Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

PubMed

Avraham, Y; Grigoriadis, Nc; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, Em

2011-04-01

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Effects of Mesalamine Treatment on Gut Barrier Integrity Following Burn Injury

PubMed Central

Cannon, Abigail R.; Akhtar, Suhail; Hammer, Adam M.; Morris, Niya L.; Javorski, Mike J.; Li, Xiaoling; Kennedy, Richard H.; Gamelli, Richard L.; Choudhry, Mashkoor A.

2016-01-01

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, we examined whether therapeutic intervention with mesalamine (5-ASA), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an ~20% total body surface area dorsal scald burn and resuscitated with either 1mL normal saline or 100mg/kg of 5-ASA dissolved in saline. We examined intestinal transit and permeability along with levels of small intestine epithelial cell pro-inflammatory cytokines and tight junction protein expression one day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed one day after burn injury, which accompanied a significant increase in gut permeability. We found a substantial increase in the levels of IL-6 (by ~1.5 fold) and IL-18 (by ~2.5 fold) in small intestine epithelial cells one day after injury. Furthermore, burn injury decreases expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn induced increase in permeability, partially restored normal intestinal transit, normalized levels of the pro-inflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin to that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury. PMID:27388883

Effects of Mesalamine Treatment on Gut Barrier Integrity After Burn Injury.

PubMed

Cannon, Abigail R; Akhtar, Suhail; Hammer, Adam M; Morris, Niya L; Javorski, Michael J; Li, Xiaoling; Kennedy, Richard H; Gamelli, Richard L; Choudhry, Mashkoor A

2016-01-01

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, the authors examined whether therapeutic intervention with mesalamine (5-aminosalicylic acid [5-ASA]), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an approximately 20% TBSA dorsal scald burn and resuscitated with either 1 ml normal saline or 100 mg/kg of 5-ASA dissolved in saline. The authors examined intestinal transit and permeability along with the levels of small intestine epithelial cell proinflammatory cytokines and tight junction protein expression 1 day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed 1 day after burn injury, which accompanied a significant increase in gut permeability. The authors found a substantial increase in the levels of interleukin (IL)-6 (by ~1.5-fold) and IL-18 (by ~2.5-fold) in the small intestine epithelial cells 1 day after injury. Furthermore, burn injury decreases the expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn-induced increase in permeability, partially restored normal intestinal transit, normalized the levels of the proinflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin compared with that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury.

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

PubMed Central

Morabito, Michael V.; Ravussin, Yann; Mueller, Bridget R.; Skowronski, Alicja A.; Watanabe, Kazuhisa; Foo, Kylie S.; Lee, Samuel X.; Lehmann, Anders; Hjorth, Stephan; Zeltser, Lori M.; LeDuc, Charles A.; Leibel, Rudolph L.

2017-01-01

Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss. PMID:28107353

Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain.

PubMed

Bai, Wei; Li, Ping; Ning, Ya-Lei; Peng, Yan; Xiong, Ren-Ping; Yang, Nan; Chen, Xing; Zhou, Yuan-Guo

2018-04-15

Excitatory amino acid transporters (EAATs) on cerebral vascular endothelial cells play an important role in maintaining glutamate homeostasis in the brain. The dysfunction of endothelial EAATs is an important reason for the dramatically elevated brain glutamate levels after brain injury, such as traumatic brain injury (TBI). The adenosine A 2A receptor (A 2A R) plays an important role in regulating the brain glutamate level after brain injury; however, researchers have not clearly determined whether this role was related to its ability to regulate endothelial EAATs. Activation of A 2A R in vitro not only decreased the PKA- and glutamate level-dependent strengthening of the interaction between NKA-α1 and the FXYD1 subunit and the subsequent decrease in the activity of Na + /K + -ATPases (NKAs) but also enhanced its interaction with EAATs and ultimately aggravated the reverse transport function of endothelial EAATs under oxygen-glucose deprivation (OGD) conditions. Conversely, inhibition of A 2A R restored the normal transport of EAAT. Moreover, A 2A R inhibition increased NKA activity and decreased its interaction with EAATs in isolated brain capillaries after TBI, further confirming its role in endothelial EAATs in vivo. Based on our results, A 2A R played an important role in regulating endothelial EAAT function, and strategies that restore the normal transport of endothelial EAATs through the inhibition of A 2A R might serve as an effective treatment for brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Nuclear-encoded mitochondrial complex I gene expression is restored to normal levels by inhibition of unedited ATP9 transgene expression in Arabidopsis thaliana.

PubMed

Busi, María V; Gómez-Casati, Diego F; Perales, Mariano; Araya, Alejandro; Zabaleta, Eduardo

2006-01-01

Mitochondria play an important role during sporogenesis in plants. The steady state levels of the nuclear-encoded mitochondrial complex I (nCI), PSST, TYKY and NADHBP transcripts increase in flowers of male-sterile plants with impairment of mitochondrial function generated by the expression of the unedited version of ATP9 (u-ATP9). This suggests a nuclear control of nCI genes in response to the mitochondrial flaw. To evaluate this hypothesis, transgenic plants carrying the GUS reporter gene, under the control of the PSST, TYKY and NADHBP promoters, were constructed. We present evidence that suppression by antisense strategy of the expression of u-ATP9 restores the normal levels of three nCI transcripts, indicating that the increase in PSST, TYKY and NADHBP in plants with a mitochondrial flaw occurs at the transcriptional level. The data presented here support the hypothesis that a mitochondrial dysfunction triggers a retrograde signaling which induce some nuclear-encoded mitochondrial genes. Moreover, these results demonstrate that this is a valuable experimental model for studying nucleus-mitochondria cross-talk events.

Anorexia Nervosa and its Associated Endocrinopathy in Young People

PubMed Central

Misra, Madhusmita; Klibanski, Anne

2016-01-01

Anorexia nervosa (AN) is a condition of severe undernutrition associated with adaptive changes in many endocrine axes. These changes include hypogonadotropic hypogonadism, acquired growth hormone resistance with low insulin like growth factor-1 (IGF-1) levels, hypercortisolemia, altered secretion of adipokines and appetite regulating hormones, and low bone mineral density (BMD). Bone health is impaired subsequent to low BMI, decreased lean mass, and the endocrine changes described above. In addition to low areal BMD, AN is characterized by a decrease in volumetric BMD, changes in bone geometry, and reductions in strength estimates, leading to an increased risk for fracture. Weight restoration is essential for restoration of normal endocrine function; however, hypercortisolemia, high PYY levels, and ghrelin dynamics may not completely normalize. In some patients, hypogonadotropic hypogonadism persists despite weight restoration. Weight gain and menstrual recovery are critical for improving bone health in AN, however, residual deficits may persist. Physiologic estrogen replacement using transdermal, but not oral, estrogen increases bone accrual in adolescents with AN, while bisphosphonates improve BMD in adults. Recombinant human IGF-1 and teriparatide have been used in a few studies as bone anabolic therapies. More data are necessary to determine the optimal therapeutic strategies for low BMD in AN. PMID:26863308

Functional restoration of cirrhotic liver after partial hepatectomy in the rat.

PubMed

Hashimoto, Masaji; Watanabe, Goro

2005-01-01

Although cirrhosis is the terminal stage of various liver diseases, thanks to recent advances one might eliminate some causes of liver damage. Liver has a potent regeneration capacity. It is important to evaluate the regenerating cirrhotic liver after partial hepatectomy, morphologically and functionally, in the long term. We evaluated the functional capacity of the rat liver rendered cirrhotic by orally administered thioacetamide, and examined the correlation between morphological and functional restoration after 2/3 hepatectomy in comparison with hepatectomized normal rats and sham-operated cirrhotic rats. Morphological restoration was evaluated by remnant liver weight, proliferating cell nuclear antigen labeling index, and fibrosis ratio. Functional restoration was evaluated by the indocyanine green disappearance rate and aminopyrine clearance. Cirrhotic rats were functionally deteriorated in comparison with the normal rats. Morphological restoration in cirrhotic rats was delayed in comparison with normal rats. Functional restoration after 2/3 hepatectomy was advanced in comparison with morphological restoration. In comparison with sham-operated cirrhotic rats, functional restoration of the cirrhotic liver was accelerated by partial hepatectomy. In cirrhotic rats, functional restoration of the liver after 2/3 hepatectomy was advanced in comparison with morphological restoration. Partial hepatectomy seemed to promote functional restoration of the cirrhotic liver.

Biological Perspectives of Delayed Fracture Healing

PubMed Central

Hankenson, KD; Zmmerman, G; Marcucio, R

2015-01-01

Fracture healing is a complex biological process that requires interaction among a series of different cell types. Maintaining the appropriate temporal progression and spatial pattern is essential to achieve robust healing. We can temporally assess the biological phases via gene expression, protein analysis, histologically, or non-invasively using biomarkers as well as imaging techniques. However, determining what leads to normal verses abnormal healing is more challenging. Since the ultimate outcome of the process of fracture healing is to restore the original functions of bone, assessment of fracture healing should include not only monitoring the restoration of structure and mechanical function, but also an evaluation of the restoration of normal bone biology. Currently very few non-invasive measures of the biology of healing exist; however, recent studies that have correlated non-invasive measures with fracture healing outcome in humans have shown that serum TGFbeta1 levels appear to be an indicator of healing vs non-healing. In the future, developing additional serum measures to assess biological healing will improve the reliability and permit us to assess stages of fracture healing. Additionally, new functional imaging technologies could prove useful for better understanding both normal fracture healing and predicting dysfunctional healing in human patients. PMID:24857030

Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused by Theileria parva infection

PubMed Central

Palmer, Guy H.; Machado, Joel; Fernandez, Paula; Heussler, Volker; Perinat, Therese; Dobbelaere, Dirk A. E.

1997-01-01

Infection of cattle with the protozoan Theileria parva results in uncontrolled T lymphocyte proliferation resulting in lesions resembling multicentric lymphoma. Parasitized cells exhibit autocrine growth characterized by persistent translocation of the transcriptional regulatory factor nuclear factor κB (NFκB) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How T. parva induces persistent NFκB activation, required for T cell activation and proliferation, is unknown. We hypothesized that the parasite induces degradation of the IκB molecules which normally sequester NFκB in the cytoplasm and that continuous degradation requires viable parasites. Using T. parva-infected T cells, we showed that the parasite mediates continuous phosphorylation and proteolysis of IκBα. However, IκBα reaccumulated to high levels in parasitized cells, which indicated that T. parva did not alter the normal NFκB-mediated positive feedback loop which restores cytoplasmic IκBα. In contrast, T. parva mediated continuous degradation of IκBβ resulting in persistently low cytoplasmic IκBβ levels. Normal IκBβ levels were only restored following T. parva killing, indicating that viable parasites are required for IκBβ degradation. Treatment of T. parva-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both IκB degradation and consequent enhanced expression of NFκB dependent genes. However treatment using the antioxidant N-acetylcysteine had no effect on either IκB levels or NFκB activation, indicating that the parasite subverts the normal IκB regulatory pathway downstream of the requirement for reactive oxygen intermediates. Identification of the critical points regulated by T. parva may provide new approaches for disease control as well as increase our understanding of normal T cell function. PMID:9356483

The impact of the fecal stream and stasis on immunologic reactions in ileal pouch after restorative proctocolectomy for ulcerative colitis: a prospective, pilot study.

PubMed

Yamamoto, Takayuki; Umegae, Satoru; Kitagawa, Tatsushi; Matsumoto, Koichi

2005-10-01

The etiology of pouch inflammation after restorative proctocolectomy is unknown. The fecal stream and immunological reactions are potential pathological factors. This study was performed to examine the impact of the fecal stream and stasis on immunological reactions in the pouch. Patients who underwent a restorative proctocolectomy with a covering ileostomy for ulcerative colitis were studied. Mucosal biopsy specimens were obtained from both the pouch and the proximal ileum at the time of ileostomy closure, and 3, 6, and 12 months after ileostomy closure. As a control group, normal ileal biopsies were obtained from patients with colonic polyps. At the time of ileostomy closure, mucosal interleukin-1beta, interleukin-6, interleukin-8, and tumor necrosis factor-alpha levels in the pouch and the proximal ileum were not significantly different from those in the normal control group. At 3 months after ileostomy closure, the mucosal cytokine levels in the pouch increased significantly compared with those at ileostomy closure, and their levels were significantly higher than those in the proximal ileum. At 6 and 12 months after ileostomy closure, the mucosal cytokine levels in the pouch did not change significantly compared with those at 3 months after ileostomy closure. The mucosal cytokine levels in the proximal ileum did not change significantly during the entire study. The immunological reactions in the pouch occurred soon after ileostomy closure, and continued for at least 1 yr. The fecal stream and stasis play an important part in the pathogenesis of immunological reactions in the ileal pouch.

Improvement of Insulin Secretion and Pancreatic β-cell Function in Streptozotocin-induced Diabetic Rats Treated with Aloe vera Extract

PubMed Central

Noor, Ayesha; Gunasekaran, S.; Vijayalakshmi, M. A.

2017-01-01

Background: Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. Plant extracts and their products are being used as an alternative system of medicine for the treatment of diabetes. Aloe vera has been traditionally used to treat several diseases and it exhibits antioxidant, anti-inflammatory, and wound-healing effects. Streptozotocin (STZ)-induced Wistar diabetic rats were used in this study to understand the potential protective effect of A. vera extract on the pancreatic islets. Objective: The aim of the present study was to evaluate the A. vera extract on improvement of insulin secretion and pancreatic β-cell function by morphometric analysis of pancreatic islets in STZ-induced diabetic Wistar rats. Materials and Methods: After acclimatization, male Wistar rats, maintained as per the Committee for the Purpose of Control and Supervision of Experiments on Animals guidelines, were randomly divided into four groups of six rats each. Fasting plasma glucose and insulin levels were assessed. The effect of A. vera extract in STZ-induced diabetic rats on the pancreatic islets by morphometric analysis was evaluated. Results: Oral administration of A. vera extract (300 mg/kg) daily to diabetic rats for 3 weeks showed restoration of blood glucose levels to normal levels with a concomitant increase in insulin levels upon feeding with A. vera extract in STZ-induced diabetic rats. Morphometric analysis of pancreatic sections revealed quantitative and qualitative gain in terms of number, diameter, volume, and area of the pancreatic islets of diabetic rats treated with A. vera extract when compared to the untreated diabetic rats. Conclusion: A. vera extract exerts antidiabetic effects by improving insulin secretion and pancreatic β-cell function by restoring pancreatic islet mass in STZ-induced diabetic Wistar rats. SUMMARY Fasting plasma glucose (FPG) and insulin levels were restored to normal levels in diabetic rats treated with Aloe vera extractIslets of pancreas were qualitatively and quantitatively restored to normalcy leading to restoration of FPG and insulin levels of diabetic rats treated with Aloe vera extractMorphometric analysis of pancreatic sections revealed quantitative and qualitative gain in terms of number, diameter, volume, and area of the pancreatic islets of diabetic rats treated with Aloe vera extract when compared to the untreated diabetic rats. Abbreviations Used: A. vera, FPG: Fasting plasma glucose, STZ: Streptozotocin, BW: Body weight PMID:29333050

Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study.

PubMed

Foulks, Gary N; Borchman, Douglas; Yappert, Marta; Kakar, Shelley

2013-01-01

Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal. Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment. The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes.

Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS

PubMed Central

Cardoso, Rodolfo C.; Burns, Ashleigh; Moeller, Jacob; Skinner, Donal C.

2016-01-01

Prenatal testosterone (T) treatment recapitulates the reproductive and metabolic phenotypes of polycystic ovary syndrome in female sheep. At the neuroendocrine level, prenatal T treatment results in disrupted steroid feedback on gonadotropin release, increased pituitary sensitivity to GnRH, and subsequent LH hypersecretion. Because prenatal T-treated sheep manifest functional hyperandrogenism and hyperinsulinemia, gonadal steroids and/or insulin may play a role in programming and/or maintaining these neuroendocrine defects. Here, we investigated the effects of prenatal and postnatal treatments with an androgen antagonist (flutamide [F]) or an insulin sensitizer (rosiglitazone [R]) on GnRH-stimulated LH secretion in prenatal T-treated sheep. As expected, prenatal T treatment increased the pituitary responsiveness to GnRH leading to LH hypersecretion. Neither prenatal interventions nor postnatal F treatment normalized the GnRH-stimulated LH secretion. Conversely, postnatal R treatment completely normalized the GnRH-stimulated LH secretion. At the tissue level, gestational T increased pituitary LHβ, androgen receptor, and insulin receptor-β, whereas it reduced estrogen receptor (ER)α protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-β, it failed to prevent an increase in LHβ expression. Contrarily, postnatal R treatment restored ERα and partially normalized LHβ pituitary levels. Immunohistochemical findings confirmed changes in pituitary ERα expression to be specific to gonadotropes. In conclusion, these findings indicate that increased pituitary responsiveness to GnRH in prenatal T-treated sheep is likely a function of reduced peripheral insulin sensitivity. Moreover, results suggest that restoration of ERα levels in the pituitary may be one mechanism by which R prevents GnRH-stimulated LH hypersecretion in this sheep model of polycystic ovary syndrome-like phenotype. PMID:27792406

Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS.

