain temperature decreased to 33-34 degrees C. Brain temperature was maintained at 37 +/- 0.3 degrees C in the normothermia group. The ICP, cerebral perfusion pressure (CPP), brain tissue oxygen pressure (P(br)O(2)), brain tissue carbon dioxide pressure (P(br)CO(2)), and brain tissue pH value (pH(br)) were continuously monitored for 3 h in all animals. Compared to normothermia group, ICP values significantly decreased and CPP markedly improved in the hypothermia group (p < 0.05). Further, pH(br) also markedly increased and P(br)CO(2) decreased significantly in the hypothermia group (p < 0.05). However, P(br)O(2) did not statistically significantly improve in the hypothermia group (p > 0.05). In sum, moderate hypothermia significantly decreased ICP, reduced P(br)CO(2), and increased pH(br) values, but did not improve cerebral oxygenation following acute intracranial hypertension.

Fetal asphyxia induces acute and persisting changes in the ceramide metabolism in rat brain[S

PubMed Central

Vlassaks, Evi; Mencarelli, Chiara; Nikiforou, Maria; Strackx, Eveline; Ferraz, Maria J.; Aerts, Johannes M.; De Baets, Marc H.; Martinez-Martinez, Pilar; Gavilanes, Antonio W. D.

2013-01-01

Fetal asphyctic preconditioning, induced by a brief episode of experimental hypoxia-ischemia, offers neuroprotection to a subsequent more severe asphyctic insult at birth. Extensive cell stress and apoptosis are important contributing factors of damage in the asphyctic neonatal brain. Because ceramide acts as a second messenger for multiple apoptotic stimuli, including hypoxia/ischemia, we sought to investigate the possible involvement of the ceramide pathway in endogenous neuroprotection induced by fetal asphyctic preconditioning. Global fetal asphyxia was induced in rats by clamping both uterine and ovarian vasculature for 30 min. Fetal asphyxia resulted in acute changes in brain ceramide/sphingomyelin metabolic enzymes, ceramide synthase 1, 2, and 5, acid sphingomyelinase, sphingosine-1-phosphate phosphatase, and the ceramide transporter. This observation correlated with an increase in neuronal apoptosis and in astrocyte number. After birth, ceramide and sphingomyelin levels remained high in fetal asphyxia brains, suggesting that a long-term regulation of the ceramide pathway may be involved in the mechanism of tolerance to a subsequent, otherwise lethal, asphyctic event. PMID:23625371

Selection and visualisation of outcome measures for complex post-acute acquired brain injury rehabilitation interventions

PubMed Central

Ford, Catherine Elaine Longworth; Malley, Donna; Bateman, Andrew; Clare, Isabel C.H.; Wagner, Adam P.; Gracey, Fergus

2016-01-01

Background Outcome measurement challenges rehabilitation services to select tools that promote stakeholder engagement in measuring complex interventions. Objectives To examine the suitability of outcome measures for complex post-acute acquired brain injury (ABI) rehabilitation interventions, report outcomes of a holistic, neuropsychological ABI rehabilitation program and propose a simple way of visualizing complex outcomes. Methods Patient/carer reported outcome measures (PROMS), experience measures (PREMS) and staff-rated measures were collected for consecutive admissions over 1 year to an 18-week holistic, neuropsychological rehabilitation programme at baseline, 18 weeks and 3- and 6-month follow-up. Results Engagement with outcome measurement was poorest for carers and at follow-up for all stakeholders. Dependence, abilities, adjustment, unmet needs, symptomatology including executive dysfunction, and self-reassurance showed improvements at 18 weeks. Adjustment, social participation, perceived health, symptomatology including dysexecutive difficulties, and anxiety were worse at baseline for those who did not complete rehabilitation, than those who did. A radar plot facilitated outcome visualization. Conclusions Engagement with outcome measurement was best when time and support were provided. Supplementing patient- with staff-rated and attendance measures may explain missing data and help quantify healthcare needs. The MPAI4, EBIQ and DEX-R appeared suitable measures to evaluate outcomes and distinguish those completing and not completing neuropsychological rehabilitation. PMID:27341362

Traumatic brain injury and post-acute decline: what role does environmental enrichment play? A scoping review

PubMed Central

Frasca, Diana; Tomaszczyk, Jennifer; McFadyen, Bradford J.; Green, Robin E.

2013-01-01

Objectives: While a growing number of studies provide evidence of neural and cognitive decline in traumatic brain injury (TBI) survivors during the post-acute stages of injury, there is limited research as of yet on environmental factors that may influence this decline. The purposes of this paper, therefore, are to (1) examine evidence that environmental enrichment (EE) can influence long-term outcome following TBI, and (2) examine the nature of post-acute environments, whether they vary in degree of EE, and what impact these variations have on outcomes. Methods: We conducted a scoping review to identify studies on EE in animals and humans, and post-discharge experiences that relate to barriers to recovery. Results: One hundred and twenty-three articles that met inclusion criteria demonstrated the benefits of EE on brain and behavior in healthy and brain-injured animals and humans. Nineteen papers on post-discharge experiences revealed that variables such as insurance coverage, financial, and social support, home therapy, and transition from hospital to home, can have an impact on clinical outcomes. Conclusion: There is evidence to suggest that lack of EE, whether from lack of resources or limited ability to engage in such environments, may play a role in post-acute cognitive and neural decline. Maximizing EE in the post-acute stages of TBI may improve long-term outcomes for the individual, their family and society. PMID:23616755

Association of acute adverse effects with high local SAR induced in the brain from prolonged RF head and neck hyperthermia

NASA Astrophysics Data System (ADS)

Adibzadeh, F.; Verhaart, R. F.; Verduijn, G. M.; Fortunati, V.; Rijnen, Z.; Franckena, M.; van Rhoon, G. C.; Paulides, M. M.

2015-02-01

To provide an adequate level of protection for humans from exposure to radio-frequency (RF) electromagnetic fields (EMF) and to assure that any adverse health effects are avoided. The basic restrictions in terms of the specific energy absorption rate (SAR) were prescribed by IEEE and ICNIRP. An example of a therapeutic application of non-ionizing EMF is hyperthermia (HT), in which intense RF energy is focused at a target region. Deep HT in the head and neck (H&N) region involves inducing energy at 434 MHz for 60 min on target. Still, stray exposure of the brain is considerable, but to date only very limited side-effects were observed. The objective of this study is to investigate the stringency of the current basic restrictions by relating the induced EM dose in the brain of patients treated with deep head and neck (H&N) HT to the scored acute health effects. We performed a simulation study to calculate the induced peak 10 g spatial-averaged SAR (psSAR10g) in the brains of 16 selected H&N patients who received the highest SAR exposure in the brain, i.e. who had the minimum brain-target distance and received high forwarded power during treatment. The results show that the maximum induced SAR in the brain of the patients can exceed the current basic restrictions (IEEE and ICNIRP) on psSAR10g for occupational environments by 14 times. Even considering the high local SAR in the brain, evaluation of acute effects by the common toxicity criteria (CTC) scores revealed no indication of a serious acute neurological effect. In addition, this study provides pioneering quantitative human data on the association between maximum brain SAR level and acute adverse effects when brains are exposed to prolonged RF EMF.

Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: relevance to hepatic encephalopathy treatment

PubMed Central

Niknahad, Hossein; Jamshidzadeh, Akram; Zarei, Mahdi; Ommati, Mohammad Mehdi

2017-01-01

Introduction Ammonia-induced oxidative stress, mitochondrial dysfunction, and energy crisis are known as some the major mechanisms of brain injury in hepatic encephalopathy (HE). Hyperammonemia also affects the liver and hepatocytes. Therefore, targeting mitochondria seems to be a therapeutic point of intervention in the treatment of HE. Taurine is an abundant amino acid in the human body. Several biological functions including the mitochondrial protective properties are attributed to this amino acid. The aim of this study is to evaluate the effect of taurine administration on ammonia-induced mitochondrial dysfunction. Material and methods Isolated mice liver and brain mitochondria were exposed to different concentrations of ammonia (1, 5, 10, and 20 mM) and taurine (1, 5, and 10 mM), and several mitochondrial indices were assessed. Results It was found that ammonia inhibited mitochondrial dehydrogenases activity caused collapse of mitochondrial membrane potential (MMP), induced mitochondrial swelling (MPP), and increased reactive oxygen species (ROS) in isolated liver and brain mitochondria. Furthermore, a significant amount of lipid peroxidation (LPO), along with glutathione (GSH) and ATP depletion, was detected in ammonia exposed mitochondria. Taurine administration (5 and 10 mM) mitigated ammonia-induced mitochondrial dysfunction. Conclusions The current investigation demonstrates that taurine is instrumental in preserving brain and liver mitochondrial function in a hyperammonemic environment. The data suggest taurine as a potential protective agent with a therapeutic capability against hepatic encephalopathy and hyperammonemia. PMID:29062904

Early care of acute hyperglycemia benefits the outcome of traumatic brain injury in rats.

PubMed

Kang, Xin; Liu, Yuepeng; Yuan, Tao; Jiang, Na-Na; Dong, Yan-Bin; Wang, Jian-Wei; Fu, Guang-Hui; Liu, Yu-Liang; Wang, Wen-Xue

2016-11-01

Previous animal studies showed contradictory clinical observations on whether acute hyperglycemia contributes to poor outcome in traumatic brain injury (TBI). Herein, we tried to clarify this issue. Striking with depths of 3.0-4.25mm at right occipitoparietal brain region and with depth of 3.75mm at right/left occipitoparietal or right/left frontoparietal brain region were performed, respectively. Blood glucose and insulin levels were traced every four hours from 1 to 72h after striking. HOMA2-%S and HOMA2-%β were calculated. Modified neurological severity scores (mNSS) were used to evaluate neurological deficit within 72h. Striking with depths of 3.5-4.25mm induced increase in blood glucose lasting up to 24h after striking. The levels of blood glucose after striking with depths of 3.75-4.25mm were significantly different from that of striking with the depth of 3.0mm. Striking with depth of 3.75mm at right/left occipitoparietal region induced higher blood glucose in 24h than that at right/left frontoparietal region. Insulin concentration increased slowly during 72h after striking. Striking also induced decrease in insulin sensitivity and secretion lasting 72h. Evaluation of mNSS revealed that severe striking (beyond 3.75mm) worsened nerve function than slight striking (<3.0mm). Intervention of acute hyperglycemia could decrease the mNSS from 2 to 7 days after TBI. Our results suggested that only severe TBI could induce acute hyperglycemia by itself, and early care of acute hyperglycemia could benefit the outcome of TBI patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Volumetric Integral Phase-shift Spectroscopy for Noninvasive Detection of Hemispheric Bioimpedance Asymmetry in Acute Brain Pathology

ClinicalTrials.gov

2018-05-10

Stroke; Stroke, Acute; Ischemic Stroke; Hemorrhage; Clot (Blood); Brain; Subarachnoid Hemorrhage; Cerebral Infarction; Cerebral Hemorrhage; Cerebral Stroke; Intracerebral Hemorrhage; Intracerebral Injury

Diagnostic Accuracy of Right Ventricular Dysfunction Markers in Normotensive Emergency Department Patients With Acute Pulmonary Embolism.

PubMed

Weekes, Anthony J; Thacker, Gregory; Troha, Daniel; Johnson, Angela K; Chanler-Berat, Jordan; Norton, H James; Runyon, Michael

2016-09-01

We determine the diagnostic accuracy of goal-directed echocardiography, cardiac biomarkers, and computed tomography (CT) in early identification of severe right ventricular dysfunction in normotensive emergency department patients with pulmonary embolism compared with comprehensive echocardiography. This was a prospective observational study of consecutive normotensive patients with confirmed pulmonary embolism. Investigators, blinded to clot burden and biomarkers, performed qualitative goal-directed echocardiography for right ventricular dysfunction: right ventricular enlargement (diameter greater than or equal to that of the left ventricle), severe right ventricular systolic dysfunction, and septal bowing. Brain natriuretic peptide and troponin cutoffs of greater than or equal to 90 pg/mL and greater than or equal to 0.07 ng/mL and CT right ventricular:left ventricular diameter ratio greater than or equal to 1.0 were also compared with comprehensive echocardiography. One hundred sixteen normotensive pulmonary embolism patients (111 confirmed by CT, 5 by ventilation-perfusion scan) were enrolled. Twenty-six of 116 patients (22%) had right ventricular dysfunction on comprehensive echocardiography. Goal-directed echocardiography had a sensitivity of 100% (95% confidence interval [CI] 87% to 100%), specificity of 99% (95% CI 94% to 100%), positive likelihood ratio (+LR) of 90.0 (95% CI 16.3 to 499.8), and negative likelihood ratio (-LR) of 0 (95% CI 0 to 0.13). Brain natriuretic peptide had a sensitivity of 88% (95% CI 70% to 98%), specificity of 68% (95% CI 57% to 78%), +LR of 2.8 (95% CI 2.0 to 3.9), and -LR of 0.17 (95% CI 0.06 to 0.43). Troponin had a sensitivity of 62% (95% CI 41% to 80%), specificity of 93% (95% CI 86% to 98%), +LR of 9.2 (95% CI 4.1 to 20.9), and -LR of 0.41 (95% CI 0.24 to 0.62). CT had a sensitivity of 91% (95% CI 72% to 99%), specificity of 79% (95% CI 69% to 87%), +LR of 4.3 (95% CI 2.8 to 6.7), and -LR of 0.11 (95% CI 0.03 to 0

Acute SSRI-induced anxiogenic and brain metabolic effects are attenuated 6 months after initial MDMA-induced depletion.

PubMed

Andó, Rómeó D; Adori, Csaba; Kirilly, Eszter; Molnár, Eszter; Kovács, Gábor G; Ferrington, Linda; Kelly, Paul A T; Bagdy, György

2010-03-05

To assess the functional state of the serotonergic system, the acute behavioural and brain metabolic effect of SSRI antidepressants were studied during the recovery period after MDMA-induced neuronal damage. The effects of the SSRI fluoxetine and the serotonin receptor agonist meta-chloro-phenylpiperazine (m-CPP) were investigated in the social interaction test in Dark Agouti rats, 6 months after treatment with a single dose of MDMA (15 or 30 mg kg(-1), i.p.). At earlier time points these doses of MDMA have been shown to cause 30-60% loss in axonal densities in several brain regions. Densities of the serotonergic axons were assessed using serotonin-transporter and tryptophan-hydroxylase immunohistochemistry. In a parallel group of animals, brain function was examined following an acute challenge with either fluoxetine or citalopram, using 2-deoxyglucose autoradiographic imaging. Six months after MDMA treatment the densities of serotonergic axons were decreased in only a few brain areas including hippocampus and thalamus. Basal anxiety was unaltered in MDMA-treated animals. However, the acute anxiogenic effects of fluoxetine, but not m-CPP, were attenuated in animals pretreated with MDMA. The metabolic response to both citalopram and fluoxetine was normal in most of the brain areas examined with the exception of ventromedial thalamus and hippocampal sub-fields where the response was attenuated. These data provide evidence that 6 months after MDMA-induced damage serotonergic axons show recovery in most brain areas, but serotonergic functions to challenges with SSRIs including anxiety and aggression remain altered. Copyright 2009 Elsevier B.V. All rights reserved.

Heart Rate Variability in Patients with Acute Ischemic Stroke at Different Stages of Renal Dysfunction: A Cross-sectional Observational Study.

PubMed

Wei, Lin; Zhao, Wen-Bo; Ye, Huan-Wen; Chen, Yan-Hua; Zhang, Xiao-Pei; Huang, Yan; Cai, Ye-Feng; Chen, Quan-Fu; Pan, Su-Yue

2017-03-20

Renal function is associated with mortality and functional disabilities in stroke patients, and impaired autonomic function is common in stroke, but little is known regarding its effects on stroke patients with renal dysfunction. This study sought to evaluate the association between autonomic function and stroke in patients with renal dysfunction. This study comprised 232 patients with acute ischemic stroke consecutively enrolled from February 2013 to November 2014 at Guangdong Provincial Hospital of Chinese Medicine in China. All patients recruited underwent laboratory evaluation and 24 h Holter electrocardiography (ECG). Autonomic function was measured based on the heart rate variability (HRV) using 24 h Holter ECG. Renal damage was assessed through the estimated glomerular filtration rate (eGFR), and stroke severity was rated according to the National Institutes of Health Stroke Scale (NIHSS). The Barthel index and modified Rankin score were also determined following admission. All the clinical covariates that could potentially affect autonomic outcome variables were adjusted with linear regression. In the patients with a mild or moderate decreased eGFR, the values for the standard deviation of the averaged normal-to-normal RR interval (SDANN) index (P = 0.022), very low frequency (VLF) (P = 0.043), low frequency (LF) (P = 0.023), and ratio of low-to-high frequency power (LF/HF) (P = 0.001) were significantly lower than those in the patients with a normal eGFR. A multinomial linear regression indicated that eGFR (t = 2.47, P = 0.014), gender (t = -3.60, P < 0.001), and a history of hypertension (t = -2.65, P = 0.008) were the risk factors of LF/HF; the NIHSS score (SDANN index: t = -3.83, P < 0.001; VLF: t = -3.07, P = 0.002; LF: t = -2.79, P = 0.006) and a history of diabetes (SDANN index: t = -3.58, P < 0.001; VLF: t = -2.54, P = 0.012; LF: t = -2.87, P = 0.004) were independent factors for the SDANN index, VLF, and LF; the Oxfordshire Community Stroke Project

Cognitive benefit and cost of acute stress is differentially modulated by individual brain state

PubMed Central

Hermans, Erno J.; Fernández, Guillén

2017-01-01

Abstract Acute stress is associated with beneficial as well as detrimental effects on cognition in different individuals. However, it is not yet known how stress can have such opposing effects. Stroop-like tasks typically show this dissociation: stress diminishes speed, but improves accuracy. We investigated accuracy and speed during a stroop-like task of 120 healthy male subjects after an experimental stress induction or control condition in a randomized, counter-balanced cross-over design; we assessed brain–behavior associations and determined the influence of individual brain connectivity patterns on these associations, which may moderate the effect and help identify stress resilience factors. In the mean, stress was associated to increase in accuracy, but decrease in speed. Accuracy was associated to brain activation in a distributed set of brain regions overlapping with the executive control network (ECN) and speed to temporo-parietal activation. In line with a stress-related large-scale network reconfiguration, individuals showing an upregulation of the salience and down-regulation of the executive-control network under stress displayed increased speed, but decreased performance. In contrast, individuals who upregulate their ECN under stress show improved performance. Our results indicate that the individual large-scale brain network balance under acute stress moderates cognitive consequences of threat. PMID:28402480

Acute Ischemic Stroke After Moderate to Severe Traumatic Brain Injury: Incidence and Impact on Outcome.

PubMed

Kowalski, Robert G; Haarbauer-Krupa, Juliet K; Bell, Jeneita M; Corrigan, John D; Hammond, Flora M; Torbey, Michel T; Hofmann, Melissa C; Dams-O'Connor, Kristen; Miller, A Cate; Whiteneck, Gale G

2017-07-01

Traumatic brain injury (TBI) leads to nearly 300 000 annual US hospitalizations and increased lifetime risk of acute ischemic stroke (AIS). Occurrence of AIS immediately after TBI has not been well characterized. We evaluated AIS acutely after TBI and its impact on outcome. A prospective database of moderate to severe TBI survivors, admitted to inpatient rehabilitation at 22 Traumatic Brain Injury Model Systems centers and their referring acute-care hospitals, was analyzed. Outcome measures were AIS incidence, duration of posttraumatic amnesia, Functional Independence Measure, and Disability Rating Scale, at rehabilitation discharge. Between October 1, 2007, and March 31, 2015, 6488 patients with TBI were enrolled in the Traumatic Brain Injury Model Systems National Database. One hundred and fifty-nine (2.5%) patients had a concurrent AIS, and among these, median age was 40 years. AIS was associated with intracranial mass effect and carotid or vertebral artery dissection. High-velocity events more commonly caused TBI with dissection. AIS predicted poorer outcome by all measures, accounting for a 13.3-point reduction in Functional Independence Measure total score (95% confidence interval, -16.8 to -9.7; P <0.001), a 1.9-point increase in Disability Rating Scale (95% confidence interval, 1.3-2.5; P <0.001), and an 18.3-day increase in posttraumatic amnesia duration (95% confidence interval, 13.1-23.4; P <0.001). Ischemic stroke is observed acutely in 2.5% of moderate to severe TBI survivors and predicts worse functional and cognitive outcome. Half of TBI patients with AIS were aged ≤40 years, and AIS patients more often had cervical dissection. Vigilance for AIS is warranted acutely after TBI, particularly after high-velocity events. © 2017 American Heart Association, Inc.

Hypopituitarism after traumatic brain injury.

PubMed

Bondanelli, Marta; Ambrosio, Maria Rosaria; Zatelli, Maria Chiara; De Marinis, Laura; degli Uberti, Ettore C

2005-05-01

Traumatic brain injury (TBI) is one of the main causes of death and disability in young adults, with consequences ranging from physical disabilities to long-term cognitive, behavioural, psychological and social defects. Post-traumatic hypopituitarism (PTHP) was recognized more than 80 years ago, but it was thought to be a rare occurrence. Recently, clinical evidence has demonstrated that TBI may frequently cause hypothalamic-pituitary dysfunction, probably contributing to a delayed or hampered recovery from TBI. Changes in pituitary hormone secretion may be observed during the acute phase post-TBI, representing part of the acute adaptive response to the injury. Moreover, diminished pituitary hormone secretion, caused by damage to the pituitary and/or hypothalamus, may occur at any time after TBI. PTHP is observed in about 40% of patients with a history of TBI, presenting as an isolated deficiency in most cases, and more rarely as complete pituitary failure. The most common alterations appear to be gonadotropin and somatotropin deficiency, followed by corticotropin and thyrotropin deficiency. Hyper- or hypoprolactinemia may also be present. Diabetes insipidus may be frequent in the early, acute phase post-TBI, but it is rarely permanent. Severity of TBI seems to be an important risk factor for developing PTHP; however, PTHP can also manifest after mild TBI. Accurate evaluation and long-term follow-up of all TBI patients are necessary in order to detect the occurrence of PTHP, regardless of clinical evidence for pituitary dysfunction. In order to improve outcome and quality of life of TBI patients, an adequate replacement therapy is of paramount importance.

Brain-lung crosstalk in critical care: how protective mechanical ventilation can affect the brain homeostasis.