PubMed

Cardoso, Rodolfo C; Burns, Ashleigh; Moeller, Jacob; Skinner, Donal C; Padmanabhan, Vasantha

2016-12-01

Prenatal testosterone (T) treatment recapitulates the reproductive and metabolic phenotypes of polycystic ovary syndrome in female sheep. At the neuroendocrine level, prenatal T treatment results in disrupted steroid feedback on gonadotropin release, increased pituitary sensitivity to GnRH, and subsequent LH hypersecretion. Because prenatal T-treated sheep manifest functional hyperandrogenism and hyperinsulinemia, gonadal steroids and/or insulin may play a role in programming and/or maintaining these neuroendocrine defects. Here, we investigated the effects of prenatal and postnatal treatments with an androgen antagonist (flutamide [F]) or an insulin sensitizer (rosiglitazone [R]) on GnRH-stimulated LH secretion in prenatal T-treated sheep. As expected, prenatal T treatment increased the pituitary responsiveness to GnRH leading to LH hypersecretion. Neither prenatal interventions nor postnatal F treatment normalized the GnRH-stimulated LH secretion. Conversely, postnatal R treatment completely normalized the GnRH-stimulated LH secretion. At the tissue level, gestational T increased pituitary LHβ, androgen receptor, and insulin receptor-β, whereas it reduced estrogen receptor (ER)α protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-β, it failed to prevent an increase in LHβ expression. Contrarily, postnatal R treatment restored ERα and partially normalized LHβ pituitary levels. Immunohistochemical findings confirmed changes in pituitary ERα expression to be specific to gonadotropes. In conclusion, these findings indicate that increased pituitary responsiveness to GnRH in prenatal T-treated sheep is likely a function of reduced peripheral insulin sensitivity. Moreover, results suggest that restoration of ERα levels in the pituitary may be one mechanism by which R prevents GnRH-stimulated LH hypersecretion in this sheep model of polycystic ovary syndrome-like phenotype.

The model test of restoration project of the gravel beach of Chen Village fishing port

NASA Astrophysics Data System (ADS)

Wang, D. X.; Gui, J. S.; Sun, J. W.

2016-08-01

Gravel beach is a case in coastal landform by wave action. It is more and more crucial for the environment of coastal engineering in recent years. However, it is poorly studied for it in China. And this paper which is based on the model test of Restoration Project of the Gravel Beach of Chen Village Fishing Port, uses two dimensional normal physical models, aiming at exploring the movement of gravel beach under wave action and verifying the stability of the gravel beach section. The test depends on different water levels (designed high water level, designed low water level, and extreme high water level) and return periods (2, 5, 10, 25, 50 years once). Finally, two distinct experimental sections are got under the changed conditions and the movement law of gravels is obtained.

Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study.

PubMed

Le Page, Lydia M; Rider, Oliver J; Lewis, Andrew J; Ball, Vicky; Clarke, Kieran; Johansson, Edvin; Carr, Carolyn A; Heather, Lisa C; Tyler, Damian J

2015-08-01

Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 ± 0.7 vs. 8.4 ± 0.5 mmol/L), lower PDH flux (0.005 ± 0.001 vs. 0.017 ± 0.002 s(-1)), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 ± 0.8 vs. 20 ± 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 ± 0.002 s(-1)), reversed diastolic dysfunction (E/E' 14 ± 1), and normalized blood glucose levels (7.5 ± 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Correction of X-linked immunodeficient mice by competitive reconstitution with limiting numbers of normal bone marrow cells.

PubMed

Rohrer, J; Conley, M E

1999-11-15

Gene therapy for inherited disorders is more likely to succeed if gene-corrected cells have a proliferative or survival advantage compared with mutant cells. We used a competitive reconstitution model to evaluate the strength of the selective advantage that Btk normal cells have in Btk-deficient xid mice. Whereas 2,500 normal bone marrow cells when mixed with 497,500 xid cells restored serum IgM and IgG3 levels to near normal concentrations in 3 of 5 lethally irradiated mice, 25,000 normal cells mixed with 475,000 xid cells reliably restored serum IgM and IgG3 concentrations and the thymus-independent antibody response in all transplanted mice. Reconstitution was not dependent on lethal irradiation, because sublethally irradiated mice all had elevated serum IgM and IgG3 by 30 weeks postreconstitution when receiving 25,000 normal cells. Furthermore, the xid defect was corrected with as few as 10% of the splenic B cells expressing a normal Btk. When normal donor cells were sorted into B220(+)/CD19(+) committed B cells and B220(-)/CD19(-) cell populations, only the B220(-)/CD19(-) cells provided long-term B-cell reconstitution in sublethally irradiated mice. These findings suggest that even inefficient gene therapy may provide clinical benefit for patients with XLA.

In vivo study of the effectiveness of quantitative percussion diagnostics as an indicator of the level of structural pathology of teeth after restoration.

PubMed

Sheets, Cherilyn G; Wu, Jean C; Rashad, Samer; Phelan, Michael; Earthman, James C

2017-02-01

Conventional diagnostic aids based upon imagery and patient symptoms do not indicate whether restorative treatments have eliminated structural pathology. The purpose of this clinical study was to evaluate quantitative percussion diagnostics (QPD), a mechanics-based methodology that tests the structural integrity of teeth noninvasively. The study hypothesis was that QPD would provide knowledge of the structural instability of teeth after restorative work. Eight participants with 60 sites needing restoration were enrolled in an IRB-approved clinical study. Each participant was examined comprehensively, including QPD testing. Each site was disassembled and microscopically video documented, and the results were recorded on a defect assessment sheet. A predictive model was developed for the pathology rating based on normalized fit error (NFE) values using data from the before treatment phase of the study published previously. Each restored site was then tested using QPD. The mean change in NFE values after restoration was evaluated by the pathology rating before treatment. The model was then used to predictively classify the rating after restoration based on the NFE values after treatment. The diagnostic potential of the rating was explored as a marker for risk of pathology after restoration. After restoration, 51 of the 60 sites fell below an NFE of 0.04, representing a greatly stabilized tooth site sample group. Several sites remained in the high-risk category and some increased in pathologic micromovement. Two models were used to determine severity with indicative cutoff points to group sites with similar values. The data support the hypothesis that QPD can indicate a revised level of structural instability of teeth after restoration. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

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

Khangaonkar, Tarang P.; Breithaupt, Stephen A.; Kristanovich, Felix C.

A hydrodynamic and hydrologic modeling analysis was conducted to evaluate the feasibility of restoring natural estuarine functions and tidal marine wetlands habitat in the Chinook River estuary, located near the mouth of the Columbia River in Washington. The reduction in salmonid populations is attributable primarily to the construction of a Highway 101 overpass across the mouth of the Chinook River in the early 1920s with a tide gate under the overpass. This construction, which was designed to eliminate tidal action in the estuary, has impeded the upstream passage of salmonids. The goal of the Chinook River Restoration Project is tomore » restore tidal functions through the estuary, by removing the tide gate at the mouth of the river, filling drainage ditches, restoring tidal swales, and reforesting riparian areas. The hydrologic model (HEC-HMS) was used to compute Chinook River and tributary inflows for use as input to the hydrodynamic model at the project area boundary. The hydrodynamic model (RMA-10) was used to generate information on water levels, velocities, salinity, and inundation during both normal tides and 100-year storm conditions under existing conditions and under the restoration alternatives. The RMA-10 model was extended well upstream of the normal tidal flats into the watershed domain to correctly simulate flooding and drainage with tidal effects included, using the wetting and drying schemes. The major conclusion of the hydrologic and hydrodynamic modeling study was that restoration of the tidal functions in the Chinook River estuary would be feasible through opening or removal of the tide gate. Implementation of the preferred alternative (removal of the tide gate, restoration of the channel under Hwy 101 to a 200-foot width, and construction of an internal levee inside the project area) would provide the required restorations benefits (inundation, habitat, velocities, and salinity penetration, etc.) and meet flood protection requirements. The alternative design included design of storage such that relatively little difference in the drainage or inundation upstream of Chinook River Valley Road would occur as a result of the proposed restoration activities.« less

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

Khangaonkar, Tarang P.; Breithaupt, Stephen A.; Kristanovich, Felix C.

A hydrodynamic and hydrologic modeling analysis was conducted to evaluate the feasibility of restoring natural estuarine functions and tidal marine wetlands habitat in the Chinook River estuary, located near the mouth of the Columbia River in Washington. The reduction in salmonid populations is attributable primarily to the construction of a Highway 101 overpass across the mouth of the Chinook River in the early 1920s with a tide gate under the overpass. This construction, which was designed to eliminate tidal action in the estuary, has impeded the upstream passage of salmonids. The goal of the Chinook River Restoration Project is tomore » restore tidal functions through the estuary, by removing the tide gate at the mouth of the river, filling drainage ditches, restoring tidal swales, and reforesting riparian areas. The hydrologic model (HEC-HMS) was used to compute Chinook River and tributary inflows for use as input to the hydrodynamic model at the project area boundary. The hydrodynamic model (RMA-10) was used to generate information on water levels, velocities, salinity, and inundation during both normal tides and 100-year storm conditions under existing conditions and under the restoration alternatives. The RMA-10 model was extended well upstream of the normal tidal flats into the watershed domain to correctly simulate flooding anddrainage with tidal effects included, using the wetting and drying schemes. The major conclusion of the hydrologic and hydrodynamic modeling study was that restoration of the tidal functions in the Chinook River estuary would be feasible through opening or removal of the tide gate. Implementation of the preferred alternative (removal of the tide gate, restoration of the channel under Hwy 101 to a 200-foot width, and construction of an internal levee inside the project area) would provide the required restorations benefits (inundation, habitat, velocities, and salinity penetration, etc.) and meet flood protection requirements. The alternative design included design of storage such that relatively little difference in the drainage or inundation upstream of Chinook River Valley Road would occur as a result of the proposed restoration activities.« less

Central memory CD4 T cells are associated with incomplete restoration of the CD4 T cell pool after treatment-induced long-term undetectable HIV viraemia.

PubMed

Rallón, Norma; Sempere-Ortells, José M; Soriano, Vincent; Benito, José M

2013-11-01

It is unclear to what extent T cell reconstitution may be possible in HIV-1-infected individuals on continuous successful highly active antiretroviral therapy (HAART). Herein, we analysed distinct phenotypic markers of immune recovery in patients with undetectable viraemia for 8 years, taking as reference untreated patients and healthy controls. Seventy-two subjects were examined: 28 HIV-1+ patients on successful long-term HAART, 24 HIV-1+ untreated viraemic patients and 20 age-matched healthy controls. Analysis of naive and memory CD4 and CD8 T cells was combined with measurements of activation status (expression of CD38) and with thymic function (expression of CD31). Statistical significance was determined by non-parametric tests. After long-term HAART, the majority of parameters were normalized compared with age-matched control values, including T cell activation and thymic function. However, absolute counts of naive and central memory CD4 T cells remained below normal levels. The only parameters significantly associated with CD4 counts at the end of follow-up were the pre-HAART CD4 count ( β ± SD = 0.54 ± 0.16, P = 0.003) and the level of CD4 central memory cells at the end of follow-up (β ± SD = 1.18 ± 0.23, P < 0.0001). Only patients starting HAART with CD4 counts >350 cells/mm(3) reached a complete normalization of CD4 counts. Even after long-term successful HAART, complete CD4 restoration may be attainable only in patients starting therapy with moderately high CD4 counts, prompting early initiation of antiretroviral therapy. Incomplete CD4 restoration may be associated with a defective restoration of central memory CD4 T cells, a cell subset with a pivotal role in T cell homeostasis.

Partial restoration of impaired interleukin-2 production and Tac antigen (putative interleukin-2 receptor) expression in patients with acquired immune deficiency syndrome by isoprinosine treatment in vitro.

PubMed Central

Tsang, K Y; Fudenberg, H H; Galbraith, G M; Donnelly, R P; Bishop, L R; Koopmann, W R

1985-01-01

The in vitro effects of isoprinosine (ISO) on interleukin-2 (IL-2) production, the expression of Tac antigen (IL-2 receptor) on lymphocytes, and the ability of Leu 3(+) cells to absorb interleukin-1 (IL-1) were investigated in 10 patients with acquired immune deficiency syndrome (AIDS). In 9 of the 10 patients, production of IL-2 from mononuclear cells and Leu 3(+) cells was depressed; expression of Tac antigen on mononuclear cells and Leu 2(+) cells was found to be depressed in 9 of 10 patients. The ability of the Leu 3(+) lymphocytes to absorb IL-1 was depressed in all (four of four) patients studied. After ISO treatment, IL-2 production, Tac antigen expression and IL-1 absorption were restored to normal or near normal levels in most of the patients. These results suggest that ISO has an immunostimulating capacity in AIDS patients and that the potential of ISO in immune response restoration in AIDS patients deserves critical consideration. PMID:2581997

Taste Changes in Vitamin A Deficiency

PubMed Central

Bernard, Rudy A.; Halpern, Bruce P.

1968-01-01

Taste preferences were studied in two groups of rats depleted of vitamin A by dietary restriction. One group received sufficient vitamin A acid supplement to maintain normal growth. The other group was repleted with vitamin A alcohol after the classical deficiency symptoms had appeared; this group gradually lost normal preferences for NaCl and aversion to quinine solutions during depletion. Vitamin A alcohol repletion tended to restore taste preferences to normal. In contrast, the group receiving vitamin A acid showed normal taste preferences throughout the depletion period. When the vitamin A acid supplement was removed taste preferences became abnormal and returned to normal when vitamin A acid was restored. Peripheral gustatory neural activity of depleted rats without any form of vitamin A was less than normal both at rest and when the tongue was stimulated with NaCl solutions. Histological examination showed keratin infiltrating the pores of the taste buds. Accessory glandular tissues were atrophied and debris filled the trenches of the papillae. It is concluded that vitamin A acid can provide the vitamin A required for normal taste, as contrasted with its inability to maintain visual function. It is suggested that the effect of vitamin A is exerted at the receptor level, as a result of its role in the biosynthesis of mucopolysaccharides, which have been recently identified in the pore area of taste buds, as well as being present in the various secretions of the oral cavity. PMID:4299794

Eliminating animal facility light-at-night contamination and its effect on circadian regulation of rodent physiology, tumor growth, and metabolism: a challenge in the relocation of a cancer research laboratory.

PubMed

Dauchy, Robert T; Dupepe, Lynell M; Ooms, Tara G; Dauchy, Erin M; Hill, Cody R; Mao, Lulu; Belancio, Victoria P; Slakey, Lauren M; Hill, Steven M; Blask, David E

2011-05-01

Appropriate laboratory animal facility lighting and lighting protocols are essential for maintaining the health and wellbeing of laboratory animals and ensuring the credible outcome of scientific investigations. Our recent experience in relocating to a new laboratory facility illustrates the importance of these considerations. Previous studies in our laboratory demonstrated that animal room contamination with light-at-night (LAN) of as little as 0.2 lx at rodent eye level during an otherwise normal dark-phase disrupted host circadian rhythms and stimulated the metabolism and proliferation of human cancer xenografts in rats. Here we examined how simple improvements in facility design at our new location completely eliminated dark-phase LAN contamination and restored normal circadian rhythms in nontumor-bearing rats and normal tumor metabolism and growth in host rats bearing tissue-isolated MCF7(SR(-)) human breast tumor xenografts or 7288CTC rodent hepatomas. Reducing LAN contamination in the animal quarters from 24.5 ± 2.5 lx to nondetectable levels (complete darkness) restored normal circadian regulation of rodent arterial blood melatonin, glucose, total fatty and linoleic acid concentrations, tumor uptake of O(2), glucose, total fatty acid and CO(2) production and tumor levels of cAMP, triglycerides, free fatty acids, phospholipids, and cholesterol esters, as well as extracellular-signal-regulated kinase, mitogen-activated protein kinase, serine-threonine protein kinase, glycogen synthase kinase 3β, γ-histone 2AX, and proliferating cell nuclear antigen.

Eliminating Animal Facility Light-at-Night Contamination and Its Effect on Circadian Regulation of Rodent Physiology, Tumor Growth, and Metabolism: A Challenge in the Relocation of a Cancer Research Laboratory

PubMed Central

Dauchy, Robert T; Dupepe, Lynell M; Ooms, Tara G; Dauchy, Erin M; Hill, Cody R; Mao, Lulu; Belancio, Victoria P; Slakey, Lauren M; Hill, Steven M; Blask, David E

2011-01-01

Appropriate laboratory animal facility lighting and lighting protocols are essential for maintaining the health and wellbeing of laboratory animals and ensuring the credible outcome of scientific investigations. Our recent experience in relocating to a new laboratory facility illustrates the importance of these considerations. Previous studies in our laboratory demonstrated that animal room contamination with light-at-night (LAN) of as little as 0.2 lx at rodent eye level during an otherwise normal dark-phase disrupted host circadian rhythms and stimulated the metabolism and proliferation of human cancer xenografts in rats. Here we examined how simple improvements in facility design at our new location completely eliminated dark-phase LAN contamination and restored normal circadian rhythms in nontumor-bearing rats and normal tumor metabolism and growth in host rats bearing tissue-isolated MCF7(SR–) human breast tumor xenografts or 7288CTC rodent hepatomas. Reducing LAN contamination in the animal quarters from 24.5 ± 2.5 lx to nondetectable levels (complete darkness) restored normal circadian regulation of rodent arterial blood melatonin, glucose, total fatty and linoleic acid concentrations, tumor uptake of O2, glucose, total fatty acid and CO2 production and tumor levels of cAMP, triglycerides, free fatty acids, phospholipids, and cholesterol esters, as well as extracellular-signal-regulated kinase, mitogen-activated protein kinase, serine–threonine protein kinase, glycogen synthase kinase 3β, γ-histone 2AX, and proliferating cell nuclear antigen. PMID:21640027

Neuroprotective effect of the carnosine - α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease.

PubMed

Kulikova, Olga I; Berezhnoy, Daniil S; Stvolinsky, Sergey L; Lopachev, Alexander V; Orlova, Valentina S; Fedorova, Tatiana N

2018-06-01

In a model of early-stage Parkinson's disease induced by a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to Wistar rats, a neuroprotective effect of a new derivative of carnosine and α-lipoic acid (C/LA nanomicellar complex) was demonstrated. Acute intraperitoneal administration of carnosine, α-lipoic acid and C/LA complex following MPTP administration normalized the total antioxidant activity in the brain tissue. Of all the compounds tested only C/LA complex normalized the metabolism of dopamine (DA) and serotonin (5-HT), while its components did not show similar effects when used separately. C/LA complex effectively restored the level of DA metabolites: the level of DOPAC was increased by 24.7 ± 5.6% compared to the animals that had received MPTP only, and the level of HVA was restored to the values observed in the intact animals. Integral metabolic indices of DA (DOPAC/DA and HVA/DA ratios) and 5-HT turnover (5-HIAA/5-HT ratio) in the striatum tended to increase in case of C/LA complex administration. Copyright © 2018 Elsevier Inc. All rights reserved.

Silymarin: A Novel Natural Agent to Restore Defective Pancreatic β Cells in Streptozotocin (STZ)-induced Diabetic Rats

PubMed Central

Amniattalab, Amir; Malekinejad, Hassan; Rezabakhsh, Aysa; Rokhsartalab-Azar, Shirin; Alizade-Fanalou, Shahin

2016-01-01

This study aimed to investigate the potency of silymarin (SMN) and melatonin (MEL) on restoring the pancreatic   cells in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups, including: control (C), untreated diabetic (D), SMN-treated diabetic (50 mg/Kg, orally), MEL-treated diabetic (10 mg/Kg, i.p.), and SMN plus MEL-treated diabetic rats. Diabetes was induced by injection of STZ (50 mg/Kg, i.p.). The blood glucose and insulin levels were measured. After the 28 days treatment period, antioxidant status was analyzed by determination of total antioxidant capacity (TAC) in the liver and serum. The histopathological changes in the pancreatic islets were examined by histochemical staining and enumeration of   cells. Although none of the test compounds reduced the blood glucose level to normal concentration, however SMN alone and in combination with MEL was able to decline it significantly (P<0.05) after 28 days administration. Both SMN and MEL could recover the diabetes-reduced TAC values. Moreover, the diabetes-induced cellular vacuolation and   cells depletion were improved by the SMN treatment. Our data suggest that the SMN and MEL treatment was able to normalize the antioxidant status, while only SMN administration could restore the  cells of Langerhans islets in diabetic rats. PMID:27980584

Granisetron and carvedilol can protect experimental rats againstadjuvant-induced arthritis.

PubMed

Ahmed, Yasmin Moustafa; Messiha, Basim Anwar Shehata; Abo-Saif, Ali Ahmed

2017-04-01

Rheumatoid arthritis (RA), a disabling autoimmune disorder of the joints as well as other organs, affects about 1% of population. Unfortunately, all current treatments of RA cause severe gastrointestinal, renal and other complications. We aimed to evaluate the possible antiarthritic effects of a serotonin 5-HT 3 receptor blocker, granisetron, and a nonselective adrenergic receptor blocker, carvedilol, on complete Freund's adjuvant-induced RA in adult female albino rats. Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving granisetron (2.5 mg/kg/day) and carvedilol (10 mg/kg/day). Serum-specific rheumatoid, immunological, inflammatory and oxidative stress biomarkers were assessed. A confirmatory histopathological study on joints and spleens was performed. Granisetron administration significantly improved all the measured biomarkers, with the values of rheumatoid factor, matrix metalloproteinase-3, cartilage oligomeric matrix protein, immunoglobulin G, antinuclear antibody and myeloperoxidase being restored back to normal levels. Carvedilol administration significantly improved all biomarkers, with serum MPO value restored back to normal levels. Serotonin 5-HT 3 receptor blockers and adrenergic receptor blockers, represented by granisetron and carvedilol, may represent new promising protective strategies against RA, at least owing to immune-modulator, anti-inflammatory and antioxidant potentials.

Reversing Optical Damage In LiNbO3 Switches

NASA Technical Reports Server (NTRS)

Gee, C. M.; Thurmond, G. D.

1985-01-01

One symptom of optical damage in Ti-diffused LiNbO3 directional-coupler switch reversed by temporarily raising input illumination to higher-thannormal power level. Healing phenomenon used to restore normal operation, increase operating-power rating, and stabilize operating characteristics at lower powers. Higher operating power is tolerated after treatment.

Repair of traumatized mammalian hair cells via sea anemone repair proteins.

PubMed

Tang, Pei-Ciao; Smith, Karen Müller; Watson, Glen M

2016-08-01

Mammalian hair cells possess only a limited ability to repair damage after trauma. In contrast, sea anemones show a marked capability to repair damaged hair bundles by means of secreted repair proteins (RPs). Previously, it was found that recovery of traumatized hair cells in blind cavefish was enhanced by anemone-derived RPs; therefore, the ability of anemone RPs to assist recovery of damaged hair cells in mammals was tested here. After a 1 h incubation in RP-enriched culture media, uptake of FM1-43 by experimentally traumatized murine cochlear hair cells was restored to levels comparable to those exhibited by healthy controls. In addition, RP-treated explants had significantly more normally structured hair bundles than time-matched traumatized control explants. Collectively, these results indicate that anemone-derived RPs assist in restoring normal function and structure of experimentally traumatized hair cells of the mouse cochlea. © 2016. Published by The Company of Biologists Ltd.

H3 and H4 Lysine Acetylation Correlates with Developmental and Experimentally Induced Adult Experience-Dependent Plasticity in the Mouse Visual Cortex

PubMed Central

Vierci, Gabriela; Pannunzio, Bruno; Bornia, Natalia; Rossi, Francesco M.

2016-01-01

Histone posttranslational modifications play a fundamental role in orchestrating gene expression. In this work, we analyzed the acetylation of H3 and H4 histones (AcH3–AcH4) and its modulation by visual experience in the mouse visual cortex (VC) during normal development and in two experimental conditions that restore juvenile-like plasticity levels in adults (fluoxetine treatment and enriched environment). We found that AcH3–AcH4 declines with age and is upregulated by treatments restoring plasticity in the adult. We also found that visual experience modulates AcH3–AcH4 in young and adult plasticity-restored mice but not in untreated ones. Finally, we showed that the transporter vGAT is downregulated in adult plasticity-restored models. In summary, we identified a dynamic regulation of AcH3–AcH4, which is associated with high plasticity levels and enhanced by visual experience. These data, along with recent ones, indicate H3–H4 acetylation as a central hub in the control of experience-dependent plasticity in the VC. PMID:27891053

Examination of ceramic restoration adhesive coverage in cusp-replacement premolar using acoustic emission under fatigue testing.

PubMed

Chang, Yen-Hsiang; Yu, Jin-Jie; Lin, Chun-Li

2014-12-13

This study investigates CAD/CAM ceramic cusp-replacing restoration resistance with and without buccal cusp replacement under static and dynamic cyclic loads, monitored using the acoustic emission (AE) technique. The cavity was designed in a typical MODP (mesial-occlusal-distal-palatal) restoration failure shape when the palatal cusp has been lost. Two ceramic restorations [without coverage (WOC) and with (WC) buccal cuspal coverage with 2.0 mm reduction in cuspal height] were prepared to perform the fracture and fatigue tests with normal (200 N) and high (600 N) occlusal forces. The load versus AE signals in the fracture and fatigue tests were recorded to evaluate the restored tooth failure resistance. The results showed that non-significant differences in load value in the fracture test and the accumulated number of AE signals under normal occlusal force (200 N) in the fatigue test were found between with and without buccal cuspal coverage restorations. The first AE activity occurring for the WOC restoration was lower than that for the WC restoration in the fracture test. The number of AE signals increased with the cyclic load number. The accumulated number of AE signals for the WOC restoration was 187, higher than that (85) for the WC restoration under 600 N in the fatigue test. The AE technique and fatigue tests employed in this study were used as an assessment tool to evaluate the resistances in large CAD/CAM ceramic restorations. Non-significant differences in the tested fracture loads and accumulated number of AE signals under normal occlusal force (200 N) between different restorations indicated that aggressive treatment (with coverage preparation) in palatal cusp-replacing ceramic premolars require more attention for preserving and protecting the remaining tooth.

Effect of Mucuna pruriens on semen profile and biochemical parameters in seminal plasma of infertile men.

PubMed

Ahmad, Mohammad Kaleem; Mahdi, Abbas Ali; Shukla, Kamla Kant; Islam, Najmul; Jaiswar, Shyam Pyari; Ahmad, Sohail

2008-09-01

To investigate the impact of Mucuna pruriens seeds on semen profiles and biochemical levels in seminal plasma of infertile men. Prospective study. Departments of Biochemistry and Obstetrics and Gynecology, King George's Medical University, Lucknow, India. Sixty normal healthy fertile men (controls) and 60 men undergoing infertility screening. High-performance liquid chromatography assay procedure for quantitation of vitamin A and E in seminal plasma. Biochemical parameters in seminal plasma, namely lipids, fructose, and vitamin C, were estimated by standard spectrophotometric procedures. Before and after the treatment, seminal plasma lipid profile, lipid peroxide, fructose, and antioxidant vitamin levels were measured. Treatment with M. pruriens significantly inhibited lipid peroxidation, elevated spermatogenesis, and improved sperm motility. Treatment also recovered the levels of total lipids, triglycerides, cholesterol, phospholipids, and vitamin A, C, and E and corrected fructose in seminal plasma of infertile men. Treatment with M. pruriens increased sperm concentration and motility in all the infertile study groups. Oligozoospermic patients recovered sperm concentration significantly, but sperm motility was not restored to normal levels in asthenozoospermic men. Furthermore, in the seminal plasma of all the infertile groups, the levels of lipids, antioxidant vitamins, and corrected fructose were recovered after a decrease in lipid peroxides after treatment. The present study is likely to open new vistas on the possible role of M. pruriens seed powder as a restorative and invigorating agent for infertile men.

Relationship between adiponectin levels, acylated ghrelin levels, and short-term body mass index changes in children with diabetes mellitus type 1 at diagnosis and after insulin therapy.

PubMed

Martos-Moreno, Gabriel A; Barrios, Vicente; Soriano-Guillén, Leandro; Argente, Jesús

2006-11-01

To determine the effect of the initial metabolic imbalance and its restoration after insulin therapy on adiponectin and acylated ghrelin levels in children with type 1 diabetes mellitus (T1DM). Twenty prepubertal children with newly diagnosed T1DM were prospectively studied at diagnosis and after 1 and 4 months of therapy. Body mass index (BMI) and serum levels of adiponectin, resistin, total and acylated ghrelin, leptin, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) were determined. The control group comprised 40 healthy prepubertal children. BMI was decreased at diagnosis, normalized at 1 month, and remained so thereafter. Adiponectin levels at diagnosis were similar to controls, increasing significantly after 1 month and normalizing at 4 months. Acylated ghrelin levels were lower at diagnosis, with a significant increase at 1 month and normalizing at 4 months. Resistin levels were normal at all time points. Leptin levels were decreased, while TNF-alpha and IL-6 were increased at diagnosis and normalized at 1 month. These findings suggest that BMI is not the main predictor of acylated ghrelin or adiponectin levels in newly diagnosed T1DM subjects and that these peptides may play an important role in the metabolic adaptation in this disease.

A DNA segment spanning the mouse Tnfsf11 transcription unit and its upstream regulatory domain rescues the pleiotropic biologic phenotype of the RANKL null mouse.

PubMed

Onal, Melda; Bishop, Kathleen A; St John, Hillary C; Danielson, Allison L; Riley, Erin M; Piemontese, Marilina; Xiong, Jinhu; Goellner, Joseph J; O'Brien, Charles A; Pike, J Wesley

2015-05-01

Receptor activator of NF-κB ligand (RANKL) is a TNFα-like cytokine that is produced by a diverse set of lineage-specific cells and is involved in a wide variety of physiological processes that include skeletal remodeling, lymph node organogenesis, mammary gland development, and thermal regulation. Consistent with these diverse functions, control of RANKL expression is accomplished in a cell-specific fashion via a set of at least 10 regulatory enhancers that are located up to 170 kb upstream of the gene's transcriptional start site. Here we examined the in vivo consequence of introducing a contiguous DNA segment containing these components into a genetically deleted RANKL null mouse strain. In contrast to RANKL null littermates, null mice containing the transgene exhibited normalized body size, skeletal development, and bone mass as well as normal bone marrow cavities, normalized spleen weights, and the presence of developed lymph nodes. These mice also manifested normalized reproductive capacity, including the ability to lactate and to produce normal healthy litters. Consistent with this, the transgene restored endogenous-like RANKL transcript levels in several RANKL-expressing tissues. Most importantly, restoration of RANKL expression from this segment of DNA was fully capable of rescuing the complex aberrant skeletal and immune phenotype of the RANKL null mouse. RANKL also restored appropriate levels of B220+ IgM+ and B220+ IgD+ B cells in spleen. Finally, we found that RANKL expression from this transgene was regulated by exogenously administered 1,25(OH)2 D3 , parathyroid hormone (PTH), and lipopolysaccharide (LPS), thus recapitulating the ability of these same factors to regulate the endogenous gene. These findings fully highlight the properties of the Tnfsf11 gene locus predicted through previous in vitro dissection. We conclude that the mouse Tnfsf11 gene locus identified originally through unbiased chromatin immunoprecipitation with DNA microarray (ChIP-chip) analysis contains the necessary genetic information to direct appropriate tissue-specific and factor-regulated RANKL expression in vivo. © 2014 American Society for Bone and Mineral Research.

Association between malnutrition and hyperhomocysteine in Alzheimer's disease patients and diet intervention of betaine.