PubMed

Mazzeo, A T; Fanelli, V; Mascia, L

2013-03-01

The maintenance of brain homeostasis against multiple internal and external challenges occurring during the acute phase of acute brain injury may be influenced by critical care management, especially in its respiratory, hemodynamic and metabolic components. The occurrence of acute lung injury represents the most frequent extracranial complication after brain injury and deserves special attention in daily practice as optimal ventilatory strategy for patients with acute brain and lung injury are potentially in conflict. Protecting the lung while protecting the brain is thus a new target in the modern neurointensive care. This article discusses the essentials of brain-lung crosstalk and focuses on how mechanical ventilation may exert an active role in the process of maintaining or treatening brain homeostasis after acute brain injury, highlighting the following points: 1) the role of inflammation as common pathomechanism of both acute lung and brain injury; 2) the recognition of ventilatory induced lung injury as determinant of systemic inflammation affecting distal organs, included the brain; 3) the possible implication of protective mechanical ventilation strategy on the patient with an acute brain injury as an undiscovered area of research in both experimental and clinical settings.

Rapid Morphological Brain Abnormalities during Acute Methamphetamine Intoxication in the Rat. An Experimental study using Light and Electron Microscopy

PubMed Central

Sharma, Hari S.; Kiyatkin, Eugene A.

2009-01-01

This study describes morphological abnormalities of brain cells during acute methamphetamine (METH) intoxication in the rat and demonstrates the role of hyperthermia, disruption of the blood-brain barrier (BBB) and edema in their development. Rats with chronically implanted brain, muscle and skin temperature probes and an intravenous (iv) catheter were exposed to METH (9 mg/kg) at standard (23°C) and warm (29°C) ambient temperatures, allowing for the observation of hyperthermia ranging from mild to pathological levels (38–42°C). When brain temperature peaked or reached a level suggestive of possible lethality (>41.5°C), rats were injected with Evans blue (EB), rapidly anesthetized, perfused, and their brains were taken for further analyses. Four brain areas (cortex, hippocampus, thalamus and hypothalamus) were analyzed for EB extravasation, water and electrolyte (Na+, K+, Cl−) contents, immunostained for albumin and glial fibrillary acidic protein, and examined for neuronal, glial and axonal alterations using standard light and electron microscopy. These examinations revealed profound abnormalities in neuronal, glial, and endothelial cells, which were stronger with METH administered at 29°C than 23°C and tightly correlated with brain and body hyperthermia. These changes had some structural specificity, but in each structure they tightly correlated with increases in EB levels, the numbers of albumin-positive cells, and water and ion contents, suggesting leakage of the BBB, acutely developing brain edema, and serious shifts in brain ion homeostasis as leading factors underlying brain abnormalities. While most of these acute structural and functional abnormalities appear to be reversible, they could trigger subsequent cellular alterations in the brain and accelerate neurodegeneration—the most dangerous complication of chronic amphetamine-like drug abuse. PMID:18773954

Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation.

PubMed

Wang, Janice C; Bindokas, Vytautas P; Skinner, Matthew; Emrick, Todd; Marks, Jeremy D

2017-10-01

Global brain ischemia can lead to widespread neuronal death and poor neurologic outcomes in patients. Despite detailed understanding of the cellular and molecular mechanisms mediating neuronal death following focal and global brain hypoxia-ischemia, treatments to reduce ischemia-induced brain injury remain elusive. One pathway central to neuronal death following global brain ischemia is mitochondrial dysfunction, one consequence of which is the cascade of intracellular events leading to mitochondrial outer membrane permeabilization. A novel approach to rescuing injured neurons from death involves targeting cellular membranes using a class of synthetic molecules called Pluronics. Pluronics are triblock copolymers of hydrophilic poly[ethylene oxide] (PEO) and hydrophobic poly[propylene oxide] (PPO). Evidence is accumulating to suggest that hydrophilic Pluronics rescue injured neurons from death following substrate deprivation by preventing mitochondrial dysfunction. Here, we will review current understanding of the nature of interaction of Pluronic molecules with biological membranes and the efficacy of F-68, an 80% hydrophilic Pluronic, in rescuing neurons from injury. We will review data indicating that F-68 reduces mitochondrial dysfunction and mitochondria-dependent death pathways in a model of neuronal injury in vitro, and present new evidence that F-68 acts directly on mitochondria to inhibit mitochondrial outer membrane permeabilization. Finally, we will present results of a pilot, proof-of-principle study suggesting that F-68 is effective in reducing hippocampal injury induced by transient global ischemia in vivo. By targeting mitochondrial dysfunction, F-68 and other Pluronic molecules constitute an exciting new approach to rescuing neurons from acute injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of positive end-expiratory pressure on brain tissue oxygen pressure of severe traumatic brain injury patients with acute respiratory distress syndrome: A pilot study.

PubMed

Nemer, Sérgio Nogueira; Caldeira, Jefferson B; Santos, Ricardo G; Guimarães, Bruno L; Garcia, João Márcio; Prado, Darwin; Silva, Ricardo T; Azeredo, Leandro M; Faria, Eduardo R; Souza, Paulo Cesar P

2015-12-01

To verify whether high positive end-expiratory pressure levels can increase brain tissue oxygen pressure, and also their effects on pulse oxygen saturation, intracranial pressure, and cerebral perfusion pressure. Twenty traumatic brain injury patients with acute respiratory distress syndrome were submitted to positive end-expiratory pressure levels of 5, 10, and 15 cm H2O progressively. The 3 positive end-expiratory pressure levels were used during 20 minutes for each one, whereas brain tissue oxygen pressure, oxygen saturation, intracranial pressure, and cerebral perfusion pressure were recorded. Brain tissue oxygen pressure and oxygen saturation increased significantly with increasing positive end-expiratory pressure from 5 to 10 and from 10 to 15 cm H2O (P=.0001 and P=.0001 respectively). Intracranial pressure and cerebral perfusion pressure did not differ significantly with increasing positive end-expiratory pressure from 5 to 10 and from 10 to 15 cm H2O (P=.16 and P=.79 respectively). High positive end-expiratory pressure levels increased brain tissue oxygen pressure and oxygen saturation, without increase in intracranial pressure or decrease in cerebral perfusion pressure. High positive end-expiratory pressure levels can be used in severe traumatic brain injury patients with acute respiratory distress syndrome as a safe alternative to improve brain oxygenation. Copyright © 2015 Elsevier Inc. All rights reserved.

Brain metabolite alterations and cognitive dysfunction in early Huntington’s Disease

PubMed Central

Unschuld, Paul G.; Edden, Richard A. E.; Carass, Aaron; Liu, Xinyang; Shanahan, Megan; Wang, Xin; Oishi, Kenichi; Brandt, Jason; Bassett, Susan S.; Redgrave, Graham W.; Margolis, Russell L.; van Zijl, Peter C. M.; Barker, Peter B.; Ross, Christopher A.

2012-01-01

Background Huntington’s Disease (HD) is a neurodegenerative disorder characterized by early cognitive decline, which progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aims to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high field strength magnetic-resonance-spectroscopy at 7-Tesla. Methods Twelve individuals with the HD-mutation in premanifest or early stage of disease versus twelve healthy controls underwent 1H magnetic-resonance-spectroscopy (7.2ml voxel in the posterior cingulate cortex) at 7-Tesla, and also T1-weighted structural magnetic-resonance-imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Results Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (−9.6%, p=0.02) and glutamate levels (−10.1%, p=0.02) than controls. By contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r2=0.50, p=0.01) and glutamate (r2=0.64, p=0.002) in HD subjects. Conclusions Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in early stages of HD. N-acetylaspartate and glutamate magnetic-resonance-spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural

Management of fever, hyperglycemia, and swallowing dysfunction following hospital admission for acute stroke in New South Wales, Australia.

PubMed

Drury, Peta; Levi, Christopher; McInnes, Elizabeth; Hardy, Jennifer; Ward, Jeanette; Grimshaw, Jeremy M; D' Este, Catherine; Dale, Simeon; McElduff, Patrick; Cheung, N Wah; Quinn, Clare; Griffiths, Rhonda; Evans, Malcolm; Cadilhac, Dominique; Middleton, Sandy

2014-01-01

Fever, hyperglycemia, and swallow dysfunction poststroke are associated with significantly worse outcomes. We report treatment and monitoring practices for these three items from a cohort of acute stroke patients prior to randomization in the Quality in Acute Stroke Care trial. Retrospective medical record audits were undertaken for prospective patients from 19 stroke units. For the first three-days following stroke, we recorded all temperature readings and administration of paracetamol for fever (≥37·5°C) and all glucose readings and administration of insulin for hyperglycemia (>11 mmol/L). We also recorded swallow screening and assessment during the first 24 h of admission. Data for 718 (98%) patients were available; 138 (19%) had four hourly or more temperature readings and 204 patients (29%) had a fever, with 44 (22%) receiving paracetamol. A quarter of patients (n = 102/412, 25%) had six hourly or more glucose readings and 23% (95/412) had hyperglycemia, with 31% (29/95) of these treated with insulin. The majority of patients received a swallow assessment (n = 562, 78%) by a speech pathologist in the first instance rather than a swallow screen by a nonspeech pathologist (n = 156, 22%). Of those who passed a screen (n = 108 of 156, 69%), 68% (n = 73) were reassessed by a speech pathologist and 97% (n = 71) were reconfirmed to be able to swallow safely. Our results showed that acute stroke patients were: undermonitored and undertreated for fever and hyperglycemia; and underscreened for swallowing dysfunction and unnecessarily reassessed by a speech pathologist, indicating the need for urgent behavior change. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Cluster Analysis of Vulnerable Groups in Acute Traumatic Brain Injury Rehabilitation.

PubMed

Kucukboyaci, N Erkut; Long, Coralynn; Smith, Michelle; Rath, Joseph F; Bushnik, Tamara

2018-01-06

To analyze the complex relation between various social indicators that contribute to socioeconomic status and health care barriers. Cluster analysis of historical patient data obtained from inpatient visits. Inpatient rehabilitation unit in a large urban university hospital. Adult patients (N=148) receiving acute inpatient care, predominantly for closed head injury. Not applicable. We examined the membership of patients with traumatic brain injury in various "vulnerable group" clusters (eg, homeless, unemployed, racial/ethnic minority) and characterized the rehabilitation outcomes of patients (eg, duration of stay, changes in FIM scores between admission to inpatient stay and discharge). The cluster analysis revealed 4 major clusters (ie, clusters A-D) separated by vulnerable group memberships, with distinct durations of stay and FIM gains during their stay. Cluster B, the largest cluster and also consisting of mostly racial/ethnic minorities, had the shortest duration of hospital stay and one of the lowest FIM improvements among the 4 clusters despite higher FIM scores at admission. In cluster C, also consisting of mostly ethnic minorities with multiple socioeconomic status vulnerabilities, patients were characterized by low cognitive FIM scores at admission and the longest duration of stay, and they showed good improvement in FIM scores. Application of clustering techniques to inpatient data identified distinct clusters of patients who may experience differences in their rehabilitation outcome due to their membership in various "at-risk" groups. The results identified patients (ie, cluster B, with minority patients; and cluster D, with elderly patients) who attain below-average gains in brain injury rehabilitation. The results also suggested that systemic (eg, duration of stay) or clinical service improvements (eg, staff's language skills, ability to offer substance abuse therapy, provide appropriate referrals, liaise with intensive social work services, or plan

Three patients with hemophagocytic syndrome who developed acute organic brain syndrome.

PubMed

Shinno, Hideto; Hikasa, Satoshi; Matsuoka, Tatsuo; Fujita, Hidekazu; Yamamoto, Osamu; Takebayashi, Minoru; Uchida, Youzou; Nishiura, Tetsuo; Horiguchi, Jun

2006-01-01

We describe three patients with hemophagocytic syndrome (HPS) who developed acute organic brain syndrome. All three presented with high-grade fever and twilight state, and were admitted to our hospital. After admission, delirium developed in all three. As delirium improved, various other psychiatric symptoms, including hallucinations, agitation, hypoactivity, affective lability and insomnia, were noted. When treated with steroid hormones, immunoglobulin and neuroleptics, all patients demonstrated improvement in their psychiatric symptoms, as well as in their general condition and laboratory findings. Ultimately, they all recovered and were discharged. It needs to be noted that organic brain syndrome might be observed at the onset of HPS. Consequently, early diagnosis and treatment for psychiatric symptoms, as well as for HPS, are crucial.

White Matter Atrophy and Cognitive Dysfunctions in Neuromyelitis Optica

PubMed Central

Blanc, Frederic; Noblet, Vincent; Jung, Barbara; Rousseau, François; Renard, Felix; Bourre, Bertrand; Longato, Nadine; Cremel, Nadjette; Di Bitonto, Laure; Kleitz, Catherine; Collongues, Nicolas; Foucher, Jack; Kremer, Stephane; Armspach, Jean-Paul; de Seze, Jerome

2012-01-01

Neuromyelitis optica (NMO) is an inflammatory disease of central nervous system characterized by optic neuritis and longitudinally extensive acute transverse myelitis. NMO patients have cognitive dysfunctions but other clinical symptoms of brain origin are rare. In the present study, we aimed to investigate cognitive functions and brain volume in NMO. The study population consisted of 28 patients with NMO and 28 healthy control subjects matched for age, sex and educational level. We applied a French translation of the Brief Repeatable Battery (BRB-N) to the NMO patients. Using SIENAx for global brain volume (Grey Matter, GM; White Matter, WM; and whole brain) and VBM for focal brain volume (GM and WM), NMO patients and controls were compared. Voxel-level correlations between diminished brain concentration and cognitive performance for each tests were performed. Focal and global brain volume of NMO patients with and without cognitive impairment were also compared. Fifteen NMO patients (54%) had cognitive impairment with memory, executive function, attention and speed of information processing deficits. Global and focal brain atrophy of WM but not Grey Matter (GM) was found in the NMO patients group. The focal WM atrophy included the optic chiasm, pons, cerebellum, the corpus callosum and parts of the frontal, temporal and parietal lobes, including superior longitudinal fascicle. Visual memory, verbal memory, speed of information processing, short-term memory and executive functions were correlated to focal WM volumes. The comparison of patients with, to patients without cognitive impairment showed a clear decrease of global and focal WM, including brainstem, corticospinal tracts, corpus callosum but also superior and inferior longitudinal fascicles. Cognitive impairment in NMO patients is correlated to the decreased of global and focal WM volume of the brain. Further studies are needed to better understand the precise origin of cognitive impairment in NMO patients

[Cerebral metabolism and permeability of the hemato-encephalic barrier in an experimental model for brain radiotherapy].

PubMed

Cicciarello, R; Russi, E; Albiero, F; Mesiti, M; Torre, E; D'Aquino, A; Raffaele, L; Bertolani, S; D'Avella, D

1990-11-01

Whole brain irradiation (WBR) can produce acute and chronic neurological adverse effects, which are usually divided into acute, early delayed and late delayed reactions according to the time of onset. To assess the impact of WBR on brain functional parameters during the early-delayed phase, we employed the [14C]-2-deoxyglucose (2-DG) and the [14C]-alfa-aminoisobutyric (AIB) acid quantitative autoradiographic techniques to study local cerebral glucose utilization and blood-brain barrier permeability, respectively. Sprague-Dowley albino rats were exposed to conventional fractionation (200 Gy/day 5 days a week) for a total dose of 4000 Gy. Experiments were made 3 weeks after completion of the radiation exposure. In comparison with control and sham-irradiated animals, cerebral metabolic activity was diffusely decreased following irradiation. As a rule, brain areas with the highest basal metabolic rates showed the highest percentage drop in glucose utilization. Changes in blood-brain barrier function, as assessed by an increased transcapillary transport of AIB, were also demonstrated in specific brain regions. This study illustrates how moderate doses of WBR induce well-defined changes in brain metabolism and BBB function, which are possibly involved in the pathogenesis of the early-delayed radiation-induced cerebral dysfunction in humans.

Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure.

PubMed

Maldonado, José R

2017-12-26

Delirium is the most common neuropsychiatric syndrome encountered by clinicians dealing with older adults and the medically ill and is best characterized by 5 core domains: cognitive deficits, attentional deficits, circadian rhythm dysregulation, emotional dysregulation, and alteration in psychomotor functioning. An extensive literature review and consolidation of published data into a novel interpretation of known pathophysiological causes of delirium. Available data suggest that numerous pathological factors may serve as precipitants for delirium, each having differential effects depending on patient-specific patient physiological characteristics (substrate). On the basis of an extensive literature search, a newly proposed theory, the systems integration failure hypothesis, was developed to bring together the most salient previously described theories, by describing the various contributions from each into a complex web of pathways-highlighting areas of intersection and commonalities and explaining how the variable contribution of these may lead to the development of various cognitive and behavioral dysfunctions characteristic of delirium. The specific cognitive and behavioral manifestations of the specific delirium picture result from a combination of neurotransmitter function and availability, variability in integration and processing of sensory information, motor responses to both external and internal cues, and the degree of breakdown in neuronal network connectivity, hence the term acute brain failure. The systems integration failure hypothesis attempts to explain how the various proposed delirium pathophysiologic theories interact with each other, causing various clinically observed delirium phenotypes. A better understanding of the underlying pathophysiology of delirium may eventually assist in designing better prevention and management approaches. Copyright © 2017 John Wiley & Sons, Ltd.

Prominent hypointense veins on susceptibility weighted image in the cat brain with acute infarction: DWI, SWI, and PWI.

PubMed

Kim, Yong-Woo; Kim, Hak Jin; Choi, Seon Hee; Kim, Dong Chan

2014-10-01

The multiple prominent hypointense veins on susceptibility-weighted imaging (SWI) have been found in the ischemic territory of patients with acute ischemic stroke. Venous side is the unknown area in the hemodynamics of brain infarction. To evaluate the venous aspect in acute brain infarction through an animal study. The acute infarction in cat brains was induced with a bolus infusion of 0.25 mL of triolein through one side of the common carotid artery. The magnetic resonance (MR) images, including diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) map, SW, and perfusion-weighted (PWI) images, were obtained serially at 2 h (n = 17), 1 day (n = 11), and 4 days (n = 4) after triolein infusion. The obtained MR images were evaluated qualitatively and quantitatively. For qualitative assessment, the signal intensity of the serial MR images was evaluated. The presence or absence and the location with serial changes of infarction were identified on DWI and ADC map images. The presence or absence of prominent hypointense veins and the serial changes of cortical veins were also evaluated on SWI. Quantitative assessment was performed by comparing the relative cerebral blood volume (rCBV), cerebral blood flow (rCBF), and mean transit times (MTT) of the lesions with those of the contralateral normal side calculated on PWI. The serial changes of rCBV, rCBF, and MTT ratio were also evaluated. Acute infarction in the first and second medial gyrus of lesion hemisphere was found by qualitative evaluation of DWI and ADC map images. On the serial evaluation of SWI, the cortical veins of cat brain with infarction were obscured at 2 h and then re-appeared at 1 day. The hemorrhage transformation and prominent hypointense veins were seen at 4 days on SWI. The quantitative evaluation revealed increased MTT ratios and decreased rCBV and rCBF ratios on PWIs in the acute infarction of cat brain. The prominent hypointense veins on SWI were seen in the half of the acute

Acute coenurosis of dairy sheep from 11 flocks in Greece.

PubMed

Giadinis, N D; Psychas, V; Polizopoulou, Z; Papadopoulos, E; Papaioannou, N; Komnenou, A Th; Thomas, A-L; Petridou, E J; Kritsepi-Konstantinou, M; Lafi, S Q; Brellou, G D

2012-07-01

A syndrome of acute neurological dysfunction with increased mortality was observed in lambs of 10 dairy sheep flocks and adult animals in one flock in Central and Northern Greece. Each farmer completed a questionnaire regarding the management and feeding of their flocks. In seven of the 11 flocks the affected animals were grazing pasture, while in the remaining four flocks (5, 8, 9, 10) the animals were fed alfalfa hay (Medicago sativa) and concentrates indoors. A follow-up study of the affected flocks was conducted during the next 12 months. Of 42 sheep with acute coenurosis that were examined, the most prominent neurological abnormalities were ataxia, depression, blindness, scoliosis, coma and dysmetria. Except for the four sheep that were comatose, all other animals had normal body temperatures and their appetites remained normal or were slightly decreased. Haematological findings of 15 examined sheep were within normal limits. The affected sheep were subject to euthanasia. A histopathological examination was performed in 13 cases. Faecal samples from dogs associated with these flocks were negative for taeniid infections. During the following 12 months cases of chronic coenurosis in these flocks were observed. In the 42 animals that were necropsied, the main gross findings were cystic formations between 0.5-1 cm in diameter with translucent walls that were seen lying free on the leptomeninges or partly penetrating the brain tissue, sterile microabscecess and brain necrosis. Histopathological evaluation of tissue sections of 13 brains showed multifocal purulent or pyogranulomatous meningoencephalitis, accompanied by eosinophilic infiltrations. No bacteria were isolated following bacterial culture of brain tissue Parasitological examination of the cysts from five cases revealed whitish specks on the transparent cyst wall and germination membrane representing the scolices. Acute coenurosis was diagnosed in all cases studied. Acute coenurosis can be one of the

Isolated brain stem lesion in children: is it acute disseminated encephalomyelitis or not?

PubMed

Alper, G; Sreedher, G; Zuccoli, G

2013-01-01

Isolated brain stem lesions presenting with acute neurologic findings create a major diagnostic dilemma in children. Although the brain stem is frequently involved in ADEM, solitary brain stem lesions are unusual. We performed a retrospective review in 6 children who presented with an inflammatory lesion confined to the brain stem. Two children were diagnosed with connective tissue disorder, CNS lupus, and localized scleroderma. The etiology could not be determined in 1, and clinical features suggested monophasic demyelination in 3. In these 3 children, initial lesions demonstrated vasogenic edema; all showed dramatic response to high-dose corticosteroids and made a full clinical recovery. Follow-up MRI showed complete resolution of lesions, and none had relapses at >2 years of follow-up. In retrospect, these cases are best regarded as a localized form of ADEM. We conclude that though ADEM is typically a disseminated disease with multifocal lesions, it rarely presents with monofocal demyelination confined to the brain stem.

Early metabolic crisis-related brain atrophy and cognition in traumatic brain injury.

PubMed

Wright, Matthew J; McArthur, David L; Alger, Jeffry R; Van Horn, Jack; Irimia, Andrei; Filippou, Maria; Glenn, Thomas C; Hovda, David A; Vespa, Paul

2013-09-01

Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as 'frontal-temporal' in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis-related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

PubMed

Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

2017-06-01

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Protective effect of bacoside A on cigarette smoking-induced brain mitochondrial dysfunction in rats.