PubMed

Sun, Jianying; Wen, Shiling; Zhou, Jing; Ding, Shuling

2017-09-01

Alzheimer's disease (AD) is a neurodegenerative disease, which is associated with malnutrition and hyperhomocysteine. The current study aimed to analyze the relationship between malnutrition and hyperhomocysteine in AD patients, and effects of diet intervention with betaine on the disease. The nutritional statuses of the AD patients were assessed by short form mini nutritional assessment (MNA-SF). The levels of Hcy, tau hyperphosphorylation, synaptic proteins, blood inflammatory factors were measured by enzymatic cycling assay, Western blot and ELISA. The cognitive function was measured by AD assessment scale (ADAS-cog). There was a significant difference in mental status between normal people and AD patients (P<.05). Overall, malnutrition was reported in a larger proportion of AD patients and high level of Hcy was closely associated with malnutrition. Betaine decreased the levels of phosphorylated tau, elevated PP2Ac activity and inhibited Aβ accumulation (P<.05). The levels of IL-lβ and TNF-α were significantly higher in the untreatment group while much lower in the intervention group (P<.05). After intervention of betaine treatment, the expression level of Hcy can be restored and betaine can effectively suppress inflammation as well as trigger an increase in memory-related proteins. ADAS-Cog suggested that significant improvement was found after the intervention of betaine. AD was associated with both malnutrition and higher levels of Hcy. Betaine could restore Hcy expression to normal level in AD patient, which might ameliorate memory deficits. © 2016 Wiley Periodicals, Inc.

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function.

PubMed

Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J; He, Wei; Voss, Oliver H; Gonzalez-Mejia, M Elba; Guttridge, Denis C; Grotewold, Erich; Doseff, Andrea I

2016-03-01

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo.

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

PubMed

Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

2017-09-01

Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or β-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

Restoring normal eating behaviour in adolescents with anorexia nervosa: A video analysis of nursing interventions.

PubMed

Beukers, Laura; Berends, Tamara; de Man-van Ginkel, Janneke M; van Elburg, Annemarie A; van Meijel, Berno

2015-12-01

An important part of inpatient treatment for adolescents with anorexia nervosa is to restore normal eating behaviour. Health-care professionals play a significant role in this process, but little is known about their interventions during patients' meals. The purpose of the present study was to describe nursing interventions aimed at restoring normal eating behaviour in patients with anorexia nervosa. The main research question was: 'Which interventions aimed at restoring normal eating behaviour do health-care professionals in a specialist eating disorder centre use during meal times for adolescents diagnosed with anorexia nervosa? The present study was a qualitative, descriptive study that used video recordings made during mealtimes. Thematic data analysis was applied. Four categories of interventions emerged from the data: (i) monitoring and instructing; (ii) encouraging and motivating; (iii) supporting and understanding; and (iv) educating. The data revealed a directive attitude aimed at promoting behavioural change, but always in combination with empathy and understanding. In the first stage of clinical treatment, health-care professionals focus primarily on changing patients' eating behaviour. However, they also address the psychosocial needs that become visible in patients as they struggle to restore normal eating behaviour. The findings of the present study can be used to assist health-care professionals, and improve multidisciplinary guidelines and health-care professionals' training programmes. © 2015 Australian College of Mental Health Nurses Inc.

Two non-allelic nuclear genes restore fertility in a gametophytic pattern and enhance abiotic stress tolerance in the hybrid rice plant.

PubMed

Huang, Wenchao; Hu, Jun; Yu, Changchun; Huang, Qi; Wan, Lei; Wang, Lili; Qin, Xiaojian; Ji, Yanxiao; Zhu, Renshan; Li, Shaoqing; Zhu, Yingguo

2012-03-01

In indica rice, the HongLian (HL)-type combination of cytoplasmic male sterility (CMS) and fertility restoration (Rf) is widely used for the production of commercial hybrid seeds in China, Laos, Vietnam and other Southeast Asian countries. Generally, any member of the gametophytic fertility restoration system, 50% of the pollen in hybrid F(1) plants displays recovered sterility. In this study, however, a HL-type hybrid variety named HongLian You6 had approximately 75% normal (viable) pollen rather than the expected 50%. To resolve this discrepancy, several fertility segregation populations, including F(2) and BC(1)F(1) derived from the HL-CMS line Yuetai A crossed with the restorer line 9311, were constructed and subjected to genetic analysis. A gametophytic restoration model was discovered to involve two non-allelic nuclear restorer genes, Rf5 and Rf6. The Rf5 had been previously identified using a positional clone strategy. The Rf6 gene represents a new restorer gene locus, which was mapped to the short arm of chromosome 8. The hybrid F(1) plants containing one restorer gene, either Rf5 or Rf6, displayed 50% normal pollen grains with I(2)-KI solution; however, those with both Rf5 and Rf6 displayed 75% normal pollens. We also established that the hybrid F(1) plants including both non-allelic restorer genes exhibited an increased stable seed setting when subjected to stress versus the F(1) plants with only one restorer gene. Finally, we discuss the breeding scheme for the plant gametophytic CMS/Rf system.

Effect of thyroxine on munc-18 and syntaxin-1 expression in dorsal hippocampus of adult-onset hypothyroid rats

PubMed Central

Zhu, Y.; Ning, D.; Wang, F.; Liu, C.; Xu, Y.; Jia, X.; Zhu, D.

2012-01-01

Adult-onset hypothyroidism induces a variety of impairments on hippocampus- dependent neurocognitive functioningin which many synaptic proteins in hippocampus neurons are involved. Here, we observed the effect of adult-onset hypothyroidism on the expression of syntaxin-1 and munc-18 in the dorsal hippocampus and whether the altered proteins could be restored by levothyroxine (T4) treatment. All rats were separated into 4 groups randomly: hypothyroid group, 5 µg T4 /100 g body weight (BW) treated group, 20 µg T4/100 g BW treated group and control group. The radioimmunoassay kits were applied to assay the levels of serum T3 and T4, and the levels of syntaxin-1 and munc-18 in hippocampus were assessed by immunohistochemistry and Western blot. Both analysis corroborated that syntaxin-1 in the hypothyroid group was significantly higher. Munc-18 was lower in four layers of CA3 and dentate gyrus by immunohistochemistry. After two weeks of treatment with 5 µg T4/100 g BW for hypothyroidism, syntaxin-1 levels were completely restored, whereas the recovery of munc-18 only located in two of the four impaired layers. Twenty µg T4/100 g BW treatment normalized munc-18 levels. These data suggested that adult-onset hypothyroidism induced increment of syntaxin-1 and decrement of munc-18 in the dorsal hippocampus, which could be restored by T4 treatment. Larger dosage of T4 caused more effective restorations. PMID:22688303

Loss of signal transduction and inhibition of lymphocyte locomotion in a ground-based model of microgravity

NASA Technical Reports Server (NTRS)

Sundaresan, Alamelu; Risin, Diana; Pellis, Neal R.; McIntire, L. V. (Principal Investigator)

2002-01-01

Inflammatory adherence to, and locomotion through the interstitium is an important component of the immune response. Conditions such as microgravity and modeled microgravity (MMG) severely inhibit lymphocyte locomotion in vitro through gelled type I collagen. We used the NASA rotating wall vessel bioreactor or slow-turning lateral vessel as a prototype for MMG in ground-based experiments. Previous experiments from our laboratory revealed that when lymphocytes (human peripheral blood mononuclear cells [PBMCs]) were first activated with phytohemaglutinin followed by exposure to MMG, locomotory capacity was not affected. In the present study, MMG inhibits lymphocyte locomotion in a manner similar to that observed in microgravity. Phorbol myristate acetate (PMA) treatment of PBMCs restored lost locomotory capacity by a maximum of 87%. Augmentation of cellular calcium flux with ionomycin had no restorative effect. Treatment of lymphocytes with mitomycin C prior to exposure to MMG, followed by PMA, restored locomotion to the same extent as when nonmitomycin C-treated lymphocytes were exposed to MMG (80-87%), suggesting that deoxyribonucleic acid replication is not essential for the restoration of locomotion. Thus, direct activation of protein kinase C (PKC) with PMA was effective in restoring locomotion in MMG comparable to the normal levels seen in Ig cultures. Therefore, in MMG, lymphocyte calcium signaling pathways were functional, with defects occurring at either the level of PKC or upstream of PKC.

14 CFR 171.271 - Installation requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... generated. Adequate power capacity must be provided for the operation of test and working equipment of the... restoration of power, the batteries must be restored to full charge within 24 hours. When primary power is... battery must permit continuation of normal operation for at least two hours under the normal operating...

Alveolar type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis.

PubMed

Guillamat-Prats, Raquel; Gay-Jordi, Gemma; Xaubet, Antoni; Peinado, Victor I; Serrano-Mollar, Anna

2014-07-01

Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of lung surfactant protein levels, which is required for proper respiratory function. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Effect of restoration volume on stresses in a mandibular molar: a finite element study.

PubMed

Wayne, Jennifer S; Chande, Ruchi; Porter, H Christian; Janus, Charles

2014-10-01

There can be significant disagreement among dentists when planning treatment for a tooth with a failing medium-to-large--sized restoration. The clinician must determine whether the restoration should be replaced or treated with a crown, which covers and protects the remaining weakened tooth structure during function. The purpose of this study was to evaluate the stresses generated in different sized amalgam restorations via a computational modeling approach and reveal whether a predictable pattern emerges. A computer tomography scan was performed of an extracted mandibular first molar, and the resulting images were imported into a medical imaging software package for tissue segmentation. The software was used to separate the enamel, dentin, and pulp cavity through density thresholding and surface rendering. These tissue structures then were imported into 3-dimensional computer-aided design software in which material properties appropriate to the tissues in the model were assigned. A static finite element analysis was conducted to investigate the stresses that result from normal occlusal forces. Five models were analyzed, 1 with no restoration and 4 with increasingly larger restoration volume proportions: a normal-sized tooth, a small-sized restoration, 2 medium-sized restorations, and 1 large restoration as determined from bitewing radiographs and occlusal surface digital photographs. The resulting von Mises stresses for dentin-enamel of the loaded portion of the tooth grew progressively greater as the size of the restoration increased. The average stress in the normal, unrestored tooth was 4.13 MPa, whereas the smallest restoration size increased this stress to 5.52 MPa. The largest restoration had a dentin-enamel stress of 6.47 MPa. A linear correlation existed between restoration size and dentin-enamel stress, with an R(2) of 0.97. A larger restoration volume proportion resulted in higher dentin-enamel stresses under static loading. A comparison of the von Mises stresses to the yield strengths of the materials revealed a relationship between a tooth's restoration volume proportion and the potential for failure, although factors other than restoration volume proportion may also impact the stresses generated in moderate-sized restorations. Copyright © 2014 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Pharmacological Activation of the EDA/EDAR Signaling Pathway Restores Salivary Gland Function following Radiation-Induced Damage

PubMed Central

Hill, Grace; Headon, Denis; Harris, Zoey I.; Huttner, Kenneth; Limesand, Kirsten H.

2014-01-01

Radiotherapy of head and neck cancers often results in collateral damage to adjacent salivary glands associated with clinically significant hyposalivation and xerostomia. Due to the reduced capacity of salivary glands to regenerate, hyposalivation is treated by substitution with artificial saliva, rather than through functional restoration of the glands. During embryogenesis, the ectodysplasin/ectodysplasin receptor (EDA/EDAR) signaling pathway is a critical element in the development and growth of salivary glands. We have assessed the effects of pharmacological activation of this pathway in a mouse model of radiation-induced salivary gland dysfunction. We report that post-irradiation administration of an EDAR-agonist monoclonal antibody (mAbEDAR1) normalizes function of radiation damaged adult salivary glands as determined by stimulated salivary flow rates. In addition, salivary gland structure and homeostasis is restored to pre-irradiation levels. These results suggest that transient activation of pathways involved in salivary gland development could facilitate regeneration and restoration of function following damage. PMID:25409170

Synapse maintenance and restoration in the retina by NGL2

PubMed Central

Zhao, Lei

2018-01-01

Synaptic cell adhesion molecules (CAMs) promote synapse formation in the developing nervous system. To what extent they maintain and can restore connections in the mature nervous system is unknown. Furthermore, how synaptic CAMs affect the growth of synapse-bearing neurites is unclear. Here, we use adeno-associated viruses (AAVs) to delete, re-, and overexpress the synaptic CAM NGL2 in individual retinal horizontal cells. When we removed NGL2 from horizontal cells, their axons overgrew and formed fewer synapses, irrespective of whether Ngl2 was deleted during development or in mature circuits. When we re-expressed NGL2 in knockout mice, horizontal cell axon territories and synapse numbers were restored, even if AAVs were injected after phenotypes had developed. Finally, overexpression of NGL2 in wild-type horizontal cells elevated synapse numbers above normal levels. Thus, NGL2 promotes the formation, maintenance, and restoration of synapses in the developing and mature retina, and restricts axon growth throughout life. PMID:29553369

NEURO-GUMORALE SUBSTANCES OF DOG BLOOD DURING ACUTE RADIATION SICKNESS. I. CHANGES IN BLOOD ACETYLCHOLINE AND CHOLINESTERASE SYSTEM (in Russian)

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

Kuznetzova, N.E.

1963-01-01

Experiments carried out on 13 male dogs, 2 to 5 years old and weighing 10 to 20 kg, showed that in the initial stages of chroric radiation sickness the blood content of acetylcholine increased and the cholinesterase decreased. Moreove r, the increase in the acetylcholine level during the first 3 to 4 hrs proceeded at a greater rate than the cholinesterase decrease. Shifts in the enzyme system were more pronounced in dogs with greater resistance. However, during the recovery period acetylcholine and cholinesterase restoration took place at earlier periods in dogs with higher resistance. Not only was the cholinesterase activitymore » restored, but it increased to 1.5 to 2 times the initial level. The level of acetylcholine and cholinesterase was not restored in the blood of dogs during terminal periods. In dogs exposed to subacute doses, 300 r, enzyme normalization took place 29 to 41 days following exposure. Correlation of data on enzyme changes in single and chronic exposures indicated identical trends It was postulated that acetylcholine -cholinesterase participate in compensating reactions of organisms during radiation sickness. (R.V.J.)« less

Oral Tocofersolan Corrects or Prevents Vitamin E Deficiency in Children With Chronic Cholestasis.

PubMed

Thébaut, Alice; Nemeth, Antal; Le Mouhaër, Jeannie; Scheenstra, René; Baumann, Ulrich; Koot, Bart; Gottrand, Fredéric; Houwen, Roderick; Monard, Laure; de Micheaux, Sylvie Lafaye; Habes, Dalila; Jacquemin, Emmanuel

2016-12-01

D-Alpha-tocopheryl polyethylene glycol 1000 succinate (Tocofersolan, Vedrop), has been developed in Europe to provide an orally bioavailable source of vitamin E in children with cholestasis. The aim was to analyze the safety/efficacy of Vedrop in a large group of children with chronic cholestasis. Two hundred seventy-four children receiving Vedrop for vitamin E deficiency or for its prophylaxis were included from 7 European centers. Median age at treatment onset was 2 months and median follow-up was 11 months. Vedrop was prescribed at a daily dose of 0.34 mL/kg (25 IU/kg) of body weight. Three methods were used to determine a sufficient serum vitamin E status: vitamin E, vitamin E/(total cholesterol), vitamin E/(total cholesterol + triglycerides). Before Vedrop therapy, 51% of children had proven vitamin E deficiency, 30% had normal vitamin E status and 19% had an unknown vitamin E status. During the first months of treatment, vitamin E status was restored in the majority of children with insufficient levels at baseline (89% had a normal status at 6 months). All children with a normal baseline vitamin E status had a normal vitamin E status at 6 months. Among children with an unknown vitamin E status at baseline, 93% had a normal vitamin E status at 6 months. A sufficient vitamin E status was observed in 80% of children with significant cholestasis (serum total bilirubin >34.2 μmol/L). No serious adverse reaction was reported. Vedrop seems a safe and effective oral formulation of vitamin E that restores and/or maintains sufficient serum vitamin E level in the majority of children with cholestasis, avoiding the need for intramuscular vitamin E injections.

Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice.

PubMed

Yun, Jaesuk; Oliynyk, Sergiy; Lee, Yeonju; Kim, Jieun; Yun, Kyunghwa; Jeon, Raok; Ryu, Jae-Ha; Oh, Seikwan

2017-01-01

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice

PubMed Central

Nakai, Nobuhiro; Nagano, Masatoshi; Saitow, Fumihito; Watanabe, Yasuhito; Kawamura, Yoshinobu; Kawamoto, Akiko; Tamada, Kota; Mizuma, Hiroshi; Onoe, Hirotaka; Watanabe, Yasuyoshi; Monai, Hiromu; Hirase, Hajime; Nakatani, Jin; Inagaki, Hirofumi; Kawada, Tomoyuki; Miyazaki, Taisuke; Watanabe, Masahiko; Sato, Yuka; Okabe, Shigeo; Kitamura, Kazuo; Kano, Masanobu; Hashimoto, Kouichi; Suzuki, Hidenori; Takumi, Toru

2017-01-01

Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms. PMID:28691086

Twofold processing for denoising ultrasound medical images.

PubMed

Kishore, P V V; Kumar, K V V; Kumar, D Anil; Prasad, M V D; Goutham, E N D; Rahul, R; Krishna, C B S Vamsi; Sandeep, Y

2015-01-01

Ultrasound medical (US) imaging non-invasively pictures inside of a human body for disease diagnostics. Speckle noise attacks ultrasound images degrading their visual quality. A twofold processing algorithm is proposed in this work to reduce this multiplicative speckle noise. First fold used block based thresholding, both hard (BHT) and soft (BST), on pixels in wavelet domain with 8, 16, 32 and 64 non-overlapping block sizes. This first fold process is a better denoising method for reducing speckle and also inducing object of interest blurring. The second fold process initiates to restore object boundaries and texture with adaptive wavelet fusion. The degraded object restoration in block thresholded US image is carried through wavelet coefficient fusion of object in original US mage and block thresholded US image. Fusion rules and wavelet decomposition levels are made adaptive for each block using gradient histograms with normalized differential mean (NDF) to introduce highest level of contrast between the denoised pixels and the object pixels in the resultant image. Thus the proposed twofold methods are named as adaptive NDF block fusion with hard and soft thresholding (ANBF-HT and ANBF-ST). The results indicate visual quality improvement to an interesting level with the proposed twofold processing, where the first fold removes noise and second fold restores object properties. Peak signal to noise ratio (PSNR), normalized cross correlation coefficient (NCC), edge strength (ES), image quality Index (IQI) and structural similarity index (SSIM), measure the quantitative quality of the twofold processing technique. Validation of the proposed method is done by comparing with anisotropic diffusion (AD), total variational filtering (TVF) and empirical mode decomposition (EMD) for enhancement of US images. The US images are provided by AMMA hospital radiology labs at Vijayawada, India.

Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.

PubMed

Ribera, Albert; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Motas, Sandra; Villacampa, Pilar; Maggioni, Luca; León, Xavier; Molas, Maria; Sánchez, Víctor; Muñoz, Sergio; Leborgne, Christian; Moll, Xavier; Pumarola, Martí; Mingozzi, Federico; Ruberte, Jesús; Añor, Sònia; Bosch, Fatima

2015-04-01

Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A fermented soy permeate improves the skeletal muscle glucose level without restoring the glycogen content in streptozotocin-induced diabetic rats.

PubMed

Malardé, Ludivine; Vincent, Sophie; Lefeuvre-Orfila, Luz; Efstathiou, Théo; Groussard, Carole; Gratas-Delamarche, Arlette

2013-02-01

Exercise is essential into the therapeutic management of diabetic patients, but their level of exercise tolerance is lowered due to alterations of glucose metabolism. As soy isoflavones have been shown to improve glucose metabolism, this study aimed to assess the effects of a dietary supplement containing soy isoflavones and alpha-galactooligosaccharides on muscular glucose, glycogen synthase (GSase), and glycogen content in a type 1 diabetic animal model. The dietary supplement tested was a patented compound, Fermented Soy Permeate (FSP), developed by the French Company Sojasun Technologies. Forty male Wistar rats were randomly assigned to control or diabetic groups (streptozotocin, 45 mg/kg). Each group was then divided into placebo or FSP-supplemented groups. Both groups received by oral gavage, respectively, water or diluted FSP (0.1 g/day), daily for a period of 3 weeks. At the end of the protocol, glycemia was noticed after a 24-h fasting period. Glucose, total GSase, and the glycogen content were determined in the skeletal muscle (gastrocnemius). Diabetic animals showed a higher blood glucose concentration, but a lower glucose and glycogen muscle content than controls. Three weeks of FSP consumption allowed to restore the muscle glucose concentration, but failed to reduce glycemia and to normalize the glycogen content in diabetic rats. Furthermore, the glycogen content was increased in FSP-supplemented controls compared to placebo controls. Our results demonstrated that diabetic rats exhibited a depleted muscle glycogen content (-25%). FSP-supplementation normalized the muscle glucose level without restoring the glycogen content in diabetic rats. However, it succeeded to increase it in the control group (+20%).

Oral administration of soybean peptide Vglycin normalizes fasting glucose and restores impaired pancreatic function in Type 2 diabetic Wistar rats.

PubMed

Jiang, Hua; Feng, Jueping; Du, Zhongxia; Zhen, Hui; Lin, Mei; Jia, Shaohui; Li, Tao; Huang, Xinyuan; Ostenson, Claes-Goran; Chen, Zhengwang

2014-09-01

Vglycin, a natural 37-residue polypeptide isolated from pea seeds in which six half-cysteine residues are embedded in three pairs of disulfide bonds, is resistant to digestive enzymes and has antidiabetic potential. To investigate the pharmacological activity of Vglycin in vivo and to examine the mechanisms involved, the therapeutic effect of Vglycin in diabetic rats was examined. Diabetes was induced in Wistar rats by high-fat diet and multiple streptozotocin intraperitoneal injections. Diabetic rats were treated daily with Vglycin for 4 weeks. Body weight, food intake, fasting plasma glucose and insulin levels were assayed weekly. Glucose and insulin tolerance tests were conducted on Day 29. Subsequently, levels of p-Akt in the liver and pancreas and cleaved PARP, Pdx-1 and insulin in the pancreas were detected by immunoblotting. The morphology of the pancreas and the insulin expression in the pancreas were analyzed by hematoxylin-eosin staining and immunohistochemistry, respectively. Furthermore, human liver-derived cell lines were used to explore the in vitro effects of Vglycin on insulin sensitivity and glucose uptake. Chronic treatment with Vglycin normalized fasting glucose levels in diabetic rats. The improvement in glucose homeostasis and the increased insulin sensitivity mediated by restored insulin signaling likely contributed to decreased food intake and reduced body weight. Vglycin protected pancreatic cells from damage by streptozotocin. Although insulin synthesis and secretion in impaired β-cell were not significantly elevated, islets morphology was improved in the Vglycin-treated groups. These results suggest that Vglycin could be useful in Type 2 diabetes for restoring impaired insulin signaling, glucose tolerance and pancreatic function. Copyright © 2014 Elsevier Inc. All rights reserved.

Glucocorticoids as modulators in the control of feeding.

PubMed

Castonguay, T W

1991-01-01

Three sets of experiments have been conducted that suggest that adrenal glucocorticoids play a role in the long-term control of intake and in dietary preferences. First, obesity is dependent upon glucocorticoid-modulated metabolic pathways. Surgical or pharmacological manipulations in obese animals that eliminate or diminish corticosterone activity result in levels of intake, meal patterns, macronutrient self-selection and weight gain that revert to levels seen in lean controls. Glucocorticoid replacement of adrenalectomized genetically obese Zucker rats restores the phenotypic expression of the obese rat's genetic heritage: increased weight gain, increased fat and total daily caloric intake and adiposity are restored in a dose-dependent fashion. Second, the increased fat intake observed subsequent to fasting in Sprague-Dawley rats is correlated with an increase in circulating corticosterone. Adrenalectomy blocks the fat specific refeeding response, and corticosterone treatment of adrenalectomized rats restores the increase in fat, carbohydrate and protein observed during refeeding. Third, humans suffering from Cushing's Disease have an increased preference for dietary fat. Weight-matched but disease-free obese controls show only slight increases in fat preference when compared to normal weight controls.

Beta-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice

USDA-ARS?s Scientific Manuscript database

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosa...

Biomechanical Evaluation of Knee Joint Laxities and Graft Forces After Anterior Cruciate Ligament Reconstruction by Anteromedial Portal, Outside-In, and Transtibial Techniques

PubMed Central

Sim, Jae Ang; Gadikota, Hemanth R.; Li, Jing-Sheng; Li, Guoan; Gill, Thomas J.

2013-01-01

Background Recently, anatomic anterior cruciate ligament (ACL) reconstruction is emphasized to improve joint laxity and to potentially avert initiation of cartilage degeneration. There is a paucity of information on the efficacy of ACL reconstructions by currently practiced tunnel creation techniques in restoring normal joint laxity. Study Design Controlled laboratory study. Hypothesis Anterior cruciate ligament reconstruction by the anteromedial (AM) portal technique, outside-in (OI) technique, and modified transtibial (TT) technique can equally restore the normal knee joint laxity and ACL forces. Methods Eight fresh-frozen human cadaveric knee specimens were tested using a robotic testing system under an anterior tibial load (134 N) at 0°, 30°, 60°, and 90° of flexion and combined torques (10-N·m valgus and 5-N·m internal tibial torques) at 0° and 30° of flexion. Knee joint kinematics, ACL, and ACL graft forces were measured in each knee specimen under 5 different conditions (ACL-intact knee, ACL-deficient knee, ACL-reconstructed knee by AM portal technique, ACL-reconstructed knee by OI technique, and ACL-reconstructed knee by TT technique). Results Under anterior tibial load, no significant difference was observed between the 3 reconstructions in terms of restoring anterior tibial translation (P > .05). However, none of the 3 ACL reconstruction techniques could completely restore the normal anterior tibial translations (P <.05). Under combined tibial torques, both AM portal and OI techniques closely restored the normal knee anterior tibial translation (P > .05) at 0° of flexion but could not do so at 30° of flexion (P <.05). The ACL reconstruction by the TT technique was unable to restore normal anterior tibial translations at both 0° and 30° of flexion under combined tibial torques (P <.05). Forces experienced by the ACL grafts in the 3 reconstruction techniques were lower than those experienced by normal ACL under both the loading conditions. Conclusion Anterior cruciate ligament reconstructions by AM portal, OI, and modified TT techniques are biomechanically comparable with each other in restoring normal knee joint laxity and in situ ACL forces. Clinical Relevance Anterior cruciate ligament reconstructions by AM portal, OI, and modified TT techniques result in similar knee joint laxities. Technical perils and pearls should be carefully considered before choosing a tunnel creating technique. PMID:21908717

Acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis in the dog.

PubMed Central

Anderson, W P; Johnston, C I; Korner, P I

1979-01-01

1. The acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis were studied in chronically instrumented, unanaesthetized dogs. 2. Stenosis was induced over 30 sec by inflation of a cuff around the renal artery to lower distal pressure to 60, 40 or 20 mmHg, with stenosis maintained for 1 hr. This resulted in an immediate fall in renal vascular resistance, but over the next 5--30 min both resistance and renal artery pressure were restored back towards prestenosis values. Only transient increases in systemic arterial blood pressure and plasma renin and angiotensin levels were seen with the two milder stenoses. Despite restoration of renal artery pressure, renal blood flow remained reduced at all grades of stenosis. 3. Pre-treatment with angiotensin I converting enzyme inhibitor or sarosine1, isoleucone8 angiotensin II greatly attenuated or abolished the restoration of renal artery pressure and renal vascular resistance after stenosis, and plasma renin and angiotensin II levels remained high. Renal dilatation was indefinitely maintained, but the normal restoration of resistance and pressure could be simulated by infusing angiotensin II into the renal artery. 4. The effective resistance to blood flow by the stenosis did not remain constant but varied with changes in the renal vascular resistance. PMID:219182

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia.

PubMed

Mižíková, Ivana; Ruiz-Camp, Jordi; Steenbock, Heiko; Madurga, Alicia; Vadász, István; Herold, Susanne; Mayer, Konstantin; Seeger, Werner; Brinckmann, Jürgen; Morty, Rory E

2015-06-01

Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. Copyright © 2015 the American Physiological Society.

Fatigue failure of dentin-composite disks subjected to cyclic diametral compression

PubMed Central

Li, Yuping; Carrera, Carola; Chen, Ruoqiong; Li, Jianying; Chen, Yungchung; Lenton, Patricia; Rudney, Joel. D.; Jones, Robert S.; Aparicio, Conrado; Fok, Alex

2015-01-01

Objective Our aim was to establish the relationship between cyclic loading and fatigue life of the dentin-composite interface using the newly developed disk in diametral compression tests. The results were then used to estimate the fatigue life of restored teeth under occlusal loading. Methods Disk specimens (5mm dia. × 2mm thick) were prepared using bovine incisors and restored with either a methacrylate-based composite Z100™ with Adper Single Bond Plus (Z100) or silorane-based composite Filtek ™ LS with LS System adhesive (LS). The dentin-composite disks were tested under cyclic diametral compression to determine the number of cycles to failure (Nf) at three load levels (n = 3 per group). Finite element analysis (FEA) was used to calculate the interfacial stresses (σ) within the specimen, to establish the σ vs. Nf curves, and those within a restored tooth under normal chewing forces (15N maximum). These were then used to estimate the lifetime of the restored tooth for the two restorative systems. Results The disks restored with LS had a higher fatigue resistance than those restored with Z100. The maximum interfacial stress in the restored tooth determined by FEA was ∼0.5MPa. Based on the estimate of 300,000 cycles of chewing per year, the predicted lifetime under occlusal loading for teeth restored with LS and Z100 was 33 and 10 years, respectively. Significance The disk in cyclic diametral compression has been used successfully to provide fatigue data which allows the lifetime of composite-restored teeth under occlusal loading to be predicted using numerical simulation. PMID:25958269

The effects of nitric oxide-cGMP pathway stimulation on dopamine in the medial preoptic area and copulation in DHT-treated castrated male rats

PubMed Central

Sato, Satoru M.; Wersinger, Scott R.; Hull, Elaine M.

2007-01-01

Dopamine (DA) in the medial preoptic area (MPOA) provides important facilitative influence on male rat copulation. We have shown that the nitric oxide-cGMP (NO-cGMP) pathway modulates MPOA DA levels and copulation. We have also shown that systemic estradiol (E2) maintains neuronal NO synthase (nNOS) immunoreactivity in the MPOA of castrates, as well as relatively normal DA levels. This effect of E2 on nNOS probably accounts for at least some of the previously demonstrated behavioral facilitation by intra-MPOA E2 administration in castrates. Therefore, we hypothesized that stimulation of the MPOA NO-cGMP pathway in dihydrotestosterone (DHT)-treated castrates should restore DA levels and copulatory behaviors. Reverse-dialysis of a NO donor, sodium nitroprusside (SNP), increased extracellular DA in the MPOA of DHT-treated castrates and restored the ability to copulate to ejaculation in half of the animals. A cGMP analog, 8-Br-cGMP, also increased extracellular DA, though not as robustly, but did not restore copulatory ability. The effectiveness of the NO donor in restoring copulation and MPOA DA levels is consistent with our hypothesis. However, the lack of behavioral effects of 8-Br-cGMP, despite its increase in MPOA DA, suggests that NO may have additional mediators in the MPOA in the regulation of copulation. Furthermore, the suboptimal copulation seen in the NO donor-treated animals suggests the importance of extra-MPOA systems in the regulation of copulation. PMID:17467707

Effect of experimental diabetes on the levels of aromatic and branched-chain amino acids in rat blood and brain.

PubMed

Crandall, E A; Fernstrom, J D

1983-03-01

Male rats treated 3 wk earlier with streptozotocin showed abnormally high blood levels of leucine, isoleucine, and valine throughout the 24-h period. Serum phenylalanine levels were slightly increased, while those of tryptophan and tyrosine were occasionally reduced. In brain, the level of each branched-chain amino acid was significantly increased above normal at all times. The brain concentration of each aromatic amino acid was always below normal. These changes were restored almost to normal by exogenous insulin therapy. Since the ingestion of protein is normally a major factor influencing blood amino acid levels, the effect of ingesting single, protein-containing meals on the blood and brain levels of these amino acids was also studied. After an overnight fast, the ingestion of a protein-containing meal by diabetic rats increased substantially both blood and brain levels of each branched-chain amino acid. No such increases occurred in normal rats. Ingestion of this meal produced only small changes in the brain and blood levels of the aromatic amino acids in both diabetic and normal rats. The changes in the brain level of each large neutral amino acid in some cases paralleled those in its blood level. More often, they paralleled the changes in the blood ratio of each amino acid to the sum of the other aromatic and branched-chain amino acids. This ratio is often a good predictor of the competitive transport of these amino acids into brain (Fernstrom and Faller, 1978). The observed changes in the brain levels of these amino acids in diabetes may influence the rates at which they are consumed in metabolic pathways within this organ.

Regulation of Synaptic Structure by the Ubiquitin C-terminal Hydrolase UCH-L1

PubMed Central

Cartier, Anna E.; Djakovic, Stevan N.; Salehi, Afshin; Wilson, Scott M.; Masliah, Eliezer; Patrick, Gentry N.

2009-01-01

UCH-L1 is a de-ubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We have found that UCH-L1 activity is rapidly up-regulated by NMDA receptor activation which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of pre and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1 inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner. PMID:19535597

Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.