PubMed

Anbarasi, Kothandapani; Vani, Ganapathy; Devi, Chennam Srinivasulu Shyamala

2005-01-01

Chronic exposure to cigarette smoke affects the structure and function of mitochondria, which may account for the pathogenesis of smoking-related diseases. Bacopa monniera Linn., used in traditional Indian medicine for various neurological disorders, was shown to possess mitrochondrial membrane-stabilizing properties in the rat brain during exposure to morphine. We investigated the protective effect of bacoside A, the active principle of Bacopa monniera, against mitochondrial dysfunction in rat brain induced by cigarette smoke. Male Wistar albino rats were exposed to cigarette smoke and administered bacoside A for a period of 12 weeks. The mitochondrial damage in the brain was assessed by examining the levels of lipid peroxides, cholesterol, phospholipid, cholesterol/phospholipid (C/P) ratio, and the activities of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase, and cytochrome C oxidase. The oxidative phosphorylation (rate of succinate oxidation, respiratory control ratio and ADP/O ratio, and the levels of ATP) was evaluated for the assessment of mitochondrial functional capacity. We found significantly elevated levels of lipid peroxides, cholesterol, and C/P ratio, and decreased levels of phospholipids and mitochondrial enzymes in the rats exposed to cigarette smoke. Measurement of oxidative phosphorylation revealed a marked depletion in all the variables studied. Administration of bacoside A prevented the structural and functional impairment of mitochondria upon exposure to cigarette smoke. From the results, we suggest that chronic cigarette smoke exposure induces damage to the mitochondria and that bacoside A protects the brain from this damage by maintaining the structural and functional integrity of the mitochondrial membrane.

Therapeutic effect of Tripterygium wilfordii Hook F multiglycosides on gut barrier dysfunction in rats with acute necrotizing pancreatitis.

PubMed

Wang, Jie; Wu, Gang; Ma, Baojin; Wu, Jianhua; Cai, Duan

2013-02-01

The aim of the current study was to investigate the therapeutic effect of Tripterygium wilfordii Hook F multiglycosides (TWG) on gut barrier dysfunction in rats with acute necrotizing pancreatitis (ANP). ANP was induced in rats using 3.5% sodium taurocholate. The rats were divided into 3 groups: the sham operation (SO), ANP and ANP+TWG groups. Biochemical and pathological change of pancreatic tissue and ileal mucosa, bacterial cultures and the survival rate were measured following surgery and treatment. TWG treatment significantly decreased amylase and lipase activities and plasma endotoxin and D-lactate levels. Edema and inflammation in the pancreas and ileal mucosa were alleviated. Positive bacterial cultures were significantly reduced. The survival rate of the rats in the ANP+TWG group was higher than that of the rats in the ANP group. TWG treatment showed beneficial effects by protecting the pancreas from bacterial infection caused by gut barrier dysfunction and improving the outcomes of the rats with ANP.

Mild traumatic brain injury in children: management practices in the acute care setting.

PubMed

Kool, Bridget; King, Vivienne; Chelimo, Carol; Dalziel, Stuart; Shepherd, Michael; Neutze, Jocelyn; Chambers, Nikki; Wells, Susan

2014-08-01

Accurate diagnosis, treatment and follow up of children suffering mild traumatic brain injury (MTBI) is important as post-concussive symptoms and long-term disability might occur. This research explored the decisions clinicians make in their assessment and management of children with MTBI in acute care settings, and identified barriers and enablers to the delivery of best-practice care. A purposeful sample of 29 clinicians employed in two metropolitan paediatric EDs and one Urgent Care clinic was surveyed using a vignette-based questionnaire that also included domains of guideline awareness, attitudes to MTBI care, use of clinical decision support systems, and knowledge and skills for practising evidence-based healthcare. Overall, the evaluation and management of children presenting acutely with MTBI generally followed best-practice guidelines, particularly in relation to identifying intracranial injuries that might require surgical intervention, observation for potential deterioration, adequate pain management and the provision of written head injury advice on discharge. Larger variation emerged in regard to follow-up care and referral pathways. Potential barriers to best- practice were lack of guideline awareness, attitudes to MTBI, and lack of time or other priorities. Opportunities exist to improve care for children who present in acute care settings following mild traumatic brain injury. These include having up-to-date guidelines that are consistent across acute care settings; providing clearer pathways for referral and follow up; targeting continuing medical education towards potential complications; and providing computerised decision support so that assessment and management are conducted systematically. © 2014 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Induction of acute brain injury in mice by irradiation with high-LET charged particles

NASA Astrophysics Data System (ADS)

Liu, Yang; Zhang, Hong

The present study was performed to evaluate the induction of acute brain injury in mice after 235 Mev/u carbon ion irradiation. In our study, young outbred Kunming mice were divided into four treatment groups according to the penetration depth of carbon ions. Animals were irradiated with a sublethal dose of carbon ion beams prior to the Bragg curve. An experiment was performed to evaluate the acute alterations in histology, DNA double-strand breaks (DNA DSBs) as well as p53and Bax expression in the brain 96 h post-irradiation. The results demonstrated that various histopathological changes, a significant number of DNA DSBs and elevated p53 and Bax protein expression were induced in the brain following exposure to carbon ions. This was particularly true for mice irradiated with ions having a 9.1 cm-pentration depth, indicating that carbon ions can led to deleterious lesions in the brain of young animals within 96 h. Moreover, there was a remarkable increase in DNA DSBs and in the severity of histopathological changes as the penetration depths of ions increased, which may be associated with the complex track structure of heavy ions. These data reveal that carbon ions can promote serious neuropathological degeneration in the cerebral cortex of young mice. Given that damaged neurons cannot regenerate, these findings warrant further investigation of the adverse effects of the space radiation and the passage of a therapeutic heavy ion beam in the plateau region of the Bragg curve through healthy brain tissue.

Associations Between Left Ventricular Dysfunction and Brain Structure and Function: Findings From the SABRE (Southall and Brent Revisited) Study.

PubMed

Park, Chloe M; Williams, Emily D; Chaturvedi, Nish; Tillin, Therese; Stewart, Robert J; Richards, Marcus; Shibata, Dean; Mayet, Jamil; Hughes, Alun D

2017-04-18

Subclinical left ventricular (LV) dysfunction has been inconsistently associated with early cognitive impairment, and mechanistic pathways have been poorly considered. We investigated the cross-sectional relationship between LV dysfunction and structural/functional measures of the brain and explored the role of potential mechanisms. A total of 1338 individuals (69±6 years) from the Southall and Brent Revisited study underwent echocardiography for systolic (tissue Doppler imaging peak systolic wave) and diastolic (left atrial diameter) assessment. Cognitive function was assessed and total and hippocampal brain volumes were measured by magnetic resonance imaging. Global LV function was assessed by circulating N-terminal pro-brain natriuretic peptide. The role of potential mechanistic pathways of arterial stiffness, atherosclerosis, microvascular disease, and inflammation were explored. After adjusting for age, sex, and ethnicity, lower systolic function was associated with lower total brain (beta±standard error, 14.9±3.2 cm 3 ; P <0.0001) and hippocampal volumes (0.05±0.02 cm 3 , P =0.01). Reduced diastolic function was associated with poorer working memory (-0.21±0.07, P =0.004) and fluency scores (-0.18±0.08, P =0.02). Reduced global LV function was associated with smaller hippocampal volume (-0.10±0.03 cm 3 , P =0.004) and adverse visual memory (-0.076±0.03, P =0.02) and processing speed (0.063±0.02, P =0.006) scores. Separate adjustment for concomitant cardiovascular risk factors attenuated associations with hippocampal volume and fluency only. Further adjustment for the alternative pathways of microvascular disease or arterial stiffness attenuated the relationship between global LV function and visual memory. In a community-based sample of older people, measures of LV function were associated with structural/functional measures of the brain. These associations were not wholly explained by concomitant risk factors or potential mechanistic pathways. �

Management of chronic spinal cord dysfunction.

PubMed

Abrams, Gary M; Ganguly, Karunesh

2015-02-01

Both acute and chronic spinal cord disorders present multisystem management problems to the clinician. This article highlights key issues associated with chronic spinal cord dysfunction. Advances in symptomatic management for chronic spinal cord dysfunction include use of botulinum toxin to manage detrusor hyperreflexia, pregabalin for management of neuropathic pain, and intensive locomotor training for improved walking ability in incomplete spinal cord injuries. The care of spinal cord dysfunction has advanced significantly over the past 2 decades. Management and treatment of neurologic and non-neurologic complications of chronic myelopathies ensure that each patient will be able to maximize their functional independence and quality of life.

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

PubMed

Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy; Tucsek, Zsuzsanna; Hertelendy, Peter; Kiss, Tamas; Gautam, Tripti; Zhang, Xin A; Sonntag, William E; de Cabo, Rafael; Farkas, Eszter; Elliott, Michael H; Kinter, Michael T; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-14

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications.

PubMed

Hamed, Sherifa A

2017-04-01

Diabetes mellitus is a risk for brain injury. Brain injury is associated with acute and chronic hyperglycaemia, insulin resistance, hyperinsulinemia, diabetic ketoacidosis (DKA) and hypoglycaemic events in diabetic patients. Hyperglycemia is a cause of cognitive deterioration, low intelligent quotient, neurodegeneration, brain aging, brain atrophy and dementia. Areas covered: The current review highlights the experimental, clinical, neuroimaging and neuropathological evidence of brain injury induced by diabetes and its associated metabolic derangements. It also highlights the mechanisms of diabetes-induced brain injury. It seems that the pathogenesis of hyperglycemia-induced brain injury is complex and includes combination of vascular disease, oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, reduction of neurotrophic factors, acetylcholinesterase (AChE) activation, neurotransmitters' changes, impairment of brain repair processes, impairment of brain glymphatic system, accumulation of amyloid β and tau phosphorylation and neurodegeneration. The potentials for prevention and treatment are also discussed. Expert commentary: We summarize the risks and the possible mechanisms of DM-induced brain injury and recommend strategies for neuroprotection and neurorestoration. Recently, a number of drugs and substances [in addition to insulin and its mimics] have shown promising potentials against diabetes-induced brain injury. These include: antioxidants, neuroinflammation inhibitors, anti-apoptotics, neurotrophic factors, AChE inhibitors, mitochondrial function modifiers and cell based therapies.

Vascular dysfunctions following spinal cord injury

PubMed Central

Popa, F; Grigorean, VT; Onose, G; Sandu, AM; Popescu, M; Burnei, G; Strambu, V; Sinescu, C

2010-01-01

The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as

Brain Aquaporin-4 in Experimental Acute Liver Failure

PubMed Central

Rama Rao, Kakulavarapu V.; Jayakumar, Arumugam R.; Tong, Xiaoying; Curtis, Kevin M.; Norenberg, Michael D.

2016-01-01

Intracranial hypertension due to brain edema and associated astrocyte swelling is a potentially lethal complication of acute liver failure (ALF). Mechanisms of edema formation are not well understood but elevated levels of blood and brain ammonia and its byproduct glutamine have been implicated in this process. We examined mRNA and protein expression of the water channel protein aquaporin-4 (AQP4) in cerebral cortex in a rat model of ALF induced by the hepatotoxin thioacetamide. Rats with ALF showed increased AQP4 protein in the plasma membrane (PM). Total tissue levels of AQP4 protein and mRNA levels were not altered indicating that increased AQP4 is not transcriptionally mediated but is likely due to a conformational change in the protein, i.e. a more stable anchoring of AQP4 to the PM and/or interference with its degradation. By immunohistochemistry there was an increase in AQP4 immunoreactivity in the PM of perivascular astrocytes in ALF. Rats with ALF showed increased levels of α-syntrophin, a protein involved in the anchoring of AQP4 to perivascular astrocytic end-feet. Increased AQP4 and α-syntrophin levels were inhibited by L-histidine, an inhibitor of glutamine transport into mitochondria, suggesting a role for glutamine in the increase of PM levels of AQP4. These results indicate that increased AQP4 PM levels in perivascular astrocytic end-feet are likely critical to the development of brain edema in ALF. PMID:20720509

Regulation of Mitochondrial Function and Glutamatergic System Are the Target of Guanosine Effect in Traumatic Brain Injury.

PubMed

Dobrachinski, Fernando; da Rosa Gerbatin, Rogério; Sartori, Gláubia; Ferreira Marques, Naiani; Zemolin, Ana Paula; Almeida Silva, Luiz Fernando; Franco, Jeferson Luis; Freire Royes, Luiz Fernando; Rechia Fighera, Michele; Antunes Soares, Félix Alexandre

2017-04-01

Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Experimental trauma involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Mitochondrial dysfunction and glutamatergic excitotoxicity are the hallmark mechanisms of damage. Accordingly, a successful pharmacological intervention requires a multi-faceted approach. Guanosine (GUO) is known for its neuromodulator effects in various models of brain pathology, specifically those that involve the glutamatergic system. The aim of the study was to investigate the GUO effects against mitochondrial damage in hippocampus and cortex of rats subjected to TBI, as well as the relationship of this effect with the glutamatergic system. Adult male Wistar rats were subjected to a unilateral moderate fluid percussion brain injury (FPI) and treated 15 min later with GUO (7.5 mg/kg) or vehicle (saline 0.9%). Analyses were performed in hippocampus and cortex 3 h post-trauma and revealed significant mitochondrial dysfunction, characterized by a disrupted membrane potential, unbalanced redox system, decreased mitochondrial viability, and complex I inhibition. Further, disruption of Ca 2+ homeostasis and increased mitochondrial swelling was also noted. Our results showed that mitochondrial dysfunction contributed to decreased glutamate uptake and levels of glial glutamate transporters (glutamate transporter 1 and glutamate aspartate transporter), which leads to excitotoxicity. GUO treatment ameliorated mitochondrial damage and glutamatergic dyshomeostasis. Thus, GUO might provide a new efficacious strategy for the treatment acute physiological alterations secondary to TBI.

Comprehensive Evaluation of Neuroprotection Achieved by Extended Selective Brain Cooling Therapy in a Rat Model of Penetrating Ballistic-Like Brain Injury

PubMed Central

Shear, Deborah A.; Deng-Bryant, Ying; Leung, Lai Yee; Wei, Guo; Chen, Zhiyong; Tortella, Frank C.

2016-01-01

Brain hypothermia has been considered as a promising alternative to whole-body hypothermia in treating acute neurological disease, for example, traumatic brain injury. Previously, we demonstrated that 2-hours selective brain cooling (SBC) effectively mitigated acute (≤24 hours postinjury) neurophysiological dysfunction induced by a penetrating ballistic-like brain injury (PBBI) in rats. This study evaluated neuroprotective effects of extended SBC (4 or 8 hours in duration) on sub-acute secondary injuries between 3 and 21 days postinjury (DPI). SBC (34°C) was achieved via extraluminal cooling of rats' bilateral common carotid arteries (CCA). Depending on the experimental design, SBC was introduced either immediately or with a 2- or 4-hour delay after PBBI and maintained for 4 or 8 hours. Neuroprotective effects of SBC were evaluated by measuring brain lesion volume, axonal injury, neuroinflammation, motor and cognitive functions, and post-traumatic seizures. Compared to untreated PBBI animals, 4 or 8 hours SBC treatment initiated immediately following PBBI produced comparable neuroprotective benefits against PBBI-induced early histopathology at 3 DPI as evidenced by significant reductions in brain lesion volume, axonal pathology (beta-amyloid precursor protein staining), neuroinflammation (glial fibrillary acetic protein stained-activated astrocytes and rat major histocompatibility complex class I stained activated microglial cell), and post-traumatic nonconvulsive seizures. In the later phase of the injury (7–21 DPI), significant improvement on motor function (rotarod test) was observed under most SBC protocols, including the 2-hour delay in SBC initiation. However, SBC treatment failed to improve cognitive performance (Morris water maze test) measured 13–17 DPI. The protective effects of SBC on delayed axonal injury (silver staining) were evident out to 14 DPI. In conclusion, the CCA cooling method of SBC produced neuroprotection measured across multiple

Minimal Brain Dysfunction in Childhood: II. Late Outcome in Relation to Initial Presentation. III. Predictive Factors in Relation to Late Outcome.

ERIC Educational Resources Information Center

Milman, Doris H.

Two studies explore the late outcome of minimal brain dysfunction in 73 patients in relation to their initial presentation and predictive factors. Both studies followed the patients for a period of 10 to 20 years. Findings from the first study of initial presentation in relation to adult outcome showed that there was a strong positive correlation…

[Hypopituitarism following traumatic brain injury: diagnostic and therapeutic issues].

PubMed

Lecoq, A-L; Chanson, P

2015-10-01

Traumatic Brain Injury (TBI) is a well-known public health problem worldwide and is a leading cause of death and disability, particularly in young adults. Besides neurological and psychiatric issues, pituitary dysfunction can also occur after TBI, in the acute or chronic phase. The exact prevalence of post-traumatic hypopituitarism is difficult to assess due to the wide heterogeneity of published studies and bias in interpretation of hormonal test results in this specific population. Predictive factors for hypopituitarism have been proposed and are helpful for the screening. The pathophysiology of pituitary dysfunction after TBI is not well understood but the vascular hypothesis is privileged. Activation of pituitary stem/progenitor cells is probably involved in the recovery of pituitary functions. Those cells also play a role in the induction of pituitary tumors, highlighting their crucial place in pituitary conditions. This review updates the current data related to anterior pituitary dysfunction after TBI and discusses the bias and difficulties encountered in its diagnosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Parallel recovery of consciousness and sleep in acute traumatic brain injury.

PubMed

Duclos, Catherine; Dumont, Marie; Arbour, Caroline; Paquet, Jean; Blais, Hélène; Menon, David K; De Beaumont, Louis; Bernard, Francis; Gosselin, Nadia

2017-01-17

To investigate whether the progressive recuperation of consciousness was associated with the reconsolidation of sleep and wake states in hospitalized patients with acute traumatic brain injury (TBI). This study comprised 30 hospitalized patients (age 29.1 ± 13.5 years) in the acute phase of moderate or severe TBI. Testing started 21.0 ± 13.7 days postinjury. Consciousness level and cognitive functioning were assessed daily with the Rancho Los Amigos scale of cognitive functioning (RLA). Sleep and wake cycle characteristics were estimated with continuous wrist actigraphy. Mixed model analyses were performed on 233 days with the RLA (fixed effect) and sleep-wake variables (random effects). Linear contrast analyses were performed in order to verify if consolidation of the sleep and wake states improved linearly with increasing RLA score. Associations were found between scores on the consciousness/cognitive functioning scale and measures of sleep-wake cycle consolidation (p < 0.001), nighttime sleep duration (p = 0.018), and nighttime fragmentation index (p < 0.001). These associations showed strong linear relationships (p < 0.01 for all), revealing that consciousness and cognition improved in parallel with sleep-wake quality. Consolidated 24-hour sleep-wake cycle occurred when patients were able to give context-appropriate, goal-directed responses. Our results showed that when the brain has not sufficiently recovered a certain level of consciousness, it is also unable to generate a 24-hour sleep-wake cycle and consolidated nighttime sleep. This study contributes to elucidating the pathophysiology of severe sleep-wake cycle alterations in the acute phase of moderate to severe TBI. © 2016 American Academy of Neurology.

Cognitive control dysfunction in emotion dysregulation and psychopathology of major depression (MD): Evidence from transcranial brain stimulation of the dorsolateral prefrontal cortex (DLPFC).

PubMed

Salehinejad, Mohammad Ali; Ghanavai, Elham; Rostami, Reza; Nejati, Vahid

2017-03-01

Previous studies showed that MD is associated with a variety of cognitive deficits and executive dysfunctions which can persist even in remitted states. However, the role of cognitive impairments in MD psychopathology and treatment is not fully understood. This article aims to discuss how executive functions central components (e.g., Working memory and attention) mediate MD psychopathology considering the role of dorsolateral prefrontal cortex (dLPFC) and present findings of a brain stimulation experiment to support this notion. The effect of transcranial direct current stimulation (tDCS) of the dLPFC on enhancing cognitive control functions was investigated. Twenty-four patients with MD (Experimental group=12, Control group=12) received 10 sessions of tDCS (2mA for 30min) over 10 consecutive days. The experimental group received active stimulation and the control group received sham stimulation. Participant's performance on cognitive functions (PAL, SRM, RVP and CRT from CANTAB) and their depression scores were assessed before and after tDCS. Results showed that brain stimulation of the dLPFC improved executive dysfunction in patients and a significant improvement on depression scores was also observed suggesting that cognitive control dysfunction may be a mediator in emotional dysregulation and psychopathology of MD. No follow-up investigation was done in this study which does not allow to infer long-term effect of tDCS. Low-focality of tDCS might have stimulated adjacent areas too. Cognitive components, namely cognitive control dysfunction, play role in MD psychopathology as they are involved in emotion dysregulation in MD. The amount of contribution of cognitive components in MD psychopathology is however, an open question. tDCS can be used as an intervention to improve cognitive dysfunction in MD. Copyright © 2017 Elsevier B.V. All rights reserved.

Ameliorative effects of oleanolic acid on fluoride induced metabolic and oxidative dysfunctions in rat brain: Experimental and biochemical studies.

PubMed

Sarkar, Chaitali; Pal, Sudipta; Das, Niranjan; Dinda, Biswanath

2014-04-01

Beneficial effects of oleanolic acid on fluoride-induced oxidative stress and certain metabolic dysfunctions were studied in four regions of rat brain. Male Wistar rats were treated with sodium fluoride at a dose of 20 mg/kg b.w./day (orally) for 30 days. Results indicate marked reduction in acidic, basic and neutral protein contents due to fluoride toxicity in cerebrum, cerebellum, pons and medulla. DNA, RNA contents significantly decreased in those regions after fluoride exposure. Activities of proteolytic enzymes (such as cathepsin, trypsin and pronase) were inhibited by fluoride, whereas transaminase enzyme (GOT and GPT) activities increased significantly in brain tissue. Fluoride appreciably elevated brain malondialdehyde level, free amino acid nitrogen, NO content and free OH radical generation. Additionally, fluoride perturbed GSH content and markedly reduced SOD, GPx, GR and CAT activities in brain tissues. Oral supplementation of oleanolic acid (a plant triterpenoid), at a dose of 5mg/kgb.w./day for last 14 days of fluoride treatment appreciably ameliorated fluoride-induced alteration of brain metabolic functions. Appreciable counteractive effects of oleanolic acid against fluoride-induced changes in protein and nucleic acid contents, proteolytic enzyme activities and other oxidative stress parameters indicate that oleanolic acid has potential antioxidative effects against fluoride-induced oxidative brain damage. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hypothalamo-pituitary dysfunction in patients with chronic subdural hematoma.