PubMed

Cartier, Anna E; Djakovic, Stevan N; Salehi, Afshin; Wilson, Scott M; Masliah, Eliezer; Patrick, Gentry N

2009-06-17

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We found that UCH-L1 activity is rapidly upregulated by NMDA receptor activation, which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of presynaptic and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1-inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function

PubMed Central

Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J.; He, Wei; Voss, Oliver H.; Gonzalez-Mejia, M. Elba; Guttridge, Denis C.; Grotewold, Erich; Doseff, Andrea I.

2016-01-01

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors’ accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo. PMID:26938530

A Special Extract of Bacopa monnieri (CDRI-08) Restores Learning and Memory by Upregulating Expression of the NMDA Receptor Subunit GluN2B in the Brain of Scopolamine-Induced Amnesic Mice

PubMed Central

Rai, Rakesh; Singh, Hemant K.; Prasad, S.

2015-01-01

In the present communication, we have investigated effects of the CDRI-08, a well characterized extract of Bacopa monnieri, on expression of the GluN2B subunit of NMDAR in various brain regions of the scopolamine-induced amnesic mice. Our behavioral data reveal that scopolamine-treated amnesic mice exhibit significant decline in the spatial memory compared to the normal control mice. Our RT-PCR and immunoblotting data revealed that the scopolamine treatment resulted in a significant downregulation of the NMDAR GluN2B subunit expression in prefrontal cortex and hippocampus. Our enzyme assay data revealed that scopolamine caused a significant increase in the acetylcholinesterase activity in both the brain regions. Further, oral administration of the CDRI-08 to scopolamine-treated amnesic mice restored the spatial memory which was found to be associated with significant upregulation of the GluN2B subunit expression and decline in the acetylcholinesterase activity in prefrontal cortex as well as hippocampus towards their levels in the normal control mice. Our study provides the evidence for the mechanism underlying role of the Bacopa monnieri extract (CDRI-08) in restoring spatial memory in amnesic mice, which may have therapeutic implications. PMID:26413117

From partial to full-face transplantation: total ablation and restoration, a change in the reconstructive paradigm.

PubMed

Barret, Juan P

2014-01-01

The innovation of composite vascularized allotransplantation has provided plastic and reconstructive surgeons with the ultimate tool for those patients that present with facial deformities that cannot be reconstructed with classical or more traditional techniques. Transplanting normal tissues allows for a true restorative surgery. Initial experiences included the substitution of missing anatomy, whereas after the first world's full-face transplant performed in Barcelona in March 2010, a true ablative surgery with a total restoration proved to be effective. We review the world's experience and the performance of our restorative protocol to depict this change in the reconstructive paradigm of facial transplantation. Facial transplants should be performed after a careful analysis of the defect, with a comprehensive ablation plan following esthetic units with sacrifice of all required tissues with a focus of global restoration of anatomy, aesthetics and function, respecting normal functioning muscles. Nowadays, facial transplants following strict esthetic units should restore disfigurement extending to small central areas, whereas major defects may require a total ablation and restoration with full-face transplants. Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Effect of Pelargonium reniforme roots on alcohol-induced liver damage and oxidative stress.

PubMed

Adewusi, Emmanuel Adekanmi; Afolayan, Anthony Jide

2010-09-01

Ethnobotanical surveys conducted on Pelargonium reniforme Curtis (Geraniaceae) have shown that the aqueous root extracts are used to treat alcohol-induced liver damage. We evaluated the antioxidant properties of the extract and its effects on alcohol-induced hepatotoxicity using Wistar rats. Alcohol-induced hepatotoxicity studies were carried out by observing the effect of the aqueous root extract on some liver marker enzymes, bilirubin, and total protein after liver damage. The levels of some phenolic compounds were determined by standard methods. Also, the reducing power of the plant extract and its ability to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH*) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS*+) radicals were determined to evaluate its antioxidant activity. The results obtained show that the plant extract possessed significant antioxidant activity. It had a significant level of phenolic compounds, scavenged DPPH* and ABTS*+ radicals effectively, and demonstrated good reducing power. This may indicate that the plant contained compounds which can remove toxic metabolites following alcohol abuse. Serum analysis of animals treated with only ethanol showed a significant increase in the levels of liver marker enzymes and total and unconjugated bilirubin, while a significant decrease was observed in the levels of conjugated bilirubin and total proteins. Administration of the plant extract restored the levels of these markers to normal levels, and this indicates the ability of the plant extract to restore normal functioning of a damaged liver. The study shows that P. reniforme is a potential source of antioxidants and compounds which are useful in treating alcoholic liver damage.

Genetically engineered Escherichia coli Nissle 1917 synbiotic counters fructose-induced metabolic syndrome and iron deficiency.

PubMed

Chaudhari, Archana Somabhai; Raghuvanshi, Ruma; Kumar, G Naresh

2017-06-01

Consumption of fructose leads to metabolic syndrome, but it is also known to increase iron absorption. Present study investigates the effect of genetically modified Escherichia coli Nissle 1917 (EcN) synbiotic along with fructose on non-heme iron absorption. Charles foster rats weighing 150-200 g were fed with iron-deficient diet for 2 months. Probiotic treatment of EcN (pqq) and EcN (pqq-glf-mtlK) was given once per week, 10 9  cells after 2 months with fructose in drinking water. Iron levels, blood, and liver parameters for oxidative stress, hyperglycemia, and dyslipidemia were estimated. Transferrin-bound iron levels in the blood decreased significantly after 10 weeks of giving iron-deficient diet. Probiotic treatment of EcN (pqq-glf-mtlK) and fructose together led to the restoration of normal transferrin-bound iron levels and blood and hepatic antioxidant levels as compared to iron-deficient control group. The probiotic also led to the restoration of body weight along with levels of serum and hepatic lipid, blood glucose, and antioxidant in the blood and liver as compared to iron-deficient control group. Restoration of liver injury marker enzymes was also seen. Administration of EcN-producing PQQ and mannitol dehydrogenase enzyme together with fructose led to increase in the transferrin-bound iron levels in the blood and amelioration of consequences of metabolic syndrome caused due to fructose consumption.

Hyperkalaemic periodic paralysis: a rare presentation of Addison's disease.

PubMed Central

Sowden, J. M.; Borsey, D. Q.

1989-01-01

A 44 year old man with longstanding diabetes mellitus gave a 6-month history of periodic attacks of flaccid quadriplegia. Following one of these episodes he was admitted for assessment. In view of persistent hyperkalaemia, hypoadrenalism was suspected and Addison's disease was confirmed biochemically. Adrenal replacement therapy restored the potassium levels to normal and resulted in no further attacks of paralysis. PMID:2594601

Vitamin E Supplementation in Burn Patients

DTIC Science & Technology

2013-10-01

consequences of this severe and rapid depletion are unknown because adipose tissue alpha- tocopherol normally takes years to deplete. Our long- term...proposal were to a) attenuate alpha- tocopherol depletion in burn patients by vitamin E supplementation, b) to prevent or reverse oxidative stress, c...hypothesis is that the administration of high doses of alpha- tocopherol will prevent or restore levels of vitamin E in adipose tissue and reverse

Vitamin E Supplementation in Burn Patients

DTIC Science & Technology

2014-10-01

The consequences of this severe and rapid depletion are unknown because adipose tissue alpha- tocopherol normally takes years to deplete. Our long...our proposal were to a) attenuate alpha- tocopherol depletion in burn patients by vitamin E supplementation, b) to prevent or reverse oxidative...central hypothesis is that the administration of high doses of alpha- tocopherol will prevent or restore levels of vitamin E in adipose tissue and

Synaptic loss and firing alterations in Axotomized Motoneurons are restored by vascular endothelial growth factor (VEGF) and VEGF-B.

PubMed

Calvo, Paula M; de la Cruz, Rosa R; Pastor, Angel M

2018-06-01

Vascular endothelial growth factor (VEGF), also known as VEGF-A, was discovered due to its vasculogenic and angiogenic activity, but a neuroprotective role for VEGF was later proven for lesions and disorders. In different models of motoneuronal degeneration, VEGF administration leads to a significant reduction of motoneuronal death. However, there is no information about the physiological state of spared motoneurons. We examined the trophic role of VEGF on axotomized motoneurons with recordings in alert animals using the oculomotor system as the experimental model, complemented with a synaptic study at the confocal microscopy level. Axotomy leads to drastic alterations in the discharge characteristics of abducens motoneurons, as well as to a substantial loss of their synaptic inputs. Retrograde delivery of VEGF completely restored the discharge activity and synaptically-driven signals in injured motoneurons, as demonstrated by correlating motoneuronal firing rate with motor performance. Moreover, VEGF-treated motoneurons recovered a normal density of synaptic boutons around motoneuronal somata and in the neuropil, in contrast to the low levels of synaptic terminals found after axotomy. VEGF also reduced the astrogliosis induced by axotomy in the abducens nucleus to control values. The administration of VEGF-B produced results similar to those of VEGF. This is the first work demonstrating that VEGF and VEGF-B restore the normal operating mode and synaptic inputs on injured motoneurons. Altogether these data indicate that these molecules are relevant synaptotrophic factors for motoneurons and support their clinical potential for the treatment of motoneuronal disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Investigations on GSK-3β/NF-kB signaling in stress and stress adaptive behavior in electric foot shock subjected mice.

PubMed

Bali, Anjana; Jaggi, Amteshwar Singh

2016-04-01

The present study was designed to explore the role of GSK-3β and NF-kB signaling in electric foot shock-induced stress and stress adaptation. Mice were subjected to foot shocks of 0.5mA intensity and 1s duration of 1h to produce acute stress. Animals were exposed to the same stressor for 5 days to induce stress adaptation. The behavioral alterations were assessed using the actophotometer, hole board, open field and social interaction tests. The serum corticosterone levels were assessed as a marker of the HPA axis. The levels of total GSK-3β, p-GSK-3β-S9 and p-NF-kB were determined in the hippocampus, frontal cortex and amygdala. Acute electric foot shock stress produced behavioral and biochemical changes; decreased the levels of p-GSK-3β-S9, produced no change in total GSK-3β levels and increased p-NF-kB levels in the brain. However, repeated exposure of foot shock stress restored the behavioral and biochemical changes along with normalization of p-GSK-3β-S9 and p-NF-kB levels. Administration of AR-A01, a selective GSK-3β inhibitor, or diethyldithiocarbamic acid (DDTC), a selective NF-kB inhibitor, diminished acute stress-induced behavioral and biochemical changes. Furthermore, AR-A014418 normalized acute stress-induced alterations in p-GSK-3β-S9 and p-NF-kB levels, however, DDTC selectively restored NF-kB levels without any change in p-GSK-3β-S9 levels. It probably suggests that NF-kB is a downstream mediator of the GSK-3 signaling cascade. It may conclude that acute stress associated decrease in p-GSK-3β-S9 and increase in p-NF-kB levels in the brain contribute in the development of behavioral and biochemical alterations and normalization of GSK-3β/NF-kB signaling may contribute in stress adaptive behavior in response to repeated electric foot shock-subjected mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Preoperative therapeutic apheresis for severe medically refractory amiodarone-induced thyrotoxicosis: a case report.

PubMed

Yamamoto, Jennifer; Dostmohamed, Hanifa; Schacter, Isanne; Ariano, Robert E; Houston, Donald S; Lewis, Brenda; Knoll, Colleen; Katz, Pamela; Zarychanski, Ryan

2014-06-01

Amiodarone is associated with thyroid dysfunction and life-threatening thyrotoxicosis. In medically refractory cases, or where medical therapy is contraindicated, thyroidectomy may be required. To decrease perioperative thyroid storm and to reduce overall surgical risk, apheresis may be considered preoperatively to restore euthyroidism. We report a 46-year-old female with a history of cardiac arrhythmia and tachycardia-induced cardiomyopathy for which she received amiodarone. Months after discontinuation of amiodarone, the patient presented with wide complex tachycardia and symptoms of thyrotoxicosis. Laboratory testing confirmed severe thyrotoxicosis which was subsequently refractory to medical therapy. Total thyroidectomy was required. Following a total of 10 apheresis treatments, thyroid hormone levels were reduced to near normal levels and the patient's symptoms improved. Thyroidectomy was performed without intraoperative or postoperative complication. In the setting of life-threatening, medically refractory amiodarone-induced thyrotoxicosis, therapeutic apheresis can effectively reduce thyroid hormone levels and restore a state of clinical and biochemical euthyroidism. © 2013 Wiley Periodicals, Inc.

Treatment with PPARδ agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model.

PubMed

Li, Xiuli; Li, Jin; Lu, Xiaolan; Ma, Huihui; Shi, Haitao; Li, Hong; Xie, Danhong; Dong, Lei; Liang, Chunlian

2015-09-01

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition which is associated with certain features of metabolic syndrome and insulin resistance. Peroxisome proliferator‑activated receptor (PPAR)δ is an important regulator of energy metabolism and insulin resistance in diabetes. However, the function of PPARδ in NAFLD has not yet been fully elucidated. In the present study, in order to explore the function of PPARδ in NAFLD, we created a rat model of NALFD induced by a high-fat diet (HFD) and treated the rats with GW501516, a PPARδ agonist. We found that the lipid levels decreased, and hepatocellular ballooning and inflammatory cell infiltration were also significantly decreased following treatment of the rats with GW501516 compared to the untreated rats. Treatment with GW501516 also significantly decreased the homeostasis model assessment of insulin resistance (HOMA-IR) index, as well as the low‑density lipoprotein (LDL) levels. In addition, treatment with GW501516 increased the levels of insulin‑like growth factor‑1 (IGF-1) and high‑density lipoprotein (HDL) compared to the HFD group. Furthermore, the elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‑glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) in the HFD group were all restored to the normal control levels following treatment with GW501516. RT‑qPCR and immunohistochemical staining revealed that the expression levels of sterol regulatory element binding protein‑1c (SREBP‑1c) and glucose transporter 2 (GLUT‑2) were both restored to normal control levels following treatment with GW501516. Also, the levels of enzymes related to lipid metabolism were increased following treatment with GW501516. In conclusion, our findings demonstrate that treatment with GW501516 alleviates NAFLD by modulating glucose and fatty acid metabolism.

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection

PubMed Central

WANG, BAOXIN; YUAN, JUNJIE; XU, JIAFENG; XIE, JIN; WANG, GUOLIANG; DONG, PIN

2016-01-01

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury. PMID:26677138

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection.

PubMed

Wang, Baoxin; Yuan, Junjie; Xu, Jiafeng; Xie, Jin; Wang, Guoliang; Dong, Pin

2016-02-01

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain‑derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury.

The Effect of Early Visual Deprivation on the Neural Bases of Auditory Processing.

PubMed

Guerreiro, Maria J S; Putzar, Lisa; Röder, Brigitte

2016-02-03

Transient congenital visual deprivation affects visual and multisensory processing. In contrast, the extent to which it affects auditory processing has not been investigated systematically. Research in permanently blind individuals has revealed brain reorganization during auditory processing, involving both intramodal and crossmodal plasticity. The present study investigated the effect of transient congenital visual deprivation on the neural bases of auditory processing in humans. Cataract-reversal individuals and normally sighted controls performed a speech-in-noise task while undergoing functional magnetic resonance imaging. Although there were no behavioral group differences, groups differed in auditory cortical responses: in the normally sighted group, auditory cortex activation increased with increasing noise level, whereas in the cataract-reversal group, no activation difference was observed across noise levels. An auditory activation of visual cortex was not observed at the group level in cataract-reversal individuals. The present data suggest prevailing auditory processing advantages after transient congenital visual deprivation, even many years after sight restoration. The present study demonstrates that people whose sight was restored after a transient period of congenital blindness show more efficient cortical processing of auditory stimuli (here speech), similarly to what has been observed in congenitally permanently blind individuals. These results underscore the importance of early sensory experience in permanently shaping brain function. Copyright © 2016 the authors 0270-6474/16/361620-11$15.00/0.

The Normalized Failure Index: a method for summarizing the results of studies on restoration longevity?

PubMed

Burke, F J T; Singh, V; Wilson, N H F

2013-01-01

Satisfactory restoration longevity is central to operative dentistry and is the subject of a wide variety of publications. However, combining the results of a number of studies to provide an overview, for example, for a meta-analysis may be problematic because of the heterogeneity of the data, and a high proportion of studies may therefore not be included. It is the purpose of this study to present a means whereby the data from cohort studies may be combined to present a representation of restoration longevity, termed the "Normalized Failure Index."

Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke.