PubMed

Hána, V; Kosák, M; Masopust, V; Netuka, D; Lacinová, Z; Kršek, M; Marek, J; Pecen, L

2012-01-01

Relatively frequent pituitary hormone deficiencies are observed after traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and according to the published studies the neuroendocrine consequenses of traumatic brain injury are underdiagnosed. In a cohort of 59 patients (49 males, mean age 68.3 years, 36-88 years) after evacuation of subdural hematoma (SDH) were evaluated hypothalamo-pituitary functions one week after surgery, after three months and after one year. Hypogonadism was present in 26 % of patients in an acute phase, but in the majority had a transient character. Less than half of patients was GH deficient (GHD) according to the GHRH+arginine test. We did not find any serious case of hypocortisolism, hypothyroidism, diabetes insipidus centralis nor syndrome of inappropriate secretion of ADH (SIADH). Transient partial hypocortisolism was present in two cases, but resolved. We did not find relation between extension of SDH or clinical severity and development of hypopituitarism. In conclusion, in some patients with SDH growth hormone deficiency or hypogonadism was present. No serious hypocortisolism, hypothyroidism, diabetes insipidus nor SIADH was observed. The possibility of neuroendocrine dysfunction should be considered in patients with SDH, although the deficits are less frequent than in patients after TBI or SAH.

The central role of renal microcirculatory dysfunction in the pathogenesis of acute kidney injury.

PubMed

Ince, Can

2014-01-01

Acute kidney injury (AKI) is a rapidly developing condition often associated with critical illness, with a high degree of morbidity and mortality, whose pathophysiology is ill understood. Recent investigations have identified the dysfunction of the renal microcirculation and its cellular and subcellular constituents as being central to the etiology of AKI. Injury is caused by inflammatory activation involving endothelial leucocyte interactions in combination with dysregulation of the homeostatis between oxygen, nitric oxide, and reactive oxygen species. Effective therapies expected to resolve AKI will have to control inflammation and restore this homeostasis. In order to apply and guide these therapies effectively, diagnostic tools aimed at physiological biomarkers of AKI for monitoring renal microcirculatory function in advance of changes in pharmacological biomarkers associated with structural damage of the kidney will need to be developed. 2014 S. Karger AG, Basel.

Distribution of trans-resveratrol and its metabolites after acute or sustained administration in mouse heart, brain, and liver.

PubMed

Menet, Marie-Claude; Baron, Stephanie; Taghi, Meryam; Diestra, Remi; Dargère, Delphine; Laprévote, Olivier; Nivet-Antoine, Valérie; Beaudeux, Jean-Louis; Bédarida, Tatiana; Cottart, Charles-Henry

2017-08-01

Trans-resveratrol is widely studied for its potentially beneficial effects on numerous disorders. It is rapidly metabolized and its metabolites can exhibit biological activity. The present study aimed to investigate whether acute or sustained trans-resveratrol administration impacted on the distribution of trans-resveratrol and its metabolites in brain, heart, and liver. We used ultra-HPLC quadrupole-TOF (UHPLC-Q-TOF) in a full-scan mode to identify and assess large numbers of resveratrol metabolites. For acute intake, mice were overfed with a single dose of trans-resveratrol (150 mg/kg) and organs were collected after 30 and 60 min. For sustained intake, trans-resveratrol was given in the chow (0.04% w/w corresponding to 40 mg/kg/day), and plasma and the organs were collected after 3 months of this resveratrol diet. We found that trans-resveratrol-3-O-glucuronide and resveratrol-3-sulfate were the main metabolites found after acute intake, and free trans-resveratrol (in the brain and heart) and dihydroresveratrol derivatives were found after sustained administration CONCLUSIONS: Our results show notable differences between acute and sustained administration of trans-resveratrol and distribution of trans-resveratrol and its metabolites in mouse heart, brain, and liver. The results suggest a strategy for development of galenic forms of resveratrol. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

PubMed

Tudurí, E; Beiroa, D; Porteiro, B; López, M; Diéguez, C; Nogueiras, R

2015-08-01

To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents. © 2015 John Wiley & Sons Ltd.

Iron assessment to protect the developing brain.

PubMed

Georgieff, Michael K

2017-12-01

Iron deficiency (ID) before the age of 3 y can lead to long-term neurological deficits despite prompt diagnosis of ID anemia (IDA) by screening of hemoglobin concentrations followed by iron treatment. Furthermore, pre- or nonanemic ID alters neurobehavioral function and is 3 times more common than IDA in toddlers. Given the global prevalence of ID and the enormous societal cost of developmental disabilities across the life span, better methods are needed to detect the risk of inadequate concentrations of iron for brain development (i.e., brain tissue ID) before dysfunction occurs and to monitor its amelioration after diagnosis and treatment. The current screening and treatment strategy for IDA fails to achieve this goal for 3 reasons. First, anemia is the final state in iron depletion. Thus, the developing brain is already iron deficient when IDA is diagnosed owing to the prioritization of available iron to red blood cells over all other tissues during negative iron balance in development. Second, brain ID, independently of IDA, is responsible for long-term neurological deficits. Thus, starting iron treatment after the onset of IDA is less effective than prevention. Multiple studies in humans and animal models show that post hoc treatment strategies do not reliably prevent ID-induced neurological deficits. Third, most currently used indexes of ID are population statistical cutoffs for either hematologic or iron status but are not bioindicators of brain ID and brain dysfunction in children. Furthermore, their relation to brain iron status is not known. To protect the developing brain, there is a need to generate serum measures that index brain dysfunction in the preanemic stage of ID, assess the ability of standard iron indicators to detect ID-induced brain dysfunction, and evaluate the efficacy of early iron treatment in preventing ID-induced brain dysfunction. © 2017 American Society for Nutrition.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome may have a hypothalamus-periaqueductal gray localization.

PubMed

Chow, Cristelle; Fortier, Marielle Valerie; Das, Lena; Menon, Anuradha P; Vasanwala, Rashida; Lam, Joyce C M; Ng, Zhi Min; Ling, Simon Robert; Chan, Derrick W S; Choong, Chew Thye; Liew, Wendy K M; Thomas, Terrence

2015-05-01

Anatomical localization of the rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome has proved elusive. Most patients had neuroimaging after cardiorespiratory collapse, revealing a range of ischemic lesions. A 15-year-old obese boy with an acute febrile encephalopathy had hypoventilation, autonomic dysfunction, visual hallucinations, hyperekplexia, and disordered body temperature, and saltwater regulation. These features describe the ROHHAD syndrome. Cerebrospinal fluid analysis showed pleocytosis, elevated neopterins, and oligoclonal bands, and serology for systemic and antineuronal antibodies was negative. He improved after receiving intravenous steroids, immunoglobulins, and long-term mycophenolate. Screening for neural crest tumors was negative. Magnetic resonance imaging of the brain early in his illness showed focal inflammation in the periaqueductal gray matter and hypothalamus. This unique localization explains almost all symptoms of this rare autoimmune encephalitis. Copyright © 2015 Elsevier Inc. All rights reserved.

Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure

PubMed Central

Chen, Florence; Ohashi, Norifumi; Li, Wensheng; Eckman, Christopher; Nguyen, Justin H.

2010-01-01

Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells with MMP-9 cDNA using pc DNA3.1 (+)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain endothelial cells resulted in significant degradation of tight junction proteins occludin and claudin-5. The alterations in tight junction proteins correlated with increased permeability to FITC-dextran molecules. The degradation of tight junction proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain EC. We also found that tight junction proteins degradation was reversed with GM6001 in brains of mice with ALF. Conclusions Tight junction proteins are significantly perturbed in brains of mice with ALF. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALF. PMID:19821483

High risk of hypogonadism after traumatic brain injury: clinical implications.

PubMed

Agha, Amar; Thompson, Christopher J

2005-01-01

Several recent studies have convincingly documented a close association between traumatic brain injury (TBI) and pituitary dysfunction. Post-traumatic hypogonadism is very common in the acute post-TBI phase, though most cases recover within six to twelve months following trauma. The functional significance of early hypogonadism, which may reflect adaptation to acute illness, is not known. Hypogonadism persists, however, in 10-17% of long-term survivors. Sex steroid deficiency has implications beyond psychosexual function and fertility for survivors of TBI. Muscle weakness may impair functional recovery from trauma and osteoporosis may be exacerbated by immobility secondary to trauma. Identification and appropriate and timely management of post-traumatic hypogonadism is important in order to optimise patient recovery from head trauma, improve quality of life and avoid the long-term adverse consequences of untreated sex steroid deficiency.

Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

PubMed

Simpkins, Alexis N; Dias, Christian; Leigh, Richard

2016-09-01

Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator. © 2016 American Heart Association, Inc.

Effect of Ginkgo biloba extract on apoptosis of brain tissues in rats with acute cerebral infarction and related gene expression.

PubMed

Wu, C; Zhao, X; Zhang, X; Liu, S; Zhao, H; Chen, Y

2015-06-11

We investigated the effect of Ginkgo biloba extract on apoptosis of brain tissues in rats with acute cerebral infarction and apoptosis-related gene expression. Rat models of acute cerebral infarction were constructed using the suture method, and randomly divided into the control group, model, and treatment groups. In the treatment group, 4 mg/kg G. biloba extract was intravenously injected into the rat tail vein. Phosphate-buffered saline solution was injected in the model group. Seventy-two hours after treatment, rats were euthanized, and brain tissues were removed to analyze the changes in caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) mRNA and protein levels, and variation in brain tissue cells' apoptosis indices was measured. Compared with the control group, the model and treatment groups showed significantly upregulated caspase-3, Bcl-2, and Bax mRNA and protein levels in brain tissues, but remarkably downregulated Bcl-2 mRNA and protein levels (P < 0.05). After treatment, in treatment group brain tissues, caspase-3 and Bax mRNA and protein levels were significantly lower than those in the model group, while Bcl-2 mRNA and protein levels were higher than that in the model group (P < 0.05). The model and treatment groups showed increased cell apoptosis indices of brain tissues compared to the control group; after treatment, the apoptosis index in the treatment group was significantly downregulated compared with that in the model group (P < 0.05). In conclusion, G. biloba extract significantly reduced apoptosis in rat brain tissue cells with acute cerebral infarction and thus protected brain tissues.

Acute Ethanol Administration Rapidly Increases Phosphorylation of Conventional Protein Kinase C in Specific Mammalian Brain Regions in Vivo

PubMed Central

Wilkie, Mary Beth; Besheer, Joyce; Kelley, Stephen P.; Kumar, Sandeep; O’Buckley, Todd K.; Morrow, A. Leslie; Hodge, Clyde W.

2010-01-01

Background Protein kinase C (PKC) is a family of isoenzymes that regulate a variety of functions in the central nervous system including neurotransmitter release, ion channel activity, and cell differentiation. Growing evidence suggests that specific isoforms of PKC influence a variety of behavioral, biochemical, and physiological effects of ethanol in mammals. The purpose of this study was to determine whether acute ethanol exposure alters phosphorylation of conventional PKC isoforms at a threonine 674 (p-cPKC) site in the hydrophobic domain of the kinase, which is required for its catalytic activity. Methods Male rats were administered a dose range of ethanol (0, 0.5, 1, or 2 g/kg, intragastric) and brain tissue was removed 10 minutes later for evaluation of changes in p-cPKC expression using immunohistochemistry and Western blot methods. Results Immunohistochemical data show that the highest dose of ethanol (2 g/kg) rapidly increases p-cPKC immunoreactivity specifically in the nucleus accumbens (core and shell), lateral septum, and hippocampus (CA3 and dentate gyrus). Western blot analysis further showed that ethanol (2 g/kg) increased p-cPKC expression in the P2 membrane fraction of tissue from the nucleus accumbens and hippocampus. Although p-cPKC was expressed in numerous other brain regions, including the caudate nucleus, amygdala, and cortex, no changes were observed in response to acute ethanol. Total PKCγ immunoreactivity was surveyed throughout the brain and showed no change following acute ethanol injection. Conclusions These results suggest that ethanol rapidly promotes phosphorylation of cPKC in limbic brain regions, which may underlie effects of acute ethanol on the nervous system and behavior. PMID:17511744

Cognitive Impairment and Whole Brain Diffusion in Patients with Neuromyelitis Optica after Acute Relapse

ERIC Educational Resources Information Center

He, Diane; Wu, Qizhu; Chen, Xiuying; Zhao, Daidi; Gong, Qiyong; Zhou, Hongyu

2011-01-01

The objective of this study investigated cognitive impairments and their correlations with fractional anisotropy (FA) and mean diffusivity (MD) in patients with neuromyelitis optica (NMO) without visible lesions on conventional brain MRI during acute relapse. Twenty one patients with NMO and 21 normal control subjects received several cognitive…

Cognitive dysfunction and functional magnetic resonance imaging in systemic lupus erythematosus.

PubMed

Barraclough, M; Elliott, R; McKie, S; Parker, B; Bruce, I N

2015-10-01

Cognitive dysfunction is a common aspect of systemic lupus erythematosus (SLE) and is increasingly reported as a problem by patients. In many cases the exact cause is unclear. Limited correlations between specific autoantibodies or structural brain abnormalities and cognitive dysfunction in SLE have been reported. It may be that the most appropriate biomarkers have yet to be found. Functional magnetic resonance imaging (fMRI) is a technique used in many other conditions and provides sensitive measures of brain functionality during cognitive tasks. It is now beginning to be employed in SLE studies. These studies have shown that patients with SLE often perform similarly to healthy controls in terms of behavioural measures on cognitive tasks. However, SLE patients appear to employ compensatory brain mechanisms, such as increased response in fronto-parietal regions, to maintain adequate cognitive performance. As there have been only a few studies using fMRI in SLE to investigate cognitive dysfunction, many questions remain unanswered. Further research could, however, help to identify biomarkers for cognitive dysfunction in SLE. © The Author(s) 2015.

Takotsubo-like Myocardial Dysfunction in a Patient with Botulism.

PubMed

Tonomura, Shuichi; Kakehi, Yoshiaki; Sato, Masatoshi; Naito, Yuki; Shimizu, Hisao; Goto, Yasunobu; Takahashi, Nobuyuki

2017-11-01

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease.

Takotsubo-like Myocardial Dysfunction in a Patient with Botulism

PubMed Central

Tonomura, Shuichi; Kakehi, Yoshiaki; Sato, Masatoshi; Naito, Yuki; Shimizu, Hisao; Goto, Yasunobu; Takahashi, Nobuyuki

2017-01-01

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease. PMID:28924131

Association between in-hospital mortality and renal dysfunction in 186,219 patients hospitalized for acute stroke in the Emilia-Romagna region of Italy.

PubMed

Fabbian, Fabio; Gallerani, Massimo; Pala, Marco; De Giorgi, Alfredo; Salmi, Raffaella; Dentali, Francesco; Ageno, Walter; Manfredini, Roberto

2014-11-01

Using a regional Italian database, we evaluated the relationship between renal dysfunction and in-hospital mortality (IHM) in patients with acute stroke (ischemic/hemorrhagic). Patients were classified on the basis of renal damage: without renal dysfunction, with chronic kidney disease (CKD), and with end-stage renal disease (ESRD). Of a total of 186,219 patients with a first episode of stroke, 1626 (0.9%) had CKD and 819 (0.4%) had ESRD. Stroke-related IHM (total cases) was independently associated with CKD, ESRD, atrial fibrillation (AF), age, and Charlson comorbidity index (CCI). In patients with ischemic stroke (n=154,026), IHM remained independently associated with CKD, ESRD, AF, and CCI. In patients with hemorrhagic stroke (n=32,189), variables that were independently associated with IHM were CKD, ESRD, and AF. Renal dysfunction is associated with IHM related to stroke, both ischemic and hemorrhagic, with even higher odds ratios than those of other established risk factors, such as age, comorbidities, and AF. © The Author(s) 2013.

Adolescent TBI-induced hypopituitarism causes sexual dysfunction in adult male rats.

PubMed

Greco, Tiffany; Hovda, David A; Prins, Mayumi L

2015-02-01

Adolescents are at greatest risk for traumatic brain injury (TBI) and repeat TBI (RTBI). TBI-induced hypopituitarism has been documented in both adults and juveniles and despite the necessity of pituitary function for normal physical and brain development, it is still unrecognized and untreated in adolescents following TBI. TBI induced hormonal dysfunction during a critical developmental window has the potential to cause long-term cognitive and behavioral deficits and the topic currently remains unaddressed. The purpose of this study was to determine if four mild TBIs delivered to adolescent male rats disrupts testosterone production and adult behavioral outcomes. Plasma testosterone was quantified from 72 hrs preinjury to 3 months postinjury and pubertal onset, reproductive organ growth, erectile function and reproductive behaviors were assessed at 1 and 2 months postinjury. RTBI resulted in both acute and chronic decreases in testosterone production and delayed onset of puberty. Significant deficits were observed in reproductive organ growth, erectile function and reproductive behaviors in adult rats at both 1 and 2 months postinjury. These data suggest adolescent RTBI-induced hypopituitarism underlies abnormal behavioral changes observed during adulthood. The impact of undiagnosed hypopituitarism following RTBI in adolescence has significance not only for growth and puberty, but also for brain development and neurobehavioral function as adults. © 2014 Wiley Periodicals, Inc.

The Risk of Neurological Dysfunctions after Deep Hypothermic Circulatory Arrest with Retrograde Cerebral Perfusion.

PubMed

Gatti, Giuseppe; Benussi, Bernardo; Currò, Placido; Forti, Gabriella; Rauber, Elisabetta; Minati, Alessandro; Gabrielli, Marco; Tognolli, Umberto; Sinagra, Gianfranco; Pappalardo, Aniello

2017-12-01

Retrograde cerebral perfusion (RCP) is a brain protection technique that is adopted generally for anticipated short periods of deep hypothermic circulatory arrest (DHCA). However, the real impact of this technique on cerebral protection during DHCA remains a controversial issue. For 344 (59.5%) of 578 consecutive patients (mean age, 66.9 ± 10.9 years) who underwent cardiovascular surgery under DHCA at the present authors' institution (1999-2015), RCP was the sole technique of cerebral protection that was adopted in addition to deep hypothermia. Surgery of the thoracic aorta was performed in 95.9% of these RCP patients; in 92 cases there was an aortic arch involvement. Outcomes were reviewed retrospectively. The focus was on postoperative neurological dysfunctions. There were 33 (9.6%) in-hospital deaths. Thirty-one (9%) patients had permanent neurological dysfunctions and 66 (19.1%) transitory neurological dysfunctions alone. Age older than 74 years (odds ratio [OR], 1.88, P = .023), surgery for acute aortic dissection (OR, 2.57; P = .0009), and DHCA time longer than 25 minutes (OR, 2.44; P = .0021) were predictors of neurological dysfunctions. The 10-year nonparametric estimate of freedom from all-cause death was 61.8% (95% confidence interval, 57.8%-65.8%). Permanent postoperative neurological dysfunctions were risk factors for cardiac or cerebrovascular death (hazard ratio, 2.6; P = .039) even after an adjusted survival analysis (P < .04). According to the study findings, RCP, in addition to deep hypothermia, combines with a low risk of neurological dysfunctions provided that DHCA length is 25 minutes or less. Permanent postoperative neurological dysfunctions are predictors of poor late survival. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice.

PubMed

Edut, S; Rubovitch, V; Rehavi, M; Schreiber, S; Pick, C G

2014-12-01

Driving under methylenedioxymethamphetamine (MDMA) influence increases the risk of being involved in a car accident, which in turn can lead to traumatic brain injury. The behavioral deficits after traumatic brain injury (TBI) are closely connected to dopamine pathway dysregulation. We have previously demonstrated in mice that low MDMA doses prior to mTBI can lead to better performances in cognitive tests. The purpose of this study was to assess in mice the changes in the dopamine system that occurs after both MDMA and minimal traumatic brain injury (mTBI). Experimental mTBI was induced using a concussive head trauma device. One hour before injury, animals were subjected to MDMA. Administration of MDMA before injury normalized the alterations in tyrosine hydroxylase (TH) levels that were observed in mTBI mice. This normalization was also able to lower the elevated dopamine receptor type 2 (D2) levels observed after mTBI. Brain-derived neurotrophic factor (BDNF) levels did not change following injury alone, but in mice subjected to MDMA and mTBI, significant elevations were observed. In the behavioral tests, haloperidol reversed the neuroprotection seen when MDMA was administered prior to injury. Altered catecholamine synthesis and high D2 receptor levels contribute to cognitive dysfunction, and strategies to normalize TH signaling and D2 levels may provide relief for the deficits observed after injury. Pretreatment with MDMA kept TH and D2 receptor at normal levels, allowing regular dopamine system activity. While the beneficial effect we observe was due to a dangerous recreational drug, understanding the alterations in dopamine and the mechanism of dysfunction at a cellular level can lead to legal therapies and potential candidates for clinical use.

Global brain atrophy and metabolic dysfunction in LGI1 encephalitis: A prospective multimodal MRI study.

PubMed

Szots, Monika; Blaabjerg, Morten; Orsi, Gergely; Iversen, Pernille; Kondziella, Daniel; Madsen, Camilla G; Garde, Ellen; Magnusson, Peter O; Barsi, Peter; Nagy, Ferenc; Siebner, Hartwig R; Illes, Zsolt

2017-05-15

Chronic cognitive deficits are frequent in leucin-rich glioma-inactivated 1 protein (LGI1) encephalitis. We examined structural and metabolic brain abnormalities following LGI1 encephalitis and correlated findings with acute and follow-up clinical outcomes. Nine patients underwent prospective multimodal 3 Tesla MRI 33.1±18months after disease onset, including automated volumetry, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). Data were compared to 9 age- and sex-matched healthy controls. Although extratemporal lesions were not present on MRI in the acute stage, tract-based spatial statistics analyses of DTI during follow-up showed widespread changes in the cerebral and cerebellar white matter (WM), most prominent in the anterior parts of the corona radiata, capsula interna and corpus callosum. MRS revealed lower glutamine/glutamate WM levels compared to controls. Higher cerebellar gray matter volume was associated with better function at disease onset (measured by the modified Rankin Scale), and higher putaminal volume was associated with better cognition by Addenbrooke's Cognitive Examination test at 23.4±7.6months. Poor clinical outcome following LGI1 encephalitis is associated with global brain atrophy and disintegration of white matter tracts. The pathological changes affect not only temporomesial structures but also frontal lobes and the cerebellum. Copyright © 2017 Elsevier B.V. All rights reserved.