PubMed

Khodaparast, N; Hays, S A; Sloan, A M; Hulsey, D R; Ruiz, A; Pantoja, M; Rennaker, R L; Kilgard, M P

2013-12-01

Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement. We have recently developed a novel method that uses vagus nerve stimulation (VNS) paired with forelimb movements to drive specific, long-lasting map plasticity in rat primary motor cortex. Here we report that VNS paired with rehabilitative training can enhance recovery of forelimb force generation following infarction of primary motor cortex in rats. Quantitative measures of forelimb function returned to pre-lesion levels when VNS was delivered during rehab training. Intensive rehab training without VNS failed to restore function back to pre-lesion levels. Animals that received VNS during rehab improved twice as much as rats that received the same rehabilitation without VNS. VNS delivered during physical rehabilitation represents a novel method that may provide long-lasting benefits towards stroke recovery. © 2013.

Ultralow concentrations of bupivacaine exert anti-inflammatory effects on inflammation-reactive astrocytes

PubMed Central

Block, Linda; Jörneberg, Per; Björklund, Ulrika; Westerlund, Anna; Biber, Björn; Hansson, Elisabeth

2013-01-01

Bupivacaine is a widely used, local anesthetic agent that blocks voltage-gated Na+ channels when used for neuro-axial blockades. Much lower concentrations of bupivacaine than in normal clinical use, < 10−8 m, evoked Ca2+ transients in astrocytes from rat cerebral cortex, that were inositol trisphosphate receptor-dependent. We investigated whether bupivacaine exerts an influence on the Ca2+ signaling and interleukin-1β (IL-1β) secretion in inflammation-reactive astrocytes when used at ultralow concentrations, < 10−8 m. Furthermore, we wanted to determine if bupivacaine interacts with the opioid-, 5-hydroxytryptamine- (5-HT) and glutamate-receptor systems. With respect to the μ-opioid- and 5-HT-receptor systems, bupivacaine restored the inflammation-reactive astrocytes to their normal non-inflammatory levels. With respect to the glutamate-receptor system, bupivacaine, in combination with an ultralow concentration of the μ-opioid receptor antagonist naloxone and μ-opioid receptor agonists, restored the inflammation-reactive astrocytes to their normal non-inflammatory levels. Ultralow concentrations of bupivacaine attenuated the inflammation-induced upregulation of IL-1β secretion. The results indicate that bupivacaine interacts with the opioid-, 5-HT- and glutamate-receptor systems by affecting Ca2+ signaling and IL-1β release in inflammation-reactive astrocytes. These results suggest that bupivacaine may be used at ultralow concentrations as an anti-inflammatory drug, either alone or in combination with opioid agonists and ultralow concentrations of an opioid antagonist. PMID:24083665

Restoration of blood 2,3-diphosphoglycerate levels in multi-transfused patients: effect of organic and inorganic phosphate.

PubMed

Iapichino, G; Radrizzani, D; Solca, M; Franzosi, M G; Pallavicini, F B; Spina, G; Scherini, A

1984-01-01

Blood stored in acid-citrate-dextrose (ACD) shows a progressive decrease in 2,3-diphosphoglycerate (DPG) content. Since the decrease in DPG increases hemoglobin oxygen affinity, which in turn may reduce tissue and venous PO2 and peripheral oxygen delivery, many efforts have been made to preserve or restore DPG levels in stored blood. An in vivo rejuvenating technique, employing fructose-1,6-diphosphate (FDP) at a mean dosage of 1 mmol kg-1 day-1 of phosphate, to increase the DPG circulating level in multi-transfused patients is proposed. Eighteen patients, who received at least one-third of their estimated blood volume (3990 +/- 480 (SEM) ml of ACD stored blood) in blood transfusion, were treated: nine with inorganic phosphate, and nine with FDP. Basal DPG was very low in both groups: 12.61 +/- 1.34 (SEM) and 10.42 +/- 0.98 (SEM) mumol g-1, respectively (normal value is 14.5 mumol g-1, at pH 7.40). However, DPG values increased significantly and promptly in patients receiving FDP, whereas in cases of inorganic phosphate administration, it was not significantly raised over the basal value until the third day. Phosphatemia remained normal and constant with FDP, but it rose significantly on the third day of treatment with inorganic phosphate. FDP appears to consistently and rapidly increase DPG levels after transfusion with blood stored in ACD, and to be particularly safe.

Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

PubMed Central

Chen, Li; Lodge, Daniel J

2015-01-01

Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Methods: Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID:25539511

Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction

PubMed Central

Lamping, KL; Nuno, DW; Coppey, LJ; Holmes, AJ; Hu, S; Oltman, CL; Norris, AW; Yorek, MA

2013-01-01

Aims The ability of dietary enrichment with monounsaturated (MUFA), n-3, or n-6 polyunsaturated fatty acids (PUFA) to reverse glucose intolerance and vascular dysfunction resulting from excessive dietary saturated fatty acids is not resolved. We hypothesized that partial replacement of dietary saturated fats with n-3 PUFA enriched menhaden oil (MO) would provide greater improvement in glucose tolerance and vascular function compared to n-6 enriched safflower oil (SO) or MUFA-enriched olive oil (OO). Material and Methods We fed mice a high saturated fat diet (60% kcal from lard) for 12 weeks before substituting half the lard with MO, SO or OO for an additional 4 weeks. At the end of 4 weeks, we assessed glucose tolerance, insulin signaling and reactivity of isolated pressurized gracilis arteries. Results After 12 weeks of saturated fat diet, body weights were elevated and glucose tolerance abnormal compared to mice on control diet (13% kcal lard). Diet substituted with MO restored basal glucose levels, glucose tolerance, and indices of insulin signaling (phosphorylated Akt) to normal whereas restoration was limited for SO and OO substitutions. Although dilation to acetylcholine was reduced in arteries from mice on HF, OO and SO diets compared to normal diet, dilation to acetylcholine was fully restored and constriction to phenylephrine reduced in MO fed mice compared to normal. Conclusion We conclude that short term enrichment of an ongoing high fat diet with n-3 PUFA rich MO but not MUFA rich OO or n-6 PUFA rich SO reverses glucose tolerance, insulin signaling, and vascular dysfunction. PMID:22950668

Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice

PubMed Central

Wong, Wen Mai; Durakoglugil, Murat S.; Wasser, Catherine R.; Jiang, Shan; Xian, Xunde

2016-01-01

Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain. SIGNIFICANCE STATEMENT One proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk factor for the disease. A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to wild-type levels normalizes plasma lipids in ApoE KO mice. While this does not rescue synaptic loss, it does completely restore learning and memory in the mice, suggesting that both CNS and plasma ApoE are independent parameters that affect brain health. PMID:27683909

GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress.

PubMed

Mian, Omar Y; Khattab, Mohamed H; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M; Veeraswamy, Ravi K; Brooks, James D; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G; Yegnasubramanian, Srinivasan; DeWeese, Theodore L

2016-02-01

Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. © 2015 Wiley Periodicals, Inc.

GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress

PubMed Central

Mian, Omar Y.; Khattab, Mohamed H.; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M.; Veeraswamy, Ravi K.; Brooks, James D.; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G.; Yegnasubramanian, Srinivasan; DeWeese, Theodore L.

2016-01-01

BACKGROUND Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1-transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. PMID:26447830

N-stearoylethanolamine restores pancreas lipid composition in obesity-induced insulin resistant rats.

PubMed

Onopchenko, Oleksandra V; Kosiakova, Galina V; Oz, Murat; Klimashevsky, Vitaliy M; Gula, Nadiya M

2015-01-01

This study investigates the protective effect of N-stearoylethanolamine (NSE), a bioactive N-acylethanolamine , on the lipid profile distribution in the pancreas of obesity-induced insulin resistant (IR) rats fed with prolonged high fat diet (58% of fat for 6 months). The phospholipid composition was determined using 2D thin-layer chromatography. The level of individual phospholipids was estimated by measuring inorganic phosphorus content. The fatty acid (FA) composition and cholesterol level were investigated by gas-liquid chromatography. Compared to controls, plasma levels of triglycerides and insulin were significantly increased in IR rats. The pancreas lipid composition indicated a significant reduction of the free cholesterol level and some phospholipids such as phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer) compared to controls. Moreover, the FA composition of pancreas showed a significant redistribution of the main FA (18:1n-9, 18:2n-6, 18:3n-6 and 20:4n-6) levels between phospholipid, free FA, triglyceride fractions under IR conditions that was accompanied by a change in the estimated activities of Δ9-, Δ6-, Δ5-desaturase. Administration of N-stearoylethanolamine (NSE, 50 mg/kg daily per os for 2 weeks) IR rats triggered an increase in the content of free cholesterol, PtdCho and normalization of PtdEtn, PtdSer level. Furthermore, the NSE modulated the activity of desaturases, thus influenced FA composition and restored the FA ratios in the lipid fractions. These NSE-induced changes were associated with a normalization of plasma triglyceride content, considerable decrease of insulin and index HOMA-IR level in rats under IR conditions.

Exon skipping and gene transfer restore dystrophin expression in human induced pluripotent stem cells-cardiomyocytes harboring DMD mutations.

PubMed

Dick, Emily; Kalra, Spandan; Anderson, David; George, Vinoj; Ritso, Morten; Laval, Steven H; Barresi, Rita; Aartsma-Rus, Annemieke; Lochmüller, Hanns; Denning, Chris

2013-10-15

With an incidence of ∼1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to ∼30% of normal levels in hiPSC-cardiomyocytes carrying exon 47-50 or 48-50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart.

Exon Skipping and Gene Transfer Restore Dystrophin Expression in Human Induced Pluripotent Stem Cells-Cardiomyocytes Harboring DMD Mutations

PubMed Central

Dick, Emily; Kalra, Spandan; Anderson, David; George, Vinoj; Ritso, Morten; Laval, Steven H.; Barresi, Rita; Aartsma-Rus, Annemieke; Lochmüller, Hanns

2013-01-01

With an incidence of ∼1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to ∼30% of normal levels in hiPSC-cardiomyocytes carrying exon 47–50 or 48–50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart. PMID:23829870

Cystamine restores GSTA3 levels in Vanin-1 null mice.

PubMed

Di Leandro, Luana; Maras, Bruno; Schininà, M Eugenia; Dupré, Silvestro; Koutris, Ilias; Martin, Florent M; Naquet, Philippe; Galland, Franck; Pitari, Giuseppina

2008-03-15

Free cysteamine levels in mouse tissues have been strictly correlated to the presence of membrane-bound pantetheinase activity encoded by Vanin-1. Vanin-1 is involved in many biological processes in mouse, from thymus homing to sexual development. Vanin-1 -/- mice are fertile and grow and develop normally; they better control inflammation and most of the knockout effects were rescued by cystamine treatment. Gene structure analysis showed the presence of an oxidative stimuli-responsive ARE-like sequence in the promoter. In this paper we investigate antioxidant-detoxifying enzymatic activities at the tissue level, comparing Vanin-1 -/- and wild-type mice. In Vanin-1 null animals we pointed out a decrease in the Se-independent glutathione peroxidase activity. The decrease in enzymatic activity appeared to be correlated to an impairment of GST isoenzyme levels. In particular a significant drop in GSTA3 together with a minor decrement in GSTM1 and an increase in GSTP1 levels was detected in Vanin-1 -/- livers. Cystamine administration to Vanin-1 -/- mice restored specifically GSTA3 levels and the corresponding enzymatic activity without influencing protein expression. A possible role of cystamine on protein stability/folding can be postulated.

Effect of excessive saccharose administration on metabolic processes in the liver of rabbits with restricted mobility

NASA Technical Reports Server (NTRS)

Rylnikov, Y. P.

1980-01-01

The administration of saccharose (3 g per 1 kg for 2 months) intensified changes encountered in hypokinesia. There was a more marked increase in the content of cholesterol, pre-beta and beta-lipoproteins, phospholipids, and glycosaminoglycans in the blood. At the same time, the administration of saccharose improved the course of metabolic processes in the liver of immobilized rabbits, restored to normal levels the reduced glycogen level, the rate of glycolysis and the conversion of cholesterol to bile acids and their discharge in the cystic bile.

Restoration of euglycemia after duodenal bypass surgery is reliant on central and peripheral inputs in Zucker fa/fa rats.

PubMed

Jiao, Jian; Bae, Eun Ju; Bandyopadhyay, Gautam; Oliver, Jason; Marathe, Chaitra; Chen, Michael; Hsu, Jer-Yuan; Chen, Yu; Tian, Hui; Olefsky, Jerrold M; Saberi, Maziyar

2013-04-01

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system-derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.

BAAV mediated GJB2 gene transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice.

PubMed

Crispino, Giulia; Di Pasquale, Giovanni; Scimemi, Pietro; Rodriguez, Laura; Galindo Ramirez, Fabian; De Siati, Romolo Daniele; Santarelli, Rosa Maria; Arslan, Edoardo; Bortolozzi, Mario; Chiorini, John A; Mammano, Fabio

2011-01-01

The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26(Sox10Cre) mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans.

Central leptin action on euglycemia restoration in type 1 diabetes: Restraining responses normally induced by fasting?

PubMed

Xu, Yuanzhong; Tong, Qingchun

2017-07-01

Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D. Copyright © 2016 Elsevier Ltd. All rights reserved.

WASP family proteins and formins compete in pseudopod- and bleb-based migration

PubMed Central

2018-01-01

Actin pseudopods induced by SCAR/WAVE drive normal migration and chemotaxis in eukaryotic cells. Cells can also migrate using blebs, in which the edge is driven forward by hydrostatic pressure instead of actin. In Dictyostelium discoideum, loss of SCAR is compensated by WASP moving to the leading edge to generate morphologically normal pseudopods. Here we use an inducible double knockout to show that cells lacking both SCAR and WASP are unable to grow, make pseudopods or, unexpectedly, migrate using blebs. Remarkably, amounts and dynamics of actin polymerization are normal. Pseudopods are replaced in double SCAR/WASP mutants by aberrant filopods, induced by the formin dDia2. Further disruption of the gene for dDia2 restores cells’ ability to initiate blebs and thus migrate, though pseudopods are still lost. Triple knockout cells still contain near-normal F-actin levels. This work shows that SCAR, WASP, and dDia2 compete for actin. Loss of SCAR and WASP causes excessive dDia2 activity, maintaining F-actin levels but blocking pseudopod and bleb formation and migration. PMID:29191847

Effectiveness of surgical reconstruction to restore radiocarpal joint mechanics after scapholunate ligament injury: an in vivo modeling study.

PubMed

Johnson, Joshua E; Lee, Phil; McIff, Terence E; Toby, E Bruce; Fischer, Kenneth J

2013-05-31

Disruption of the scapholunate ligament can cause a loss of normal scapholunate mechanics and eventually lead to osteoarthritis. Surgical reconstruction attempts to restore scapholunate relationship show improvement in functional outcomes, but postoperative effectiveness in restoring normal radiocarpal mechanics still remains a question. The objective of this study was to investigate the benefits of surgical repair by observing changes in contact mechanics on the cartilage surface before and after surgical treatment. Six patients with unilateral scapholunate dissociation were enrolled in the study, and displacement driven magnetic resonance image-based surface contact modeling was used to investigate normal, injured and postoperative radiocarpal mechanics. Model geometry was acquired from images of wrists taken in a relaxed position. Kinematics were acquired from image registration between the relaxed images, and images taken during functional loading. Results showed a trend for increase in radiocarpal contact parameters with injury. Peak and mean contact pressures significantly decreased after surgery in the radiolunate articulation and there were no significant differences between normal and postoperative wrists. Results indicated that surgical repair improves contact mechanics after injury and that contact mechanics can be surgically restored to be similar to normal. This study provides novel contact mechanics data on the effects of surgical repair after scapholunate ligament injury. With further work, it may be possible to more effectively differentiate between treatments and degenerative changes based on in vivo contact mechanics data. Copyright © 2013 Elsevier Ltd. All rights reserved.

CaNa2EDTA chelation attenuates cell damage in workers exposed to lead--a pilot study.