Salt and nitric oxide synthase inhibition-induced hypertension: kidney dysfunction and brain anti-oxidant capacity.

PubMed

Oktar, Süleyman; Ilhan, Selçuk; Meydan, Sedat; Aydin, Mehmet; Yönden, Zafer; Gökçe, Ahmet

2010-01-01

The specific aim of this study was to examine the effects of salt-loading on kidney function and brain antioxidant capacity. Wistar rats were divided into four groups: Control rats were given normal drinking water and no drug treatment for 2 weeks. LNNA group: rats were given normal drinking water and the nitric oxide (NO) inhibitor NG-nitro-L-arginine (L-NNA), 3 mg/kg/day. LNNA + Salt group: rats were given drinking water containing salt 2% and 3 mg/kg L-NNA. Salt group: rats were given drinking water containing salt 2% and no drug treatment. Basal blood pressure and the levels of serum BUN, creatinine, uric acid, cortisol, electrolyte, serum antioxidant capacity, and oxidative stress were measured. NO, superoxide dismutase (SOD), and catalase (CAT) levels were measured in the hypothalamus, brainstem, and cerebellum. Salt overload increased the blood pressure of the LNNA + Salt group. Salt-loading enhanced BUN, creatinine, sodium retention. High salt produced an increase in uric acid levels and a decrease in cortisol levels in serum. Additionally, the oxidative stress index in serum increased in the LNNA + Salt group. Salt-loading enhanced brain NO levels, but not SOD and CAT activity. L-NNA increased brain SOD activity, but not CAT and NO levels. In conclusion, salt-loading causes hypertension, kidney dysfunction, and enhances oxidative stress in salt-sensitive rats.

How acute total sleep loss affects the attending brain: a meta-analysis of neuroimaging studies.

PubMed

Ma, Ning; Dinges, David F; Basner, Mathias; Rao, Hengyi

2015-02-01

Attention is a cognitive domain that can be severely affected by sleep deprivation. Previous neuroimaging studies have used different attention paradigms and reported both increased and reduced brain activation after sleep deprivation. However, due to large variability in sleep deprivation protocols, task paradigms, experimental designs, characteristics of subject populations, and imaging techniques, there is no consensus regarding the effects of sleep loss on the attending brain. The aim of this meta-analysis was to identify brain activations that are commonly altered by acute total sleep deprivation across different attention tasks. Coordinate-based meta-analysis of neuroimaging studies of performance on attention tasks during experimental sleep deprivation. The current version of the activation likelihood estimation (ALE) approach was used for meta-analysis. The authors searched published articles and identified 11 sleep deprivation neuroimaging studies using different attention tasks with a total of 185 participants, equaling 81 foci for ALE analysis. The meta-analysis revealed significantly reduced brain activation in multiple regions following sleep deprivation compared to rested wakefulness, including bilateral intraparietal sulcus, bilateral insula, right prefrontal cortex, medial frontal cortex, and right parahippocampal gyrus. Increased activation was found only in bilateral thalamus after sleep deprivation compared to rested wakefulness. Acute total sleep deprivation decreases brain activation in the fronto-parietal attention network (prefrontal cortex and intraparietal sulcus) and in the salience network (insula and medial frontal cortex). Increased thalamic activation after sleep deprivation may reflect a complex interaction between the de-arousing effects of sleep loss and the arousing effects of task performance on thalamic activity. © 2015 Associated Professional Sleep Societies, LLC.

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning.

PubMed

Zakharov, Sergey; Kotikova, Katerina; Nurieva, Olga; Hlusicka, Jiri; Kacer, Petr; Urban, Pavel; Vaneckova, Manuela; Seidl, Zdenek; Diblik, Pavel; Kuthan, Pavel; Navratil, Tomas; Pelclova, Daniela

2017-04-01

The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. The acute maximum (C max ) LT concentrations were higher than concentrations in survivors: C max for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.

Metyrapone prevents acute glucose hypermetabolism and short-term brain damage induced by intrahippocampal administration of 4-aminopyridine in rats.

PubMed

García-García, Luis; Fernández de la Rosa, Rubén; Delgado, Mercedes; Silván, Ágata; Bascuñana, Pablo; Bankstahl, Jens P; Gomez, Francisca; Pozo, Miguel A

2018-02-01

Intracerebral administration of the potassium channel blocker 4-aminopyridine (4-AP) triggers neuronal depolarization and intense acute seizure activity followed by neuronal damage. We have recently shown that, in the lithium-pilocarpine rat model of status epilepticus (SE), a single administration of metyrapone, an inhibitor of the 11β-hydroxylase enzyme, had protective properties of preventive nature against signs of brain damage and neuroinflammation. Herein, our aim was to investigate to which extent, pretreatment with metyrapone (150 mg/kg, i.p.) was also able to prevent eventual changes in the acute brain metabolism and short-term neuronal damage induced by intrahippocampal injection of 4-AP (7 μg/5 μl). To this end, regional brain metabolism was assessed by 2-deoxy-2-[ 18 F]fluoro-d-glucose ([ 18 F]FDG) positron emission tomography (PET) during the ictal period. Three days later, markers of neuronal death and hippocampal integrity and apoptosis (Nissl staining, NeuN and active caspase-3 immunohistochemistry), neurodegeneration (Fluoro-Jade C labeling), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and microglia-mediated neuroinflammation (in vitro [ 18 F]GE180 autoradiography) were evaluated. 4-AP administration acutely triggered marked brain hypermetabolism within and around the site of injection as well as short-term signs of brain damage and inflammation. Most important, metyrapone pretreatment was able to reduce ictal hypermetabolism as well as all the markers of brain damage except microglia-mediated neuroinflammation. Overall, our study corroborates the neuroprotective effects of metyrapone against multiple signs of brain damage caused by seizures triggered by 4-AP. Ultimately, our data add up to the consistent protective effect of metyrapone pretreatment reported in other models of neurological disorders of different etiology. Copyright © 2017 Elsevier Ltd. All rights reserved.

New insights into environmental enteric dysfunction

USDA-ARS?s Scientific Manuscript database

Environmental enteric dysfunction (EED) has been recognised as an important contributing factor to physical and cognitive stunting, poor response to oral vaccines, limited resilience to acute infections and ultimately global childhood mortality. The aetiology of EED remains poorly defined but the ep...

Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection

PubMed Central

Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

2016-01-01

Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells. PMID:27031961

Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection.

PubMed

Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

2016-03-31

Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.

Diastolic dysfunction in the critically ill patient.

PubMed

Suárez, J C; López, P; Mancebo, J; Zapata, L

2016-11-01

Left ventricular diastolic dysfunction is a common finding in critically ill patients. It is characterized by a progressive deterioration of the relaxation and the compliance of the left ventricle. Two-dimensional and Doppler echocardiography is a cornerstone in its diagnosis. Acute pulmonary edema associated with hypertensive crisis is the most frequent presentation of diastolic dysfunction critically ill patients. Myocardial ischemia, sepsis and weaning failure from mechanical ventilation also may be associated with diastolic dysfunction. The treatment is based on the reduction of pulmonary congestion and left ventricular filling pressures. Some studies have found a prognostic role of diastolic dysfunction in some diseases such as sepsis. The present review aims to analyze thoroughly the echocardiographic diagnosis and the most frequent scenarios in critically ill patients in whom diastolic dysfunction plays a key role. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 1. Microdialysis Assessment of Brain Extracellular Fluid Concentrations in Patients with Acute Brain Injury

PubMed Central

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William

2014-01-01

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0–τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml−1. This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution. PMID:24277041

Metronidazole and hydroxymetronidazole central nervous system distribution: 1. microdialysis assessment of brain extracellular fluid concentrations in patients with acute brain injury.

PubMed

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William; Marchand, Sandrine

2014-01-01

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0-τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml(-1). This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.

Hepatic encephalopathy in acute-on-chronic liver failure.

PubMed

Lee, Guan-Huei

2015-10-01

The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication.

PubMed

Faria, Melissa; Prats, Eva; Padrós, Francesc; Soares, Amadeu M V M; Raldúa, Demetrio

2017-04-01

Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included "standard therapy" drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-D-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC 50 )] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.

Monitoring inflammation (including fever) in acute brain injury.

PubMed

Provencio, J Javier; Badjatia, Neeraj

2014-12-01

Inflammation is an important part of the normal physiologic response to acute brain injury (ABI). How inflammation is manifest determines if it augments or hinders the resolution of ABI. Monitoring body temperature, the cellular arm of the inflammatory cascade, and inflammatory proteins may help guide therapy. This summary will address the utility of inflammation monitoring in brain-injured adults. An electronic literature search was conducted for English language articles describing the testing, utility, and optimal methods to measure inflammation in ABI. Ninety-four articles were included in this review. Current evidence suggests that control of inflammation after ABI may hold promise for advances in good outcomes. However, our understanding of how much inflammation is good and how much is deleterious is not yet clear. Several important concepts emerge form our review. First, while continuous temperature monitoring of core body temperature is recommended, temperature pattern alone is not useful in distinguishing infectious from noninfectious fever. Second, when targeted temperature management is used, shivering should be monitored at least hourly. Finally, white blood cell levels and protein markers of inflammation may have a limited role in distinguishing infectious from noninfectious fever. Our understanding of optimal use of inflammation monitoring after ABI is limited currently but is an area of active investigation.

Resting State Functional Connectivity in Mild Traumatic Brain Injury at the Acute Stage: Independent Component and Seed-Based Analyses

PubMed Central

Iraji, Armin; Benson, Randall R.; Welch, Robert D.; O'Neil, Brian J.; Woodard, John L.; Imran Ayaz, Syed; Kulek, Andrew; Mika, Valerie; Medado, Patrick; Soltanian-Zadeh, Hamid; Liu, Tianming; Haacke, E. Mark

2015-01-01

Abstract Mild traumatic brain injury (mTBI) accounts for more than 1 million emergency visits each year. Most of the injured stay in the emergency department for a few hours and are discharged home without a specific follow-up plan because of their negative clinical structural imaging. Advanced magnetic resonance imaging (MRI), particularly functional MRI (fMRI), has been reported as being sensitive to functional disturbances after brain injury. In this study, a cohort of 12 patients with mTBI were prospectively recruited from the emergency department of our local Level-1 trauma center for an advanced MRI scan at the acute stage. Sixteen age- and sex-matched controls were also recruited for comparison. Both group-based and individual-based independent component analysis of resting-state fMRI (rsfMRI) demonstrated reduced functional connectivity in both posterior cingulate cortex (PCC) and precuneus regions in comparison with controls, which is part of the default mode network (DMN). Further seed-based analysis confirmed reduced functional connectivity in these two regions and also demonstrated increased connectivity between these regions and other regions of the brain in mTBI. Seed-based analysis using the thalamus, hippocampus, and amygdala regions further demonstrated increased functional connectivity between these regions and other regions of the brain, particularly in the frontal lobe, in mTBI. Our data demonstrate alterations of multiple brain networks at the resting state, particularly increased functional connectivity in the frontal lobe, in response to brain concussion at the acute stage. Resting-state functional connectivity of the DMN could serve as a potential biomarker for improved detection of mTBI in the acute setting. PMID:25285363

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.

PubMed

Olivier, A; Girerd, N; Michel, J B; Ketelslegers, J M; Fay, R; Vincent, J; Bramlage, P; Pitt, B; Zannad, F; Rossignol, P

2017-08-15

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while

Cortisol evaluation during the acute phase of traumatic brain injury-A prospective study.

PubMed

Bensalah, Meriem; Donaldson, Malcolm; Aribi, Yamina; Iabassen, Malek; Cherfi, Lyes; Nebbal, Mustapha; Medjaher, Meriem; Haffaf, ElMehdi; Abdennebi, Benaissa; Guenane, Kamel; Djermane, Adel; Kemali, Zahra; OuldKablia, Samia

2018-05-01

Biochemical diagnosis of adrenal insufficiency (AI) is difficult in the context of traumatic brain injury (TBI). To assess the frequency and predictive factors of AI in victims of TBI from Algiers. Between November 2009 and December 2013, TBI victims had a single 8-9 am serum cortisol measurement during the acute postinjury period (0-7 days). AI was defined according to basal cortisol levels of 83, 276 and 414 nmol/L. Variables studied were TBI severity according to Glasgow coma scale, duration of intubation and coma, pupillary status, hypotension, anaemia, brain imaging findings, diabetes insipidus and medication. Insulin tolerance test was performed during the recovery phase, defining AI as peak cortisol <500 nmol/L. Cortisol samples were obtained at median 3 (1-7) days from 277 patients (257M: 20F) aged 32 (18-65) years. Acute AI frequency was 8 (2.8%), 20 (21%) and 35 (37%), respectively using the three cortisol cut-offs. Factors predicting AI were diastolic hypotension, sedative medication, diabetes insipidus, skull base fracture and intraparenchymal haematoma. Mortality was highest in patients with acute cortisol <276 nmol/L (44.6% with OR for death 1.64, 95% CI 0.92-3.0, P = .12). During the recovery phase, AI was present in 3 of 3, 12 of 24, 4 of 16 and 20 of 66 patients with week 1 cortisol <83, 83-276, 277-414 and >414 nmol/L. Hydrocortisone replacement is advised in TBI patients with morning cortisol <276 nmol/L or those <414 nmol/L with additional risk factors for AI. As acute and subsequent AI are poorly correlated, patients with moderate/severe TBI require adrenal re-evaluation during the recovery phase. © 2018 John Wiley & Sons Ltd.

Diffusion-weighted imaging score of the brain stem: A predictor of outcome in acute basilar artery occlusion treated with the Solitaire FR device.

PubMed

Mourand, I; Machi, P; Nogué, E; Arquizan, C; Costalat, V; Picot, M-C; Bonafé, A; Milhaud, D

2014-06-01

The prognosis for ischemic stroke due to acute basilar artery occlusion is very poor: Early recanalization remains the main factor that can improve outcomes. The baseline extent of brain stem ischemic damage can also influence outcomes. We evaluated the validity of an easy-to-use DWI score to predict clinical outcome in patients with acute basilar artery occlusion treated by mechanical thrombectomy. We analyzed the baseline clinical and DWI parameters of 31 patients with acute basilar artery occlusion, treated within 24 hours of symptom onset by using a Solitaire FR device. The DWI score of the brain stem was assessed with a 12-point semiquantitative score that separately considered each side of the medulla, pons, and midbrain. Clinical outcome was assessed at 180 days by using the mRS. According to receiver operating characteristic analyses, the cutoff score determined the optimal positive predictive value for outcome. The Spearman rank correlation coefficient assessed the correlation between the DWI brain stem score and baseline characteristics. Successful recanalization (Thrombolysis in Cerebral Infarction 3-2b) was achieved in 23 patients (74%). A favorable outcome (mRS ≤ 2) was observed in 11 patients (35%). An optimal DWI brain stem score of <3 predicted a favorable outcome. The probability of a very poor outcome (mRS ≥ 5) if the DWI brain stem score was ≥5 reached 80% (positive predictive value) and 100% if this score was ≥6. Interobserver reliability of the DWI brain stem score was excellent, with an intraclass correlation coefficient of 0.97 (95% CI, 0.96-0.99). The DWI brain stem score was significantly associated with baseline tetraplegia (P = .001) and coma (P = .005). In patients with acute basilar artery occlusion treated by mechanical thrombectomy, the baseline DWI brain lesion score seems to predict clinical outcome. © 2014 by American Journal of Neuroradiology.

Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis

PubMed Central

Lowes, D. A.; Webster, N. R.; Murphy, M. P.; Galley, H. F.

2013-01-01

Background Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage. Methods Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines. Results MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001). Conclusions Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis. PMID:23381720

Altered Cortical Activation in Adolescents With Acute Migraine: A Magnetoencephalography Study

PubMed Central

Xiang, Jing; deGrauw, Xinyao; Korostenskaja, Milena; Korman, Abraham M.; O’Brien, Hope L.; Kabbouche, Marielle A.; Powers, Scott W.; Hershey, Andrew D.

2013-01-01

To quantitatively assess cortical dysfunction in pediatric migraine, 31 adolescents with acute migraine and age- and gender-matched controls were studied using a magnetoencephalography (MEG) system at a sampling rate of 6,000 Hz. Neuromagnetic brain activation was elicited by a finger-tapping task. The spectral and spatial signatures of magnetoencephalography data in 5 to 2,884 Hz were analyzed using Morlet wavelet and beamformers. Compared with controls, 31 migraine subjects during their headache attack phases (ictal) showed significantly prolonged latencies of neuromagnetic activation in 5 to 30 Hz, increased spectral power in 100 to 200 Hz, and a higher likelihood of neuromagnetic activation in the supplementary motor area, the occipital and ipsilateral sensorimotor cortices, in 2,200 to 2,800 Hz. Of the 31 migraine subjects, 16 migraine subjects during their headache-free phases (interictal) showed that there were no significant differences between interictal and control MEG data except that interictal spectral power in 100 to 200 Hz was significantly decreased. The results demonstrated that migraine subjects had significantly aberrant ictal brain activation, which can normalize interictally. The spread of abnormal ictal brain activation in both low- and high-frequency ranges triggered by movements may play a key role in the cascade of migraine attacks. Perspective This is the first study focusing on the spectral and spatial signatures of cortical dysfunction in adolescents with migraine using MEG signals in a frequency range of 5 to 2,884 Hz. This analyzing aberrant brain activation may be important for developing new therapeutic interventions for migraine in the future. PMID:23792072

Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits

PubMed Central

Corser-Jensen, Chelsea E.; Goodell, Dayton J.; Freund, Ronald K.; Serbedzija, Predrag; Murphy, Robert C.; Farias, Santiago E.; Dell'Acqua, Mark L.; Frey, Lauren C.; Serkova, Natalie; Heidenreich, Kim A.

2014-01-01

Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11 weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arms water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits. PMID:24681156

Acute right ventricular dysfunction: real-time management with echocardiography.

PubMed

Krishnan, Sundar; Schmidt, Gregory A

2015-03-01

In critically ill patients, the right ventricle is susceptible to dysfunction due to increased afterload, decreased contractility, or alterations in preload. With the increased use of point-of-care ultrasonography and a decline in the use of pulmonary artery catheters, echocardiography can be the ideal tool for evaluation and to guide hemodynamic and respiratory therapy. We review the epidemiology of right ventricular failure in critically ill patients; echocardiographic parameters for evaluating the right ventricle; and the impact of mechanical ventilation, fluid therapy, and vasoactive infusions on the right ventricle. Finally, we summarize the principles of management in the context of right ventricular dysfunction and provide recommendations for echocardiography-guided management.

Changes in compressed neurons from dogs with acute and severe cauda equina constrictions following intrathecal injection of brain-derived neurotrophic factor-conjugated polymer nanoparticles☆

PubMed Central

Tan, Junming; Shi, Jiangang; Shi, Guodong; Liu, Yanling; Liu, Xiaohong; Wang, Chaoyang; Chen, Dechun; Xing, Shunming; Shen, Lianbing; Jia, Lianshun; Ye, Xiaojian; He, Hailong; Li, Jiashun

2013-01-01

This study established a dog model of acute multiple cauda equina constriction by experimental constriction injury (48 hours) of the lumbosacral central processes in dorsal root ganglia neurons. The repair effect of intrathecal injection of brain-derived neurotrophic factor with 15 mg encapsulated biodegradable poly(lactide-co-glycolide) nanoparticles on this injury was then analyzed. Dorsal root ganglion cells (L7) of all experimental dogs were analyzed using hematoxylin-eosin staining and immunohistochemistry at 1, 2 and 4 weeks following model induction. Intrathecal injection of brain-derived neurotrophic factor can relieve degeneration and inflammation, and elevate the expression of brain-derived neurotrophic factor in sensory neurons of compressed dorsal root ganglion. Simultaneously, intrathecal injection of brain-derived neurotrophic factor obviously improved neurological function in the dog model of acute multiple cauda equina constriction. Results verified that sustained intraspinal delivery of brain-derived neurotrophic factor encapsulated in biodegradable nanoparticles promoted the repair of histomorphology and function of neurons within the dorsal root ganglia in dogs with acute and severe cauda equina syndrome. PMID:25206593

Targeting Extracellular Histones with Novel RNA Biodrugs for the Treatment of Acute Lung Injury

DTIC Science & Technology

2017-10-01

inactivate) circulating histones and prevent the morbidity and mortality associated with multiple organ dysfunction/ acute respiratory distress syndrome ...patients. 15. SUBJECT TERMS Acute lung injury (ALI), acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome , extracellular...are acute lung injury (ALI) from smoke/chlorine gas inhalation, burns, radiation , influenza and severe infection. Only recently have investigators

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up.

PubMed

Meybohm, Patrick; Kohlhaas, Madeline; Stoppe, Christian; Gruenewald, Matthias; Renner, Jochen; Bein, Berthold; Albrecht, Martin; Cremer, Jochen; Coburn, Mark; Schaelte, Gereon; Boening, Andreas; Niemann, Bernd; Sander, Michael; Roesner, Jan; Kletzin, Frank; Mutlak, Haitham; Westphal, Sabine; Laufenberg-Feldmann, Rita; Ferner, Marion; Brandes, Ivo F; Bauer, Martin; Stehr, Sebastian N; Kortgen, Andreas; Wittmann, Maria; Baumgarten, Georg; Meyer-Treschan, Tanja; Kienbaum, Peter; Heringlake, Matthias; Schoen, Julika; Treskatsch, Sascha; Smul, Thorsten; Wolwender, Ewa; Schilling, Thomas; Fuernau, Georg; Bogatsch, Holger; Brosteanu, Oana; Hasenclever, Dirk; Zacharowski, Kai

2018-03-26

Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

[Magnetic resonance spectroscopy of metabolic changes in mice brain after 2-deoxy-D-glucose injection].

PubMed

Moshkin, M P; Akulov, A E; Petrovskiĭ, D V; Saĭk, O V; Petrovskiĭ, E D; Savelov, A A; Koptug, I V

2012-10-01

In vivo proton magnetic resonance spectroscopy (1H MRS) of ICR male mice was used to study the brain (hippocampus) metabolic response to the acute deficiency of the available energy or to the pro-inflammatory stimulus. Inhibition of glycolysis by means of an intraperitoneal injection with 2-deoxy-D-glucose (2DG) reduced the levels of gamma-aminobutiric acid (GABA), N-acetylaspartate (NAA) and choline compounds, and at the same time increased the levels of glutamate and glutamine. An opposite effect was found after injection with bacterial lipopolysaccharide (LPS)--a very common pro-inflammatory inducer. An increase in the amounts of GABA, NAA and choline compounds in the brain occurred three hours after the injection of LPS. Different metabolic responses to the energy deficiency and the pro-inflammatory stimuli can explain the contradictory results of the brain MRS studies under neurodegenerative pathology, which is accompanied by both mitochondrial dysfunction and inflammation. Prevalence of the excitatory metabolites such as glutamate and glutamine in 2DG treated mice is in good agreement with excitation observed during temporary reduction of the available energy under acute hypoxia or starvation. In turn, LPS, as an inducer of the sickness behavior, shifts brain metabolic pattern to prevalence of the inhibitory neurotransmitter GABA.

Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury.

PubMed

Cuesta, Martín; Hannon, Mark J; Crowley, Rachel K; Behan, Lucy Ann; Tormey, William; Rawluk, Daniel; Delargy, Mark; Agha, Amar; Thompson, Christopher J

2016-01-01

The economic and logistic burden of screening for hypopituitarism following moderate/severe traumatic brain injury (TBI) is considerable. A key recommendation in published guidelines is to prioritize for screening those patients with symptoms suggestive of pituitary dysfunction. The purpose of this study was to evaluate the utility of targeted screening for hypopituitarism in long-term survivors after moderate/severe TBI using referrals on the basis of symptoms. In group 1 (G1), consecutive, unselected patients were screened from the Irish National Neurosurgery Centre, whereas in group 2 (G2) patients were targeted based on the presence of symptoms suggestive of pituitary dysfunction. A total of 137 patients (113 male) were systematically screened (G1) and compared to 112 patients (77 male) referred for pituitary evaluation on the basis of suggestive symptoms (G2). The rate of GH, ACTH, gonadotrophin (GT), TSH and ADH deficiency was compared among groups. Patients referred with menstrual dysfunction had more GH (50% vs 11%, P = 0·001), ACTH (60% vs 14%, P < 0·0001), GT (90% vs 16%, P < 0·0001) deficiency and any pituitary hormone deficit (80% vs 33%, P = 0·003) than G1. Men with symptoms of hypogonadism had more GH (33% vs 11%, P = 0·003), GT (58% vs 16%, P < 0·0001) and TSH (16% vs 1%, P = 0·03) deficiency than G1. Patients with nonspecific symptoms were no more likely to have hypopituitarism than those consecutively screened. Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe TBI. Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening. © 2015 John Wiley & Sons Ltd.

A new threshold of apparent diffusion coefficient values in white matter after successful tissue plasminogen activator treatment for acute brain ischemia.

PubMed

Sato, Atsushi; Shimizu, Yusaku; Koyama, Junichi; Hongo, Kazuhiro

2017-06-01

Tissue plasminogen activator (tPA) is effective for the treatment of acute brain ischemia, but may trigger fatal brain edema or hemorrhage if the brain ischemia results in a large infarct. Herein, we attempted to predict the extent of infarcts by determining the optimal threshold of ADC values on DWI that predictively distinguishes between infarct and reversible areas, and by reconstructing color-coded images based on this threshold. The study subjects consisted of 36 patients with acute brain ischemia in whom MRA had confirmed reopening of the occluded arteries in a short time (mean: 99min) after tPA treatment. We measured the apparetnt diffusion coefficient (ADC) values in several small regions of interest over the white matter within high-intensity areas on the initial diffusion weighted image (DWI); then, by comparing the findings to the follow-up images, we obtained the optimal threshold of ADC values using receiver-operating characteristic analysis. The threshold obtained (583×10 -6 m 2 /s) was lower than those previously reported; this threshold could distinguish between infarct and reversible areas with considerable accuracy (sensitivity: 0.87, specificity: 0.94). The threshold obtained and the reconstructed images were predictive of the final radiological result of tPA treatment, and this threshold may be helpful in determining the appropriate management of patients with acute brain ischemia. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Right ventricular dysfunction as an echocardiographic prognostic factor in hemodynamically stable patients with acute pulmonary embolism: a meta-analysis.

PubMed

Cho, Jae Hyung; Kutti Sridharan, Gurusaravanan; Kim, Seon Ha; Kaw, Roop; Abburi, Triveni; Irfan, Affan; Kocheril, Abraham G

2014-05-06

We investigated whether right ventricular dysfunction (RVD) as assessed by echocardiogram can be used as a prognostic factor in hemodynamically stable patients with acute pulmonary embolism (PE). Short-term mortality has been investigated only in small studies and the results have been controversial. A PubMed search was conducted using two keywords, "pulmonary embolism" and "echocardiogram", for articles published between January 1st 1998 and December 31st 2011. Out of 991 articles, after careful review, we found 12 articles that investigated the implications of RVD as assessed by echocardiogram in predicting short-term mortality for hemodynamically stable patients with acute PE. We conducted a meta-analysis of these data to identify whether the presence of RVD increased short-term mortality. Among 3283 hemodynamically stable patients with acute PE, 1223 patients (37.3%) had RVD, as assessed by echocardiogram, while 2060 patients (62.7%) had normal right ventricular function. Short-term mortality was reported in 167 (13.7%) out of 1223 patients with RVD and in 134 (6.5%) out of 2060 patients without RVD. Hemodynamically stable patients with acute PE who had RVD as assessed by echocardiogram had a 2.29-fold increase in short-term mortality (odds ratio 2.29, 95% confidence interval 1.61-3.26) compared with patients without RVD. In hemodynamically stable patients with acute PE, RVD as assessed by echocardiogram increases short-term mortality by 2.29 times. Consideration should be given to obtaining echocardiogram to identify high-risk patients even if they are hemodynamically stable.

Autophagy inhibitor 3-methyladenine protects against endothelial cell barrier dysfunction in acute lung injury.

PubMed

Slavin, Spencer A; Leonard, Antony; Grose, Valerie; Fazal, Fabeha; Rahman, Arshad

2018-03-01

Autophagy is an evolutionarily conserved cellular process that facilitates the continuous recycling of intracellular components (organelles and proteins) and provides an alternative source of energy when nutrients are scarce. Recent studies have implicated autophagy in many disorders, including pulmonary diseases. However, the role of autophagy in endothelial cell (EC) barrier dysfunction and its relevance in the context of acute lung injury (ALI) remain uncertain. Here, we provide evidence that autophagy is a critical component of EC barrier disruption in ALI. Using an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI, we found that administration of the autophagy inhibitor 3-methyladenine (3-MA), either prophylactically or therapeutically, markedly reduced lung vascular leakage and tissue edema. 3-MA was also effective in reducing the levels of proinflammatory mediators and lung neutrophil sequestration induced by LPS. To test the possibility that autophagy in EC could contribute to lung vascular injury, we addressed its role in the mechanism of EC barrier disruption. Knockdown of ATG5, an essential regulator of autophagy, attenuated thrombin-induced EC barrier disruption, confirming the involvement of autophagy in the response. Similarly, exposure of cells to 3-MA, either before or after thrombin, protected against EC barrier dysfunction by inhibiting the cleavage and loss of vascular endothelial cadherin at adherens junctions, as well as formation of actin stress fibers. 3-MA also reversed LPS-induced EC barrier disruption. Together, these data imply a role of autophagy in lung vascular injury and reveal the protective and therapeutic utility of 3-MA against ALI.

Functional brain imaging of cognitive dysfunction in Parkinson's disease.

PubMed

Hirano, Shigeki; Shinotoh, Hitoshi; Eidelberg, David

2012-10-01

Multiple factors are involved in the development of cognitive impairment in Parkinson's disease (PD) and related disorders. Notably, several underlying factors, such as monoaminergic dysfunction, Lewy body pathology, Alzheimer disease-like pathology and cerebrovascular disease are implied in the PD pathophysiology of cognitive impairment. The mesocortical dopaminergic system is associated with executive functions which are frequently affected in PD and are influenced by local levodopa concentration, dopamine metabolism and baseline performance status. The ventral striatum and frontal cortex are associated with impulse control disorders reported in PD patients treated with dopamine replacement therapy. Cholinergic impairment in PD plays a cardinal role in the development of dementia. Acetylcholinesterase positron emission tomography demonstrates that posterior brain areas are related to cognitive decline in PD patients. Amyloid radiotracer illustrates that patients with PD with severe cognitive impairment were prone to accompanied cortical amyloid deposition. Metabolism/perfusion change associated with cognitive impairment in PD, so-called PD related cognitive pattern, is characterised by reduced frontoparietal activity and is an effective way to differentiate and monitor cognitive function of individual PD patients. Cognitive impairment in PD cannot be explained by a single mechanism and is entangled by multiple factors. Imaging studies can unravel each pathological domain, further shed light on the interrelation between different pathomechanisms, not only in PD but also in other dementia related disorders, and thereby integrate its interpretation to apply to therapeutics in individual patients.

[Acute brain expansion during emergency neck clipping surgery for cerebral aneurysms in a patient with dilated cardiomyopathy].

PubMed

Nakao, M; Kawaguchi, R; Nakatani, K; Niinai, H; Takezaki, T; Hanaki, C

1996-06-01

A 61-year-old male with coma and undiagnosed dilated cardiomyopathy received emergency cerebral aneurysm surgery. Anesthesia was induced with thiamylal, fentanyl and vecuronium and maintained with 66% N2O and 1.0% isoflurane. Five hundred ml of 20% mannitol was infused in 30 min. At the end of the infusion, hypotension occurred. Immediately after the injection of ephedrine, acute brain swelling was observed. The operation was switched to external decompression. Post-operative echocardiography revealed the presence of dilated cardiomyopathy (DCM). The ejection fraction was 34%. Two weeks later, the second operation was scheduled. The anesthesia was induced with fentanyl, midazolam and vecuronium and maintained with N2O and 0.7% isoflurane. Nitroglycerine, lidocaine, PGE1, dopamine and dobutamine were infused throughout the operation. Five hundred ml of 20% mannitol was infused in 60 min. There were no considerable hemodynamic changes and no episode of brain expansion during operation. We conclude that the rapid infusion of mannitol can trigger acute cardiac failure and brain edema in patients with DCM.

SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats.

PubMed

Sa-Nguanmoo, Piangkwan; Tanajak, Pongpan; Kerdphoo, Sasiwan; Jaiwongkam, Thidarat; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-10-15

Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice

PubMed Central

Sun, Kaihua; Johnson, Brian S.; Gunn, Teresa M.

2007-01-01

Oxidative stress, ubiquitination defects and mitochondrial dysfunction are commonly associated with neurodegeneration. Mice lacking mahogunin ring finger-1 (MGRN1) or attractin (ATRN) develop age-dependent spongiform neurodegeneration through an unknown mechanism. It has been suggested that they act in a common pathway. As MGRN1 is an E3 ubiquitin ligase, proteomic analysis of Mgrn1 mutant and control brains was performed to explore the hypothesis that loss of MGRN1 causes neurodegeneration via accumulation of its substrates. Many mitochondrial proteins were reduced in Mgrn1 mutants. Subsequent assays confirmed significantly reduced mitochondrial complex IV expression and activity as well as increased oxidative stress in mutant brains. Mitochondrial dysfunction was obvious many months before onset of vacuolation, implicating this as a causative factor. Compatible with the hypothesis that ATRN and MGRN1 act in the same pathway, mitochondrial dysfunction and increased oxidative stress were also observed in the brains of Atrn mutants. Our results suggest that the study of Mgrn1 and Atrn mutant mice will provide insight into a causative molecular mechanism common to many neurodegenerative disorders. PMID:17720281

Acute cortical deafness in a child with MELAS syndrome.

PubMed

Pittet, Marie P; Idan, Roni B; Kern, Ilse; Guinand, Nils; Van, Hélène Cao; Toso, Seema; Fluss, Joël

2016-05-01

Auditory impairment in mitochondrial disorders are usually due to peripheral sensorineural dysfunction. Central deafness is only rarely reported. We report here an 11-year-old boy with MELAS syndrome who presented with subacute deafness after waking up from sleep. Peripheral hearing loss was rapidly excluded. A brain MRI documented bilateral stroke-like lesions predominantly affecting the superior temporal lobe, including the primary auditory cortex, confirming the central nature of deafness. Slow recovery was observed in the following weeks. This case serves to illustrate the numerous challenges caused by MELAS and the unusual occurrence of acute cortical deafness, that to our knowledge has not be described so far in a child in this setting.

Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain.

PubMed

Siegel, Jennifer J; Chitwood, Raymond A; Ding, James M; Payne, Clayton; Taylor, William; Gray, Richard; Zemelman, Boris V; Johnston, Daniel

2017-08-02

Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein-protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain. SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC

Brain regions involved in the development of acute phase responses accompanying fever in rabbits.

PubMed Central

Morimoto, A; Murakami, N; Nakamori, T; Sakata, Y; Watanabe, T

1989-01-01

1. The effects of microinjection of rabbit endogenous pyrogen and human recombinant interleukin-1 alpha on rectal temperature and acute phase responses were extensively examined in forty different brain regions of rabbits. The acute phase responses that were investigated were the changes in plasma levels of iron, zinc and copper concentration and the changes in circulating leucocyte count. 2. The rostral hypothalamic regions, such as nucleus broca ventralis, preoptic area and anterior hypothalamic region, responded to the microinjection of endogenous pyrogen or interleukin-1 by producing both fever and acute phase responses. 3. The microinjection of endogenous pyrogen or interleukin-1 into the rostral hypothalamic regions significantly decreased the plasma levels of iron and zinc concentration 8 and 24 h after injection. The circulating leucocyte count increased 8 h after injection. However, neither the injections of endogenous pyrogen nor interleukin-1 affected the number of red blood cells. 4. The present results show that the rostral hypothalamic regions respond directly to endogenous pyrogen or interleukin-1 with the consequent development of fever and acute phase responses. PMID:2514261

The TNF-α/NF-κB signaling pathway has a key role in methamphetamine–induced blood–brain barrier dysfunction

PubMed Central

Coelho-Santos, Vanessa; Leitão, Ricardo A; Cardoso, Filipa L; Palmela, Inês; Rito, Manuel; Barbosa, Marcos; Brito, Maria A; Fontes-Ribeiro, Carlos A; Silva, Ana P

2015-01-01

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction. PMID:25899299

Bladder, bowel, and sexual dysfunction in Parkinson's disease.

PubMed

Sakakibara, Ryuji; Kishi, Masahiko; Ogawa, Emina; Tateno, Fuyuki; Uchiyama, Tomoyuki; Yamamoto, Tatsuya; Yamanishi, Tomonori

2011-01-01

Bladder dysfunction (urinary urgency/frequency), bowel dysfunction (constipation), and sexual dysfunction (erectile dysfunction) (also called "pelvic organ" dysfunctions) are common nonmotor disorders in Parkinson's disease (PD). In contrast to motor disorders, pelvic organ autonomic dysfunctions are often nonresponsive to levodopa treatment. The brain pathology causing the bladder dysfunction (appearance of overactivity) involves an altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. By contrast, peripheral myenteric pathology causing slowed colonic transit (loss of rectal contractions) and central pathology causing weak strain and paradoxical anal sphincter contraction on defecation (PSD, also called as anismus) are responsible for the bowel dysfunction. In addition, hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection. The pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore, it might aid in differential diagnosis. Anticholinergic agents are used to treat bladder dysfunction in PD, although these drugs should be used with caution particularly in elderly patients who have cognitive decline. Dietary fibers, laxatives, and "prokinetic" drugs such as serotonergic agonists are used to treat bowel dysfunction in PD. Phosphodiesterase inhibitors are used to treat sexual dysfunction in PD. These treatments might be beneficial in maximizing the patients' quality of life.

Bladder, Bowel, and Sexual Dysfunction in Parkinson's Disease

PubMed Central

Sakakibara, Ryuji; Kishi, Masahiko; Ogawa, Emina; Tateno, Fuyuki; Uchiyama, Tomoyuki; Yamamoto, Tatsuya; Yamanishi, Tomonori

2011-01-01

Bladder dysfunction (urinary urgency/frequency), bowel dysfunction (constipation), and sexual dysfunction (erectile dysfunction) (also called “pelvic organ” dysfunctions) are common nonmotor disorders in Parkinson's disease (PD). In contrast to motor disorders, pelvic organ autonomic dysfunctions are often nonresponsive to levodopa treatment. The brain pathology causing the bladder dysfunction (appearance of overactivity) involves an altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. By contrast, peripheral myenteric pathology causing slowed colonic transit (loss of rectal contractions) and central pathology causing weak strain and paradoxical anal sphincter contraction on defecation (PSD, also called as anismus) are responsible for the bowel dysfunction. In addition, hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection. The pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore, it might aid in differential diagnosis. Anticholinergic agents are used to treat bladder dysfunction in PD, although these drugs should be used with caution particularly in elderly patients who have cognitive decline. Dietary fibers, laxatives, and “prokinetic” drugs such as serotonergic agonists are used to treat bowel dysfunction in PD. Phosphodiesterase inhibitors are used to treat sexual dysfunction in PD. These treatments might be beneficial in maximizing the patients' quality of life. PMID:21918729

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

PubMed Central

Sajja, Ravi K; Rahman, Shafiqur

2015-01-01

Psychostimulants and nicotine are the most widely abused drugs with a detrimental impact on public health globally. While the long-term neurobehavioral deficits and synaptic perturbations are well documented with chronic use of methamphetamine, cocaine, and nicotine, emerging human and experimental studies also suggest an increasing incidence of neurovascular complications associated with drug abuse. Short- or long-term administration of psychostimulants or nicotine is known to disrupt blood-brain barrier (BBB) integrity/function, thus leading to an increased risk of brain edema and neuroinflammation. Various pathophysiological mechanisms have been proposed to underlie drug abuse-induced BBB dysfunction suggesting a central and unifying role for oxidative stress in BBB endothelium and perivascular cells. This review discusses drug-specific effects of methamphetamine, cocaine, and tobacco smoking on brain microvascular crisis and provides critical assessment of oxidative stress-dependent molecular pathways focal to the global compromise of BBB. Additionally, given the increased risk of human immunodeficiency virus (HIV) encephalitis in drug abusers, we have summarized the synergistic pathological impact of psychostimulants and HIV infection on BBB integrity with an emphasis on unifying role of endothelial oxidative stress. This mechanistic framework would guide further investigations on specific molecular pathways to accelerate therapeutic approaches for the prevention of neurovascular deficits by drugs of abuse. PMID:26661236

Cognitive rehabilitation for executive dysfunction in adults with stroke or other adult non-progressive acquired brain damage.

PubMed

Chung, Charlie S Y; Pollock, Alex; Campbell, Tanya; Durward, Brian R; Hagen, Suzanne

2013-04-30

Executive functions are the controlling mechanisms of the brain and include the processes of planning, initiation, organisation, inhibition, problem solving, self monitoring and error correction. They are essential for goal-oriented behaviour and responding to new and novel situations. A high number of people with acquired brain injury, including around 75% of stroke survivors, will experience executive dysfunction. Executive dysfunction reduces capacity to regain independence in activities of daily living (ADL), particularly when alternative movement strategies are necessary to compensate for limb weakness. Improving executive function may lead to increased independence with ADL. There are various cognitive rehabilitation strategies for training executive function used within clinical practice and it is necessary to determine the effectiveness of these interventions. To determine the effects of cognitive rehabilitation on executive dysfunction for adults with stroke or other non-progressive acquired brain injuries. We searched the Cochrane Stroke Group Trials Register (August 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library, August 2012), MEDLINE (1950 to August 2012), EMBASE (1980 to August 2012), CINAHL (1982 to August 2012), PsycINFO (1806 to August 2012), AMED (1985 to August 2012) and 11 additional databases. We also searched reference lists and trials registers, handsearched journals and conference proceedings, and contacted experts. We included randomised trials in adults after non-progressive acquired brain injury, where the intervention was specifically targeted at improving cognition including separable executive function data (restorative interventions), where the intervention was aimed at training participants in methods to compensate for lost executive function (compensative interventions) or where the intervention involved the training in the use of an adaptive technique for improving independence with ADL (adaptive

Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices

NASA Astrophysics Data System (ADS)

Varela, Juan A.; Dupuis, Julien P.; Etchepare, Laetitia; Espana, Agnès; Cognet, Laurent; Groc, Laurent

2016-03-01

Single-molecule imaging has changed the way we understand many biological mechanisms, particularly in neurobiology, by shedding light on intricate molecular events down to the nanoscale. However, current single-molecule studies in neuroscience have been limited to cultured neurons or organotypic slices, leaving as an open question the existence of fast receptor diffusion in intact brain tissue. Here, for the first time, we targeted dopamine receptors in vivo with functionalized quantum dots and were able to perform single-molecule tracking in acute rat brain slices. We propose a novel delocalized and non-inflammatory way of delivering nanoparticles (NPs) in vivo to the brain, which allowed us to label and track genetically engineered surface dopamine receptors in neocortical neurons, revealing inherent behaviour and receptor activity regulations. We thus propose a NP-based platform for single-molecule studies in the living brain, opening new avenues of research in physiological and pathological animal models.

Effect of Resveratrol Administration on the Element Metabolism in the Blood and Brain Tissues of Rats Subjected to Acute Swimming Exercise.

PubMed

Baltaci, Abdulkerim Kasim; Arslangil, Dilek; Mogulkoc, Rasim; Patlar, Suleyman

2017-02-01

The aim of the present study is to examine how resveratrol administration affects the element metabolism in the blood and brain cortex tissues of rats subjected to an acute swimming exercise. The study was carried out on Wistar-Albino-type adult male rats supplied by the Center. Group 1 is the control group. Group 2 is the swimming control group. Group 3 is the resveratrol (10 mg/kg/day) + swimming group. Group 4 is the resveratrol (10 mg/kg/day) group. Blood and brain cortex tissues were analyzed for some elements. The acute swimming exercise led to increases in the rats' serum iron, selenium, lead, cobalt, and boron levels, while the resveratrol-swimming group has increases in copper, phosphorus, and calcium values. The brain cortex tissue of the resveratrol-swimming group had significantly higher molybdenum levels than others. The results obtained in the study indicate that acute swimming exercise altered the distribution of elements in the serum to a considerable extent; however, resveratrol's affect is limited. Especially, resveratrol supplementation may have a regulatory affect on serum iron and magnesium levels.

Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury

PubMed Central

Pollen, Sean; Greco, Elisabetta; Courtneidge, Holly; Hall, Andrew M.; Duchen, Michael R.; Tam, Frederick W. K.; Unwin, Robert J.; Singer, Mervyn

2018-01-01

Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6–10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. Measurements and Main Results: By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism. PMID:29293148

T-cell infiltration into the perilesional cortex is long-lasting and associates with poor somatomotor recovery after experimental traumatic brain injury.

PubMed

Ndode-Ekane, Xavier Ekolle; Matthiesen, Liz; Bañuelos-Cabrera, Ivette; Palminha, Cátia Alexandra Pêgas; Pitkänen, Asla

2018-06-06

T-lymphocyte (T-cell) invasion into the brain parenchyma is a major consequence of traumatic brain injury (TBI). However, the role of T-cells in the post-TBI functional outcome and secondary inflammatory processes is unknown. We explored the dynamics of T-cell infiltration into the cortex after TBI to establish whether the infiltration relates to post-injury functional impairment/recovery and progression of the secondary injury. TBI was induced in rats by lateral fluid-percussion injury, and the acute functional impairment was assessed using the neuroscore. Animals were killed between 1-90 d post-TBI for immunohistochemical analysis of T-cell infiltration (CD3), chronic macrophage/microglial reaction (CD68), blood-brain barrier (BBB) dysfunction (IgG), and endophenotype of the cortical injury. Furthermore, the occurrence of spontaneous seizures and spike-and-wave discharges were assessed using video-electroencephalography. The number of T-cells peaked at 2-d post-TBI, and then dramatically decreased by 7-d post-TBI (5% of 2-d value). Unexpectedly, chronic T-cell infiltration at 1 or 3 months post-TBI did not correlate with the severity of chronic inflammation (p >  0.05) or BBB dysfunction (p >  0.05). Multiple regression analysis indicated that inflammation and BBB dysfunction is associated with 48% of the perilesional T-cell infiltration even at the chronic time-point (r = 0.695, F = 6.54, p <  0.05). The magnitude of T-cell infiltration did not predict the pathologic endophenotype of cortical injury, but the higher the number of T-cells in the cortex, the poorer the recovery index based on the neuroscore (r = - 0.538, p <  0.05). T-cell infiltration was not associated with the number or duration of age-related spike-and-wave discharges (SWD). Nevertheless, the higher the number of SWD, the poorer the recovery index (r = - 0.767, p <  0.5). These findings suggest that acute infiltration of T-cells into the brain parenchyma

Gelatin promotes rapid restoration of the blood brain barrier after acute brain injury.

PubMed

Kumosa, Lucas S; Zetterberg, Valdemar; Schouenborg, Jens

2018-01-01

Gelatin coating of brain implants is known to provide considerable benefits in terms of reduced inflammatory sequalae and long-term neuroprotective effects. However, the mechanisms for gelatin's protective role in brain injury are still unknown. To address this question, cellular and molecular markers were studied with quantitative immunohistochemical microscopy at acute (<2hours, 1, 3days), intermediate (1-2 weeks) and long-term time points (6 weeks) after transient insertion of stainless steel needles into female rat cortex cerebri with or without gelatin coating. Compared to non-coated controls, injuries caused by gelatin coated needles showed a significantly faster resolution of post-stab bleeding/leakage and differential effects on different groups of microglia cells. While similar levels of matrix metalloproteinase (MMP-2 and MMP-9, two gelatinases) was found for coated and noncoated needle stabs during the first week, markedly increased levels of both MMPs was seen for gelatin-coated but not non-coated needle stabs after 2weeks. Neuronal populations and activated astrocytes were largely unaffected. In conclusion, the beneficial effects of gelatin may be the combined results of faster healing of the blood brain barrier curtailing leakage of blood borne molecules/cells into brain parenchyma and to a modulation of the microglial population response favoring restitution of the injured tissue. These findings present an important therapeutic potential for gelatin coatings in various disease, injury and surgical conditions. The neural interfaces field holds great promise to enable elucidation of neural information processing and to develop new implantable devices for stimulation based therapy. Currently, this field is struggling to find solutions for reducing tissue reactions to implanted micro and nanotechnology. Prior studies have recently shown that gelatin coatings lower activation of digestive microglia and mitigate the ubiquitous loss of neurons adjacent to

Glutamatergic dysfunction in catatonia? Successful treatment of three acute akinetic catatonic patients with the NMDA antagonist amantadine.

PubMed Central

Northoff, G; Eckert, J; Fritze, J

1997-01-01

Therapeutic efficiacy of the NMDA antagonist amantadine is reported in three acute neuroleptic free akinetic catatonic patients. Intravenous infusion of amantadine led to the resolution of catatonic symptoms and considerable reductions of scores in various motor scales (Simpson Angus scale for extrapyramidal side effects (SEPS), the abnormal involuntary movement scale (AIMS), Rogers catatonia and schizophrenia scales). The therapeutic effect of amantadine showed a characteristic temporal pattern with most pronounced effects four to six hours after administration and recurrence of catatonic symptoms by 24 hours later, at least partially. Such a temporal pattern of therapeutic efficacy and decreasing efficacy occurred in all three patients on all days. The results suggest the central importance of glutamatergic dysfunction in catatonic syndrome. PMID:9120462

Dynamic functional-structural coupling within acute functional state change phases: Evidence from a depression recognition study.

PubMed

Bi, Kun; Hua, Lingling; Wei, Maobin; Qin, Jiaolong; Lu, Qing; Yao, Zhijian

2016-02-01

Dynamic functional-structural connectivity (FC-SC) coupling might reflect the flexibility by which SC relates to functional connectivity (FC). However, during the dynamic acute state change phases of FC, the relationship between FC and SC may be distinctive and embody the abnormality inherent in depression. This study investigated the depression-related inter-network FC-SC coupling within particular dynamic acute state change phases of FC. Magnetoencephalography (MEG) and diffusion tensor imaging (DTI) data were collected from 26 depressive patients (13 women) and 26 age-matched controls (13 women). We constructed functional brain networks based on MEG data and structural networks from DTI data. The dynamic connectivity regression algorithm was used to identify the state change points of a time series of inter-network FC. The time period of FC that contained change points were partitioned into types of dynamic phases (acute rising phase, acute falling phase,acute rising and falling phase and abrupt FC variation phase) to explore the inter-network FC-SC coupling. The selected FC-SC couplings were then fed into the support vector machine (SVM) for depression recognition. The best discrimination accuracy was 82.7% (P=0.0069) with FC-SC couplings, particularly in the acute rising phase of FC. Within the FC phases of interest, the significant discriminative network pair was related to the salience network vs ventral attention network (SN-VAN) (P=0.0126) during the early rising phase (70-170ms). This study suffers from a small sample size, and the individual acute length of the state change phases was not considered. The increased values of significant discriminative vectors of FC-SC coupling in depression suggested that the capacity to process negative emotion might be more directly related to the SC abnormally and be indicative of more stringent and less dynamic brain function in SN-VAN, especially in the acute rising phase of FC. We demonstrated that depressive brain

Near Infrared Light Scattering Changes Following Acute Brain Injury

PubMed Central

Highton, David; Tachtsidis, Ilias; Tucker, Alison; Elwell, Clare; Smith, Martin

2018-01-01

Acute brain injury (ABI) is associated with changes in near infrared light absorption reflecting haemodynamic and metabolic status via changes in cerebral oxygenation (haemoglobin oxygenation and cytochrome-c-oxidase oxidation). Light scattering has not been comprehensively investigated following ABI and may be an important confounding factor in the assessment of chromophore concentration changes, and/or a novel non-invasive optical marker of brain tissue morphology, cytostructure, hence metabolic status. The aim of this study is to characterize light scattering following adult ABI. Time resolved spectroscopy was performed as a component of multimodal neuromonitoring in critically ill brain injured patients. The scattering coefficient (μ′s), absorption coefficient and cerebral haemoglobin oxygen saturation (SO2) were derived by fitting the time resolved data. Cerebral infarction was subsequently defined on routine clinical imaging. In total, 21 patients with ABI were studied. Ten patients suffered a unilateral frontal infarction, and mean μ′s was lower over infarcted compared to non-infarcted cortex (injured 6.9/cm, non-injured 8.2/cm p = 0.002). SO2 did not differ significantly between the two sides (injured 69.3 %, non-injured 69.0 % p = 0.7). Cerebral infarction is associated with changes in μ′s which might be a novel marker of cerebral injury and will interfere with quantification of haemoglobin/cytochrome c oxidase concentration. Although further work combining optical and physiological analysis is required to elucidate the significance of these results, μ′s may be uniquely placed as a non-invasive biomarker of cerebral energy failure as well as gross tissue changes. PMID:26782205

Plasma Anti-Glial Fibrillary Acidic Protein Autoantibody Levels during the Acute and Chronic Phases of Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study.

PubMed

Wang, Kevin K W; Yang, Zhihui; Yue, John K; Zhang, Zhiqun; Winkler, Ethan A; Puccio, Ava M; Diaz-Arrastia, Ramon; Lingsma, Hester F; Yuh, Esther L; Mukherjee, Pratik; Valadka, Alex B; Gordon, Wayne A; Okonkwo, David O; Manley, Geoffrey T; Cooper, Shelly R; Dams-O'Connor, Kristen; Hricik, Allison J; Inoue, Tomoo; Maas, Andrew I R; Menon, David K; Schnyer, David M; Sinha, Tuhin K; Vassar, Mary J

2016-07-01

We described recently a subacute serum autoantibody response toward glial fibrillary acidic protein (GFAP) and its breakdown products 5-10 days after severe traumatic brain injury (TBI). Here, we expanded our anti-GFAP autoantibody (AutoAb[GFAP]) investigation to the multicenter observational study Transforming Research and Clinical Knowledge in TBI Pilot (TRACK-TBI Pilot) to cover the full spectrum of TBI (Glasgow Coma Scale 3-15) by using acute (<24 h) plasma samples from 196 patients with acute TBI admitted to three Level I trauma centers, and a second cohort of 21 participants with chronic TBI admitted to inpatient TBI rehabilitation. We find that acute patients self-reporting previous TBI with loss of consciousness (LOC) (n = 43) had higher day 1 AutoAb[GFAP] (mean ± standard error: 9.11 ± 1.42; n = 43) than healthy controls (2.90 ± 0.92; n = 16; p = 0.032) and acute patients reporting no previous TBI (2.97 ± 0.37; n = 106; p < 0.001), but not acute patients reporting previous TBI without LOC (8.01 ± 1.80; n = 47; p = 0.906). These data suggest that while exposure to TBI may trigger the AutoAb[GFAP] response, circulating antibodies are elevated specifically in acute TBI patients with a history of TBI. AutoAb[GFAP] levels for participants with chronic TBI (average post-TBI time 176 days or 6.21 months) were also significantly higher (15.08 ± 2.82; n = 21) than healthy controls (p < 0.001). These data suggest a persistent upregulation of the autoimmune response to specific brain antigen(s) in the subacute to chronic phase after TBI, as well as after repeated TBI insults. Hence, AutoAb[GFAP] may be a sensitive assay to study the dynamic interactions between post-injury brain and patient-specific autoimmune responses across acute and chronic settings after TBI.

Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway.

PubMed

Ugun-Klusek, Aslihan; Tatham, Michael H; Elkharaz, Jamal; Constantin-Teodosiu, Dumitru; Lawler, Karen; Mohamed, Hala; Paine, Simon M L; Anderson, Glen; John Mayer, R; Lowe, James; Ellen Billett, E; Bedford, Lynn

2017-01-05

The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated.

Frontal brain asymmetry in adult attention-deficit/hyperactivity disorder (ADHD): extending the motivational dysfunction hypothesis.

PubMed

Keune, Philipp M; Wiedemann, Eva; Schneidt, Alexander; Schönenberg, Michael

2015-04-01

Attention-deficit/hyperactivity disorder (ADHD) involves motivational dysfunction, characterized by excessive behavioral approach tendencies. Frontal brain asymmetry in the alpha band (8-13 Hz) in resting-state electroencephalogram (EEG) represents a neural correlate of global motivational tendencies, and abnormal asymmetry, indicating elevated approach motivation, was observed in pediatric and adult patients. To date, the relation between ADHD symptoms, depression and alpha asymmetry, its temporal metric properties and putative gender-specificity remain to be explored. Adult ADHD patients (n=52) participated in two resting-state EEG recordings, two weeks apart. Asymmetry measures were aggregated across recordings to increase trait specificity. Putative region-specific associations between asymmetry, ADHD symptoms and depression, its gender-specificity and test-retest reliability were examined. ADHD symptoms were associated with approach-related asymmetry (stronger relative right-frontal alpha power). Approach-related asymmetry was pronounced in females, and also associated with depression. The latter association was mediated by ADHD symptoms. Test-retest reliability was sufficient. The association between reliably assessable alpha asymmetry and ADHD symptoms supports the motivational dysfunction hypothesis. ADHD symptoms mediating an atypical association between asymmetry and depression may be attributed to depression arising secondary to ADHD. Gender-specific findings require replication. Frontal alpha asymmetry may represent a new reliable marker of ADHD symptoms. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Progressive Return to Activity Following Acute Concussion/Mild Traumatic Brain Injury: Guidance for the Rehabilitation Provider in Deployed and Non-deployed Settings

DTIC Science & Technology

2014-01-01

RPE and references are also included as part of the CST. DCoE Clinical Recommendation | January 2014 Progressive Return to Activity Following Acute...Recommendation | January 2014 Progressive Return to Activity Following Acute Concussion/Mild Traumatic Brain Injury: Guidance for the Rehabilitation Provider...days Symptoms are worsening 3 DCoE Clinical Recommendation | January 2014 Progressive Return to Activity Following Acute Concussion/Mild Traumatic

Physiological complexity of acute traumatic brain injury in patients treated with a brain oxygen protocol: utility of symbolic regression in predictive modeling of a dynamical system.

PubMed

Narotam, Pradeep K; Morrison, John F; Schmidt, Michael D; Nathoo, Narendra

2014-04-01

Predictive modeling of emergent behavior, inherent to complex physiological systems, requires the analysis of large complex clinical data streams currently being generated in the intensive care unit. Brain tissue oxygen protocols have yielded outcome benefits in traumatic brain injury (TBI), but the critical physiological thresholds for low brain oxygen have not been established for a dynamical patho-physiological system. High frequency, multi-modal clinical data sets from 29 patients with severe TBI who underwent multi-modality neuro-clinical care monitoring and treatment with a brain oxygen protocol were analyzed. The inter-relationship between acute physiological parameters was determined using symbolic regression (SR) as the computational framework. The mean patient age was 44.4±15 with a mean admission GCS of 6.6±3.9. Sixty-three percent sustained motor vehicle accidents and the most common pathology was intra-cerebral hemorrhage (50%). Hospital discharge mortality was 21%, poor outcome occurred in 24% of patients, and good outcome occurred in 56% of patients. Criticality for low brain oxygen was intracranial pressure (ICP) ≥22.8 mm Hg, for mortality at ICP≥37.1 mm Hg. The upper therapeutic threshold for cerebral perfusion pressure (CPP) was 75 mm Hg. Eubaric hyperoxia significantly impacted partial pressure of oxygen in brain tissue (PbtO2) at all ICP levels. Optimal brain temperature (Tbr) was 34-35°C, with an adverse effect when Tbr≥38°C. Survivors clustered at [Formula: see text] Hg vs. non-survivors [Formula: see text] 18 mm Hg. There were two mortality clusters for ICP: High ICP/low PbtO2 and low ICP/low PbtO2. Survivors maintained PbtO2 at all ranges of mean arterial pressure in contrast to non-survivors. The final SR equation for cerebral oxygenation is: [Formula: see text]. The SR-model of acute TBI advances new physiological thresholds or boundary conditions for acute TBI management: PbtO2≥25 mmHg; ICP≤22 mmHg; CPP≈60-75�

Chronic Desipramine Prevents Acute Stress-Induced Reorganization of Medial Prefrontal Cortex Architecture by Blocking Glutamate Vesicle Accumulation and Excitatory Synapse Increase

PubMed Central

Treccani, Giulia; Liebenberg, Nico; Chen, Fenghua; Popoli, Maurizio; Wegener, Gregers; Nyengaard, Jens Randel

2015-01-01

Background: Although a clear negative influence of chronic exposure to stressful experiences has been repeatedly demonstrated, the outcome of acute stress on key brain regions has only just started to be elucidated. Although it has been proposed that acute stress may produce enhancement of brain plasticity and that antidepressants may prevent such changes, we still lack ultrastructural evidence that acute stress-induced changes in neurotransmitter physiology are coupled with structural synaptic modifications. Methods: Rats were pretreated chronically (14 days) with desipramine (10mg/kg) and then subjected to acute foot-shock stress. By means of serial section electron microscopy, the structural remodeling of medial prefrontal cortex glutamate synapses was assessed soon after acute stressor cessation and stress hormone levels were measured. Results: Foot-shock stress induced a remarkable increase in the number of docked vesicles and small excitatory synapses, partially and strongly prevented by desipramine pretreatment, respectively. Acute stress-induced corticosterone elevation was not affected by drug treatment. Conclusions: Since desipramine pretreatment prevented the stress-induced structural plasticity but not the hormone level increase, we hypothesize that the preventing action of desipramine is located on pathways downstream of this process and/or other pathways. Moreover, because enhancement of glutamate system remodeling may contribute to overexcitation dysfunctions, this aspect could represent a crucial component in the pathophysiology of stress-related disorders. PMID:25522419

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance

PubMed Central

Tan, Chin Lik; Alavi, Seyed Alireza; Baldeweg, Stephanie E; Belli, Antonio; Carson, Alan; Feeney, Claire; Goldstone, Anthony P; Greenwood, Richard; Menon, David K; Simpson, Helen L; Toogood, Andrew A; Gurnell, Mark; Hutchinson, Peter J

2017-01-01

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines. PMID:28860331

Brain-Heart Interaction: Cardiac Complications After Stroke.

PubMed

Chen, Zhili; Venkat, Poornima; Seyfried, Don; Chopp, Michael; Yan, Tao; Chen, Jieli

2017-08-04

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed. © 2017 American Heart Association, Inc.

Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse.

PubMed

Harrison, Jordan L; Rowe, Rachel K; O'Hara, Bruce F; Adelson, P David; Lifshitz, Jonathan

2014-09-01

Following mild traumatic brain injury (TBI), patients may self-treat symptoms of concussion, including post-traumatic headache, taking over-the-counter (OTC) analgesics. Administering one dose of OTC analgesics immediately following experimental brain injury mimics the at-home treated population of concussed patients and may accelerate the understanding of the relationship between brain injury and OTC pharmacological intervention. In the current study, we investigate the effect of acute administration of OTC analgesics on neurological function and cortical cytokine levels after experimental diffuse TBI in the mouse. Adult, male C57BL/6 mice were injured using a midline fluid percussion (mFPI) injury model of concussion (6-10 min righting reflex time for brain-injured mice). Experimental groups included mFPI paired with either ibuprofen (60 mg/kg, i.p.; n = 16), acetaminophen (40 mg/kg, i.p.; n = 9), or vehicle (15% ethanol (v/v) in 0.9% saline; n = 13) and sham injury paired OTC medicine or vehicle (n = 7-10 per group). At 24 h after injury, functional outcome was assessed using the rotarod task and a modified neurological severity score. Following behavior assessment, cortical cytokine levels were measured by multiplex ELISA at 24 h post-injury. To evaluate efficacy on acute inflammation, cortical cytokine levels were measured also at 6 h post-injury. In the diffuse brain-injured mouse, immediate pharmacological intervention did not attenuate or exacerbate TBI-induced functional deficits. Cortical cytokine levels were affected by injury, time, or their interaction. However, levels were not affected by treatment at 6 or 24 h post-injury. These data indicate that acute administration of OTC analgesics did not exacerbate or attenuate brain-injury deficits which may inform clinical recommendations for the at-home treated mildly concussed patient.

Changes in Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to Nerve Against in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Changes in extracellular striatal acetylcholine and brain seizure activity following...Acetylcholine, acetylcholinesterase, choline, guinea pig, in vivo microdialysis, nerve agents, organophosphorus compounds, sarin, seizure activity ...RESEARCH ARTICLE Changes in extracellular striatal acetylcholine and brain seizure activity following acute exposure to nerve agents in freely

Occludin is regulated by epidermal growth factor receptor activation in brain endothelial cells and brains of mice with acute liver failure

PubMed Central

Chen, Feng; Hori, Tomohide; Ohashi, Norifumi; Baine, Ann-Marie; Eckman, Christopher B.; Nguyen, Justin H.

2011-01-01

Mechanisms of brain edema in acute liver failure (ALF) are not completely understood. We recently demonstrated that matrix metalloproteinase 9 (MMP-9) induces significant alterations to occludin in brain endothelial cells in vitro and in brains of mice with experimental ALF (Hepatology 50:1914, 2009). In this study, we show that MMP-9-induced transactivation of epidermal growth factor receptor (EGFR) and p38MAPK/NFκB signals participate in regulating brain endothelial occludin level. Mouse brain endothelial bEnd3 cells were exposed to MMP-9 or p38 MAPK upregulation in the presence and absence of EGFR inhibitor, p38 MAPK inhibitor, NFκB inhibitor, and/or appropriate small interfering RNA. RT-PCR and western blotting were used for mRNA and protein expression analyses. Immunohistochemical staining and confocal microscopy were used to demonstrate cellular EGFR activation. Intraperitoneal azoxymethane was use to induce ALF in mice. Brains of comatose ALF mice were processed for histological and biochemical analyses. When bEnd3 cells were exposed to MMP-9, EGFR was significantly transactivated, followed by p38 MAPK activation, IκBα degradation, NFκB activation, and suppression of occludin synthesis and expression. Similar EGFR activation and p38 MAPK/NFκB activation were found in the brains of ALF mice, and these changes were attenuated with GM6001 treatment. Conclusion EGFR activation with p38 MAPK/NFκB signaling contributes to the regulation of tight junction integrity in ALF. EGFR activation may thus play an important role in vasogenic brain edema in ALF. PMID:21480332

A Review: Radiographic Iodinated Contrast Media-Induced Thyroid Dysfunction

PubMed Central

Leung, Angela M.; Braverman, Lewis E.; Brent, Gregory A.; Pearce, Elizabeth N.

2015-01-01

Context: Thyroid hormone production is dependent on adequate iodine intake. Excess iodine is generally well-tolerated, but thyroid dysfunction can occur in susceptible individuals after excess iodine exposure. Radiological iodinated contrast media represent an increasingly common source of excess iodine. Objective: This review will discuss the thyroidal response after acute exposure to excess iodine; contrast iodine-induced thyroid dysfunction; risks of iodine-induced thyroid dysfunction in vulnerable populations, such as the fetus, neonate, and patients with impaired renal function; and recommendations for the assessment and treatment of contrast iodine-induced thyroid dysfunction. Methods: Data for this review were identified by searching PubMed, Google Scholar, and references from relevant articles from 1948 to 2014. Conclusions: With the increase in the use of computed tomography scans in the United States, there is increasing risk of contrast-induced thyroid dysfunction. Patients at risk of developing iodine-induced thyroid dysfunction should be closely monitored after receiving iodinated contrast media and should be treated as needed. PMID:25375985

Brain activity monitoring by compressed spectral array during deep hypothermic circulatory arrest in acute aortic dissection surgery.

PubMed

Urbanowicz, Tomasz K; Budniak, Wiktor; Buczkowski, Piotr; Perek, Bartłomiej; Walczak, Maciej; Tomczyk, Jadwiga; Katarzyński, Sławomir; Jemielity, Marek

2014-12-01

Monitoring the central nervous system during aortic dissection repair may improve the understanding of the intraoperative changes related to its bioactivity. The aim of the study was to evaluate the influence of deep hypothermia on intraoperative brain bioactivity measured by the compressed spectral array (CSA) method and to assess the influence of the operations on postoperative cognitive function. The study enrolled 40 patients (31 men and 9 women) at the mean age of 60.2 ± 8.6 years, diagnosed with acute aortic dissection. They underwent emergency operations in deep hypothermic circulatory arrest (DHCA). During the operations, brain bioactivity was monitored with the compressed spectral array method. There were no intraoperative deaths. Electrocerebral silence during DHCA was observed in 31 patients (74%). The lowest activity was observed during DHCA: it was 0.01 ± 0.05 nW in the left hemisphere and 0.01 ± 0.03 nW in the right hemisphere. The postoperative results of neurological tests deteriorated statistically significantly (26.9 ± 1.7 points vs. 22.0 ± 1.7 points; p < 0.001), especially among patients who exhibited brain activity during DHCA. The compressed spectral array method is clinically useful in monitoring brain bioactivity during emergency operations of acute aortic dissections. Electrocerebral silence occurs in 75% of patients during DHCA. The cognitive function of patients deteriorates significantly after operations with DHCA.

Acute kidney injury: not just acute renal failure anymore?

PubMed

Dirkes, Susan

2011-02-01

Until recently, no uniform standard existed for diagnosing and classifying acute renal failure. To clarify diagnosis, the Acute Dialysis Quality Initiative group stated its consensus on the need for a clear definition and classification system of renal dysfunction with measurable criteria. Today the term acute kidney injury has replaced the term acute renal failure, with an understanding that such injury is a common clinical problem in critically ill patients and typically is predictive of an increase in morbidity and mortality. A classification system, known as RIFLE (risk of injury, injury, failure, loss of function, and end-stage renal failure), includes specific goals for preventing acute kidney injury: adequate hydration, maintenance of renal perfusion, limiting exposure to nephrotoxins, drug protective strategies, and the use of renal replacement therapies that reduce renal injury.

Acute Brain Imaging in Children: Can MRI Replace CT as a Screening Tool?

PubMed

Wagner, Matthias W; Kontzialis, Marinos; Seeburg, Daniel; Stern, Steven E; Oshmyansky, Alexander; Poretti, Andrea; Huisman, Thierry A G M

2016-01-01

To determine if axial T2-weighted imaging can serve as screening tool for pediatric brain imaging. We retrospectively evaluated consecutive brain magnetic resonance imaging (MRI) data of 161 children (74 girls) with a mean age of 7.44 ± 5.71 years. Standard of reference was the final report of neuroradiology attendings. Three readers with different levels of experience were blinded for clinical diagnoses and study indications. First, readers studied only the axial T2-weighted screening sequence. Second, they studied all available anatomical and functional MRI sequences as performed per standard protocol for each clinical indication. The readings were classified as normal or abnormal. Sensitivity and specificity were measured. Axial T2 screening yielded a sensitivity of 77-88% and a specificity of 92%. The full studies/data sets had a sensitivity of 89-95% and a specificity of 86-93%. Nineteen of 167 studies were acquired for acute and 148 of 167 studies for nonacute clinical indication. Twenty-five false-negative diagnoses paneled in three groups were made by all readers together. Readers misread four of 19 studies with acute and 21 of 148 studies with nonacute clinical indication. Four of 21 misread studies with nonacute indications harbored unexpected findings needing management. Axial T2 screening can detect pediatric brain abnormalities with high sensitivity and specificity and can possibly replace CT as screening tool if the reading physician is aware of possible limitations/pitfalls. The level of experience influences sensitivity and specificity. Adding diffusion-weighted imaging and susceptibility-weighted imaging to a 3-dimensional T2-weighted sequence would most likely further increase sensitivity and specificity. Copyright © 2015 by the American Society of Neuroimaging.

Platelet activating factor induces transient blood-brain barrier opening to facilitate edaravone penetration into the brain.

PubMed

Fang, Weirong; Zhang, Rui; Sha, Lan; Lv, Peng; Shang, Erxin; Han, Dan; Wei, Jie; Geng, Xiaohan; Yang, Qichuan; Li, Yunman

2014-03-01

The blood-brain barrier (BBB) greatly limits the efficacy of many neuroprotective drugs' delivery to the brain, so improving drug penetration through the BBB has been an important focus of research. Here we report that platelet activating factor (PAF) transiently opened BBB and facilitated neuroprotectant edaravone penetration into the brain. Intravenous infusion with PAF induced a transient BBB opening in rats, reflected by increased Evans blue leakage and mild edema formation, which ceased within 6 h. Furthermore, rat regional cerebral blood flow (rCBF) declined acutely during PAF infusion, but recovered slowly. More importantly, this transient BBB opening significantly increased the penetration of edaravone into the brain, evidenced by increased edaravone concentrations in tissue interstitial fluid collected by microdialysis and analyzed by Ultra-performance liquid chromatograph combined with a hybrid quadrupole time-of-flight mass spectrometer (UPLC-MS/MS). Similarly, incubation of rat brain microvessel endothelial cells monolayer with 1 μM PAF for 1 h significantly increased monolayer permeability to (125)I-albumin, which recovered 1 h after PAF elimination. However, PAF incubation with rat brain microvessel endothelial cells for 1 h did not cause detectable cytotoxicity, and did not regulate intercellular adhesion molecule-1, matrix-metalloproteinase-9 and P-glycoprotein expression. In conclusion, PAF could induce transient and reversible BBB opening through abrupt rCBF decline, which significantly improved edaravone penetration into the brain. Platelet activating factor (PAF) transiently induces BBB dysfunction and increases BBB permeability, which may be due to vessel contraction and a temporary decline of regional cerebral blood flow (rCBF) triggered by PAF. More importantly, the PAF induced transient BBB opening facilitates neuroprotectant edaravone penetration into brain. The results of this study may provide a new approach to improve drug delivery into

Diabetes Insipidus after Traumatic Brain Injury

PubMed Central

Capatina, Cristina; Paluzzi, Alessandro; Mitchell, Rosalid; Karavitaki, Niki

2015-01-01

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in many age groups. Neuroendocrine dysfunction has been recognized as a consequence of TBI and consists of both anterior and posterior pituitary insufficiency; water and electrolyte abnormalities (diabetes insipidus (DI) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH)) are amongst the most challenging sequelae. The acute head trauma can lead (directly or indirectly) to dysfunction of the hypothalamic neurons secreting antidiuretic hormone (ADH) or of the posterior pituitary gland causing post-traumatic DI (PTDI). PTDI is usually diagnosed in the first days after the trauma presenting with hypotonic polyuria. Frequently, the poor general status of most patients prevents adequate fluid intake to compensate the losses and severe dehydration and hypernatremia occur. Management consists of careful monitoring of fluid balance and hormonal replacement. PTDI is associated with high mortality, particularly when presenting very early following the injury. In many surviving patients, the PTDI is transient, lasting a few days to a few weeks and in a minority of cases, it is permanent requiring management similar to that offered to patients with non-traumatic central DI. PMID:26239685

Early detection of consciousness in patients with acute severe traumatic brain injury.

PubMed

Edlow, Brian L; Chatelle, Camille; Spencer, Camille A; Chu, Catherine J; Bodien, Yelena G; O'Connor, Kathryn L; Hirschberg, Ronald E; Hochberg, Leigh R; Giacino, Joseph T; Rosenthal, Eric S; Wu, Ona

2017-09-01

See Schiff (doi:10.1093/awx209) for a scientific commentary on this article. Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence

Microglial activation as a measure of stress in mouse brains exposed acutely (60 minutes) and long-term (2 years) to mobile telephone radiofrequency fields.

PubMed

Finnie, John W; Cai, Zhao; Manavis, Jim; Helps, Stephen; Blumbergs, Peter C

2010-02-01

To determine whether acute or long-term exposure of the brain to mobile telephone radiofrequency (RF) fields produces activation of microglia, which normally respond rapidly to any change in their microenvironment. Using a purpose designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate (SAR) of 4 W/kg for 60 min (acute) or on five successive days per week for 104 weeks (long-term). Control mice were sham-exposed or freely mobile in a cage to control for any stress caused by immobilisation in the exposure module. Positive control brains subjected to a stab wound were also included to confirm the ability of microglia to react to any neural stress. Brains were perfusion-fixed with 4% paraformaldehyde and representative regions of the cerebral cortex and hippocampus immunostained for ionised calcium binding adaptor molecule (Iba1), a specific microglial marker. There was no increase in microglial Iba1 expression in brains short or long-term exposed to mobile telephony microwaves compared to control (sham-exposed or freely moving caged mice) brains, while substantial microglial activation occurred in damaged positive control neural tissue. Acute (60 minutes) or longer duration (2 years) exposure of murine brains to mobile telephone RF fields did not produce any microglial activation detectable by Iba1 immunostaining.

Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours.

PubMed

Makale, Milan T; McDonald, Carrie R; Hattangadi-Gluth, Jona A; Kesari, Santosh

2017-01-01

Standard treatment of primary and metastatic brain tumours includes high-dose megavoltage-range radiation to the cranial vault. About half of patients survive >6 months, and many attain long-term control or cure. However, 50-90% of survivors exhibit disabling cognitive dysfunction. The radiation-associated cognitive syndrome is poorly understood and has no effective prevention or long-term treatment. Attention has primarily focused on mechanisms of disability that appear at 6 months to 1 year after radiotherapy. However, recent studies show that CNS alterations and dysfunction develop much earlier following radiation exposure. This finding has prompted the hypothesis that subtle early forms of radiation-induced CNS damage could drive chronic pathophysiological processes that lead to permanent cognitive decline. This Review presents evidence of acute radiation-triggered CNS inflammation, injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury-related processes initiated soon after irradiation could synergistically alter the signalling microenvironment in progenitor cell niches in the brain and the hippocampus, which is a structure critical to memory and cognition. Progenitor cell niche degradation could cause progressive neuronal loss and cognitive disability. The concluding discussion addresses future directions and potential early treatments that might reverse degenerative processes before they can cause permanent cognitive disability.

Acute renal failure potentiates methylmalonate-induced oxidative stress in brain and kidney of rats.

PubMed

Schuck, P F; Alves, L; Pettenuzzo, L F; Felisberto, F; Rodrigues, L B; Freitas, B W; Petronilho, F; Dal-Pizzol, F; Streck, E L; Ferreira, G C

2013-03-01

Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. The disease is clinically characterized by progressive neurological deterioration and kidney failure, whose pathophysiology is still unclear. In the present work we investigated the effects of acute MMA administration on various parameters of oxidative stress in cerebral cortex and kidney of young rats, as well as the influence of acute renal failure on MMA-elicited effects on these parameters. Acute renal failure was induced by gentamicin, an aminoglycoside antibiotic whose utilization over prolonged periods causes nephrotoxicity. The administration of gentamicin alone increased carbonyl content and inhibited superoxide dismutase (SOD) activity in cerebral cortex, as well as increased thiobarbituric acid-reactive substances (TBA-RS) and sulfhydryl levels and diminished glutathione peroxidase activity in kidney. On the other hand, MMA administration increased TBA-RS levels in cerebral cortex and decreased SOD activity in kidney. Furthermore, the simultaneous administration of MMA and gentamicin to the rats provoked an augment in TBA-RS levels and superoxide generation in cerebral cortex and in TBA-RS, carbonyl and sulfhydryl levels in kidney, while diminished SOD activity in both studied tissues. Finally, nitrate/nitrite content, reduced glutathione levels, 2',7'-dihydrodichlorofluorescein oxidation and catalase activity were not affected by this animal treatment in either tissue. In conclusion, our present data are in line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on oxidative stress parameters in brain and peripheral tissues.

A simple brain atrophy measure improves the prediction of malignant middle cerebral artery infarction by acute DWI lesion volume.

PubMed

Beck, Christoph; Kruetzelmann, Anna; Forkert, Nils D; Juettler, Eric; Singer, Oliver C; Köhrmann, Martin; Kersten, Jan F; Sobesky, Jan; Gerloff, Christian; Fiehler, Jens; Schellinger, Peter D; Röther, Joachim; Thomalla, Götz

2014-06-01

In patients with malignant middle cerebral artery infarction (MMI) decompressive surgery within 48 h improves functional outcome. In this respect, early identification of patients at risk of developing MMI is crucial. While the acute diffusion weighted imaging (DWI) lesion volume was found to predict MMI with high predictive values, the potential impact of preexisting brain atrophy on the course of space-occupying middle cerebral artery (MCA) infarction and the development of MMI remains unclear. We tested the hypothesis that the combination of the acute DWI lesion volume with simple measures of brain atrophy improves the early prediction of MMI. Data from a prospective, multicenter, observational study, which included patients with acute middle cerebral artery main stem occlusion studied by MRI within 6 h of symptom onset, was analyzed retrospectively. The development of MMI was defined according to the European randomized controlled trials of decompressive surgery. Acute DWI lesion volume, as well as brain and cerebrospinal fluid volume (CSF) were delineated. The intercaudate distance (ICD) was assessed as a linear brain atrophy marker by measuring the hemi-ICD of the intact hemisphere to account for local brain swelling. Binary logistic regression analysis was used to identify significant predictors of MMI. Cut-off values were determined by Classification and Regression Trees analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the resulting models were calculated. Twenty-one (18 %) of 116 patients developed a MMI. Malignant middle cerebral artery infarctions patients had higher National Institutes of Health Stroke Scale scores on admission and presented more often with combined occlusion of the internal carotid artery and MCA. There were no differences in brain and CSF volume between the two groups. Diffusion weighted imaging lesion volume was larger (p < 0.001), while hemi-ICD was smaller (p = 0.029) in

Branched-chain amino acids and brain function.

PubMed

Fernstrom, John D

2005-06-01

Branched-chain amino acids (BCAAs) influence brain function by modifying large, neutral amino acid (LNAA) transport at the blood-brain barrier. Transport is shared by several LNAAs, notably the BCAAs and the aromatic amino acids (ArAAs), and is competitive. Consequently, when plasma BCAA concentrations rise, which can occur in response to food ingestion or BCAA administration, or with the onset of certain metabolic diseases (e.g., uncontrolled diabetes), brain BCAA concentrations rise, and ArAA concentrations decline. Such effects occur acutely and chronically. Such reductions in brain ArAA concentrations have functional consequences: biochemically, they reduce the synthesis and the release of neurotransmitters derived from ArAAs, notably serotonin (from tryptophan) and catecholamines (from tyrosine and phenylalanine). The functional effects of such neurochemical changes include altered hormonal function, blood pressure, and affective state. Although the BCAAs thus have biochemical and functional effects in the brain, few attempts have been made to characterize time-course or dose-response relations for such effects. And, no studies have attempted to identify levels of BCAA intake that might produce adverse effects on the brain. The only "model" of very high BCAA exposure is a very rare genetic disorder, maple syrup urine disease, a feature of which is substantial brain dysfunction but that probably cannot serve as a useful model for excessive BCAA intake by normal individuals. Given the known biochemical and functional effects of the BCAAs, it should be a straightforward exercise to design studies to assess dose-response relations for biochemical and functional effects and, in this context, to explore for adverse effect thresholds.

Evaluating the effects of maternal alcohol consumption on murine fetal brain vasculature using optical coherence tomography.

PubMed

Raghunathan, Raksha; Wu, Chen; Singh, Manmohan; Liu, Chih-Hao; Miranda, Rajesh C; Larin, Kirill V

2018-05-01

Prenatal alcohol exposure (PAE) can result in a range of anomalies including brain and behavioral dysfunctions, collectively termed fetal alcohol spectrum disorder. PAE during the 1st and 2nd trimester is common, and research in animal models has documented significant neural developmental deficits associated with PAE during this period. However, little is known about the immediate effects of PAE on fetal brain vasculature. In this study, we used in utero speckle variance optical coherence tomography, a high spatial- and temporal-resolution imaging modality, to evaluate dynamic changes in microvasculature of the 2nd trimester equivalent murine fetal brain, minutes after binge-like maternal alcohol exposure. Acute binge-like PAE resulted in a rapid (<1 hour) and significant decrease (P < .001) in vessel diameter as compared to the sham group. The data show that a single binge-like maternal alcohol exposure resulted in swift vasoconstriction in fetal brain vessels during the critical period of neurogenesis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Acute kidney injury and cardiovascular outcomes in acute severe hypertension.

PubMed

Szczech, Lynda A; Granger, Christopher B; Dasta, Joseph F; Amin, Alpesh; Peacock, W Frank; McCullough, Peter A; Devlin, John W; Weir, Matthew R; Katz, Jason N; Anderson, Frederick A; Wyman, Allison; Varon, Joseph

2010-05-25

Little is known about the association of kidney dysfunction and outcome in acute severe hypertension. This study aimed to measure the association between baseline chronic kidney disease (estimated glomerular filtration rate), acute kidney injury (AKI, decrease in estimated glomerular filtration rate > or =25% from baseline) and outcome in patients hospitalized with acute severe hypertension. The Studying the Treatment of Acute Hypertension (STAT) registry enrolled patients with acute severe hypertension, defined as > or =1 blood pressure measurement >180 mm Hg systolic and/or >110 mm Hg diastolic and treated with intravenous antihypertensive therapy. Data were compared across groups categorized by admission estimated glomerular filtration rate and AKI during admission. On admission, 79% of the cohort (n=1566) had at least mild chronic kidney disease (estimated glomerular filtration rate <60 mL/min in 46%, <30 mL/min in 22%). Chronic kidney disease patients were more likely to develop heart failure (P<0.0001), non-ST-elevation myocardial infarction (P=0.003), and AKI (P<0.007). AKI patients were at greater risk of heart failure and cardiac arrest (P< or =0.0001 for both). Subjects with AKI experienced higher mortality at 90 days (P=0.003). Any acute loss of estimated glomerular filtration rate during hospitalization was independently associated with an increased risk of death (odds ratio, 1.05; P=0.03 per 10-mL/min decline). Other independent predictors of mortality included increasing age (P<0.0001), male gender (P=0.016), white versus black race (P=0.003), and worse baseline kidney function (P=0.003). Chronic kidney disease is a common comorbidity among patients admitted with acute severe hypertension, and AKI is a frequent form of acute target organ dysfunction, particularly in those with baseline chronic kidney disease. Any degree of AKI is associated with a greater risk of morbidity and mortality.

Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase

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

Read, David J.; Li Yong; Chao, Moses V.

2010-05-15

Single doses of organophosphorus compounds (OP) which covalently inhibit neuropathy target esterase (NTE) can induce lower-limb paralysis and distal damage in long nerve axons. Clinical signs of neuropathy are evident 3 weeks post-OP dose in humans, cats and chickens. By contrast, clinical neuropathy in mice following acute dosing with OPs or any other toxic compound has never been reported. Moreover, dosing mice with ethyloctylphosphonofluoridate (EOPF) - an extremely potent NTE inhibitor - causes a different (subacute) neurotoxicity with brain oedema. These observations have raised the possibility that mice are intrinsically resistant to neuropathies induced by acute toxic insult, but maymore » incur brain oedema, rather than distal axonal damage, when NTE is inactivated. Here we provide the first report that hind-limb dysfunction and extensive axonal damage can occur in mice 3 weeks after acute dosing with a toxic compound, bromophenylacetylurea. Three weeks after acutely dosing mice with neuropathic OPs no clinical signs were observed, but distal lesions were present in the longest spinal sensory axons. Similar lesions were evident in undosed nestin-cre:NTEfl/fl mice in which NTE had been genetically-deleted from neural tissue. The extent of OP-induced axonal damage in mice was related to the duration of NTE inactivation and, as reported in chickens, was promoted by post-dosing with phenylmethanesulfonylfluoride. However, phenyldipentylphosphinate, another promoting compound in chickens, itself induced in mice lesions different from the neuropathic OP type. Finally, EOPF induced subacute neurotoxicity with brain oedema in both wild-type and nestin-cre:NTEfl/fl mice indicating that the molecular target for this effect is not neural NTE.« less

Inulin supplementation during gestation mitigates acrylamide-induced maternal and fetal brain oxidative dysfunctions and neurotoxicity in rats.

PubMed

Krishna, Gokul; Muralidhara

2015-01-01

Accumulating evidence suggests that the developing brain is more susceptible to a variety of chemicals. Recent studies have shown a link between the enteric microbiota and brain function. While supplementation of non-digestible oligosaccharides during pregnancy has been demonstrated to positively influence human health mediated through stimulation of beneficial microbiota, our understanding on their neuromodulatory propensity is limited. In the present study, our primary focus was to examine whether supplementation of inulin (a well known fructan) during gestation can abrogate acrylamide (ACR)-induced oxidative impairments and neurotoxicity in maternal and fetal brain of rats. Initially, in a dose-determinative study, we recapitulated the impact of ACR exposure during gestation days (GD 6-19) on gestational parameters, extent of oxidative impairments in brain (maternal/fetal), cholinergic function and neurotoxicity. Subsequently, pregnant rats orally (gavage) administered with inulin (IN, 2 g/kg/day in two equal installments) supplements during gestation days (GD 0-19) were exposed to ACR (200 ppm) in drinking water. IN supplements significantly attenuated ACR-induced changes in exploratory activity (reduced open field exploration) measured on GD 14. Further, IN restored the placental weights among ACR exposed dams. Analysis of biochemical markers revealed that IN supplements effectively offset ACR associated oxidative stress not only in the maternal brain, but in the fetal brain as well. Elevated levels of protein carbonyls in maternal brain regions were completely normalized with IN supplements. More importantly, IN supplements significantly augmented the number of Bifidobacteria in the cecum of ACR rats which correlated well with the neurorestorative effect as evidenced by restored dopamine levels in the maternal cortex and fetal brain acetylcholinesterase activity among ACR-exposed dams. Further, IN supplements also conferred significant protection against