PubMed

Čabarkapa, A; Borozan, S; Živković, L; Stojanović, S; Milanović-Čabarkapa, M; Bajić, V; Spremo-Potparević, B

2015-12-05

Lead induced oxidative cellular damage and long-term persistence of associated adverse effects increases risk of late-onset diseases. CaNa2EDTA chelation is known to remove contaminating metals and to reduce free radical production. The objective was to investigate the impact of chelation therapy on modulation of lead induced cellular damage, restoration of altered enzyme activities and lipid homeostasis in peripheral blood of workers exposed to lead, by comparing the selected biomarkers obtained prior and after five-day CaNa2EDTA chelation intervention. The group of smelting factory workers diagnosed with lead intoxication and current lead exposure 5.8 ± 1.2 years were administered five-day CaNa2EDTA chelation. Elevated baseline activity of antioxidant enzymes Cu, Zn-SOD and CAT as well as depleted thiols and increased protein degradation products-carbonyl groups and nitrites, pointing to Pb induced oxidative damage, were restored toward normal values following the treatment. Lead showed inhibitor potency on both RBC AChE and BChE in exposed workers, and chelation re-established the activity of BChE, while RBC AChE remained unaffected. Also, genotoxic effect of lead detected in peripheral blood lymphocytes was significantly decreased after therapy, exhibiting 18.9% DNA damage reduction. Administration of chelation reversed the depressed activity of serum PON 1 and significantly decreased lipid peroxidation detected by the post-chelation reduction of MDA levels. Lactate dehydrogenase LDH1-5 isoenzymes levels showed evident but no significant trend of restoring toward normal control values following chelation. CaNa2EDTA chelation ameliorates the alterations linked with Pb mediated oxidative stress, indicating possible benefits in reducing health risks associated with increased oxidative damage in lead exposed populations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Excess dietary cobalt in pigs

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

Huck, D.W.; Clawson, A.J.

1976-01-01

Five experiments were conducted, in which 240 growing finishing pigs were used, to determine the level of Cobalt (Co) which is toxic. Pigs tolerated up to 200 mg/kg of Co when added to corn-soybean meal diets containing 82 to 178 mg/kg of iron. The addition of 400 or 600 mg/kg of Co caused anorexia, growth depression, stiff-leggedness, humped back, incoordination and extreme muscular tremors. Serum and organ levels of Co were greatly increased and serum and organ levels of iron (Fe) were significantly reduced by added dietary cobalt. The addition of .5 or 1.0% methionine to the diet completely alleviatedmore » the toxic affects caused by the 600 mg level of Co and restored serum Fe to near normal levels. The addition of Fe, manganese (Mn) and zinc (Zn) in combination at levels of 200, 400 and 400 mg/kg, respectively, also alleviated the growth depression caused by the 400 mg level of Co and higher levels of Fe, Mn and Zn (200, 600 and 600 mg/kg) partially restored feed intake and growth when 600 mg of Co was fed. Iron alone was not effective in overcoming the growth depression caused by 400 or 600 mg/kg of dietary cobalt. 31 references, 1 figure, 11 tables.« less

Effects of sex steroids on muscarinic sties in the rat brain

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

Al-Dahan, M.I.

1986-03-01

The level of binding sites for (/sup 3/H)scopolamine in the rat hypothalamus and amygdala (but not elsewhere in the brain) is modified by hormonal status. In females, there is an inverse relation between the level of sites and estrogen (E/sub 2/) and progesterone (P) concentration. Binding is high in metoestrous (Met) and in ovariectomized (Ovx) animals but low in proestrous (Pro). Hormone replacement in ovariectomized animals lowers the level of the sites. Castration (Cast) of males reduces the level of sites but subsequent testosterone (T) treatment restores normal levels. The results support a role of hormones in sexual behavior viamore » alteration in levels of muscarinic receptors: male hormone increases and female hormones decrease receptor levels.« less

The Potential Transformation of Our Species by Neural Enhancement

PubMed Central

Zehr, E. Paul

2015-01-01

ABSTRACT. Neural enhancement represents recovery of function that has been lost due to injury or disease pathology. Restoration of functional ability is the objective. For example, a neuroprosthetic to replace a forearm and hand lost to the ravages of war or industrial accident. However, the same basic constructs used for neural enhancement after injury could amplify abilities that are already in the natural normal range. That is, neural enhancement technologies to restore function and improve daily abilities for independent living could be used to improve so-called normal function to ultimate function. Approaching that functional level by use and integration of technology takes us toward the concept of a new species. This new subspecies—homo sapiens technologicus—is one that uses technology not just to assist but to change its own inherent biological function. The author uses examples from prosthetics and neuroprosthetics to address the issue of the limitations of constructs on the accepted range of human performance ability and aims to provide a cautionary view toward reflection on where our science may take the entire species. PMID:25575224

Cardiomyocyte-specific desmin rescue of desmin null cardiomyopathy excludes vascular involvement.

PubMed

Weisleder, Noah; Soumaka, Elisavet; Abbasi, Shahrzad; Taegtmeyer, Heinrich; Capetanaki, Yassemi

2004-01-01

Mice deficient in desmin, the muscle-specific member of the intermediate filament gene family, display defects in all muscle types and particularly in the myocardium. Desmin null hearts develop cardiomyocyte hypertrophy and dilated cardiomyopathy (DCM) characterized by extensive myocyte cell death, calcific fibrosis and multiple ultrastructural defects. Several lines of evidence suggest impaired vascular function in desmin null animals. To determine whether altered capillary function or an intrinsic cardiomyocyte defect is responsible for desmin null DCM, transgenic mice were generated to rescue desmin expression specifically to cardiomyocytes. Desmin rescue mice display a wild-type cardiac phenotype with no fibrosis or calcification in the myocardium and normalization of coronary flow. Cardiomyocyte ultrastructure is also restored to normal. Markers of hypertrophy upregulated in desmin null hearts return to wild-type levels in desmin rescue mice. Working hearts were perfused to assess coronary flow and cardiac power. Restoration of a wild-type cardiac phenotype in a desmin null background by expression of desmin specifically within cardiomyocyte indicates that defects in the desmin null heart are due to an intrinsic cardiomyocytes defect rather than compromised coronary circulation.

Diabetes Impairs the Vascular Recruitment of Normal Stem Cells by Oxidant Damage, Reversed by Increases in pAMPK, Heme Oxygenase-1, and Adiponectin

PubMed Central

Sambuceti, Gianmario; Morbelli, Silvia; Vanella, Luca; Kusmic, Claudia; Marini, Cecilia; Massollo, Michela; Augeri, Carla; Corselli, Mirko; Ghersi, Chiara; Chiavarina, Barbara; Rodella, Luigi F; L'Abbate, Antonio; Drummond, George; Abraham, Nader G; Frassoni, Francesco

2009-01-01

Background Atherosclerosis progression is accelerated in diabetes mellitus (DM) by either direct endothelial damage or reduced availability and function of endothelial progenitor cells (EPCs). Both alterations are related to increased oxidant damage. Aim We examined if DM specifically impairs vascular signaling, thereby reducing the recruitment of normal EPCs, and if increases in antioxidant levels by induction of heme oxygenase-1 (HO-1) can reverse this condition. Methods Control and diabetic rats were treated with the HO-1 inducer cobalt protoporphyrin (CoPP) once a week for 3 weeks. Eight weeks after the development of diabetes, EPCs harvested from the aorta of syngenic inbred normal rats and labeled with technetium-99m-exametazime were infused via the femoral vein to estimate their blood clearance and aortic recruitment. Circulating endothelial cells (CECs) and the aortic expression of thrombomodulin (TM), CD31, and endothelial nitric oxide synthase (eNOS) were used to measure endothelial damage. Results DM reduced blood clearance and aortic recruitment of EPCs. Both parameters were returned to control levels by CoPP treatment without affecting EPC kinetics in normal animals. These abnormalities of EPCs in DM were paralleled by reduced serum adiponectin levels, increased numbers of CECs, reduced endothelial expression of phosphorylated eNOS, and reduced levels of TM, CD31, and phosphorylated AMP-activated protein kinase (pAMPK). CoPP treatment restored all of these parameters to normal levels. Conclusion Type II DM and its related oxidant damage hamper the interaction between the vascular wall and normal EPCs by mechanisms that are, at least partially, reversed by the induction of HO-1 gene expression, adiponectin, and pAMPK levels. PMID:19038792

Ramipril and haloperidol as promising approaches in managing rheumatoid arthritis in rats.

PubMed

Fahmy Wahba, Mariam Gamal; Shehata Messiha, Basim Anwar; Abo-Saif, Ali Ahmed

2015-10-15

Rheumatoid arthritis (RA) is a challenging autoimmune disorder, whose treatments usually cause severe gastrointestinal, renal and other complications. We aimed to evaluate the beneficial anti-arthritic effects of an angiotensin converting enzyme (ACE) inhibitor, ramipril and a dopamine receptor blocker, haloperidol, on Complete Freund's Adjuvant-induced RA in adult female albino rats. Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving ramipril (0.9 mg/kg/day) and haloperidol (1 mg/kg/day). Serum rheumatoid factor, matrix metalloprotinease-3 (MMP-3) and cartilage oligomeric matrix protein as specific rheumatoid biomarkers, serum immunoglobulin G and antinuclear antibody as immunological biomarkers, serum tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) as immunomodulatory cytokines, serum myeloperoxidase and C-reactive protein as inflammatory biomarkers, as well as malondialdehyde and glutathione reduced (GSH) as oxidative stress biomarkers were assessed. A histopathological study on joints and spleens was performed to support the results of biochemical estimations. Ramipril administration significantly corrected all the measured biomarkers, being restored back to normal levels except for MMP-3, TNF-α and IL-10. Haloperidol administration restored all the measured biomarkers back to normal levels except for TNF-α, IL-10 and GSH. In conclusion, ACE inhibitors represented by ramipril and dopamine receptor blockers represented by haloperidol may represent new promising protective strategies against RA, at least owing to their immunomodulatory, anti-inflammatory and antioxidant potentials. Copyright © 2015 Elsevier B.V. All rights reserved.

Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.

PubMed

Verbeek, Jef; Spincemaille, Pieter; Vanhorebeek, Ilse; Van den Berghe, Greet; Vander Elst, Ingrid; Windmolders, Petra; van Pelt, Jos; van der Merwe, Schalk; Bedossa, Pierre; Nevens, Frederik; Cammue, Bruno; Thevissen, Karin; Cassiman, David

2017-02-23

Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant. Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature. Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.

Centrobin-mediated Regulation of the Centrosomal Protein 4.1-associated Protein (CPAP) Level Limits Centriole Length during Elongation Stage*

PubMed Central

Gudi, Radhika; Haycraft, Courtney J.; Bell, P. Darwin; Li, Zihai; Vasu, Chenthamarakshan

2015-01-01

Microtubule-based centrioles in the centrosome mediate accurate bipolar cell division, spindle orientation, and primary cilia formation. Cellular checkpoints ensure that the centrioles duplicate only once in every cell cycle and achieve precise dimensions, dysregulation of which results in genetic instability and neuro- and ciliopathies. The normal cellular level of centrosomal protein 4.1-associated protein (CPAP), achieved by its degradation at mitosis, is considered as one of the major mechanisms that limits centriole growth at a predetermined length. Here we show that CPAP levels and centriole elongation are regulated by centrobin. Exogenous expression of centrobin causes abnormal elongation of centrioles due to massive accumulation of CPAP in the cell. Conversely, CPAP was undetectable in centrobin-depleted cells, suggesting that it undergoes degradation in the absence of centrobin. Only the reintroduction of full-length centrobin, but not its mutant form that lacks the CPAP binding site, could restore cellular CPAP levels in centrobin-depleted cells, indicating that persistence of CPAP requires its interaction with centrobin. Interestingly, inhibition of the proteasome in centrobin-depleted cells restored the cellular and centriolar CPAP expression, suggesting its ubiquitination and proteasome-mediated degradation when centrobin is absent. Intriguingly, however, centrobin-overexpressing cells also showed proteasome-independent accumulation of ubiquitinated CPAP and abnormal, ubiquitin-positive, elongated centrioles. Overall, our results show that centrobin interacts with ubiquitinated CPAP and prevents its degradation for normal centriole elongation function. Therefore, it appears that loss of centrobin expression destabilizes CPAP and triggers its degradation to restrict the centriole length during biogenesis. PMID:25616662

Astressin B, a corticotropin-releasing hormone receptor antagonist, accelerates the return to normal luteal function after an inflammatory-like stress challenge in the rhesus monkey.

PubMed

Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas; Rivier, Jean; Ferin, Michel

2007-02-01

Endogenous release of CRH in stress has been associated with a dysfunctional reproductive endocrine axis. In the rhesus monkey, an inflammatory-like stress challenge in the luteal phase decreases luteal secretory function. Here, we tested the effectiveness of astressin B, a nonspecific CRH receptor antagonist, in constraining the deleterious impact of a 10-d lipopolysaccharide (LPS) challenge on the menstrual cycle. Two protocols were carried out in nine animals. In the first, the animals, after showing two normal consecutive control cycles, were injected daily for 10 days with LPS (75-125 mug/d) during the luteal phase of the cycle. The animals were followed through the two postchallenge cycles. The second protocol, carried out in the following year, was identical with protocol 1, except that the animals were treated with astressin B (0.45 mg/kg) 1 h before each daily LPS challenge during the luteal phase. Blood samples were obtained daily to document cyclic hormones levels. The LPS challenge significantly decreased luteal progesterone and LH release during the challenge cycle. Inhibition of luteal progesterone extended to the two successive postchallenge cycles. Astressin B treatment prevented luteal LH but not luteal progesterone decrease during the treatment cycle and restored normal progesterone secretion during the two posttreatment cycles. We conclude that the deleterious impact of a short-term inflammatory stress challenge on luteal function is far longer than the stress period itself. Systemic administration of astressin B accelerates the return to normal luteal function, presumably by restoring normal neuroendocrine regulation of gonadotropin secretion.

Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential

PubMed Central

ALAM, BADRUL; MAJUMDER, RAJIB; AKTER, SHAHINA; LEE, SANG-HAN

2015-01-01

The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (P<0.05). Hematological and serum biochemical profiles were restored to normal levels in the extract-treated mice compared with the EAC control mice. MPBL and EPBL treatment significantly decreased lipid peroxidation (P<0.05) and restored GSH, SOD and CAT levels towards normal compared with the EAC control. Taken together, the results of the present study demonstrated that Piper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential. PMID:25624910

Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential.

PubMed

Alam, Badrul; Majumder, Rajib; Akter, Shahina; Lee, Sang-Han

2015-02-01

The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (P<0.05). Hematological and serum biochemical profiles were restored to normal levels in the extract-treated mice compared with the EAC control mice. MPBL and EPBL treatment significantly decreased lipid peroxidation (P<0.05) and restored GSH, SOD and CAT levels towards normal compared with the EAC control. Taken together, the results of the present study demonstrated that Piper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential.

Tension Regulation at the Suture Lines for Repair of Neglected Achilles Tendon Laceration.

PubMed

Massoud, Elsayed Ibraheem Elsayed

2017-03-01

Operative intervention is the preferred option for management of the neglected laceration of the Achilles tendon. However, the commonly used techniques rarely follow the principles of the regenerative medicine for the restoration of the lost tissue. This study postulated that incorporation of the autogenous tendon graft would properly progress when the interplay between mechanical loading and healing phases was correctly applied. A prospective study included 15 patients who were treated for neglected Achilles tendon laceration using the technique of lengthening of the proximal tendon stump. An absorbable reinforcement suture was used for control of the mechanical environment at the suture lines. By an average 5 years of the prospective follow-up, all the repaired tendons had restored continuity and length. The calf circumference equalized to the uninjured side in 12 patients. However, 3 patients had calf atrophy but they improved compared to the preoperative measurements. Sonogram confirmed the restoration of the normal thickness and the gliding characteristics of the repaired tendon. The technique restored continuity and tension of the repaired tendon, preserved the calf circumference, and prevented peritendinous adhesions. The absorbable reinforcement suture spontaneously allowed for the mechanical loading of the grafted tendon. Level IV, case series.

The role of the habenula-interpeduncular pathway in modulating levels of circulating adrenal hormones.

PubMed

Murray, M; Murphy, C A; Ross, L L; Haun, F

1994-01-01

The fasciculus retroflexus (FR) is the major pathway by which the medial and lateral habenular nuclei project to the interpeduncular nucleus (IPN) and ventral tegmentum. Recent work has suggested that the habenula-interpeduncular system may be involved in the regulation of states of arousal. Bilateral FR lesions have been shown to disrupt chronically, and habenula transplants have been shown to restore normal sleep patterns in rats [J. NeuroscL, 12 (1992) 3282-3290]. In this study, we examined whether FR lesions and habenula cell transplants would also modify chronically the circulating plasma levels of the stress-related hormones, norepinephrine (NE), epinephrine (EPI) and corticosterone. When plasma samples were obtained via retro-orbital eye-bleed during anesthesia, animals with FR lesions had significantly increased levels of plasma NE, EPI and corticosterone 2-3 months postoperatively compared to unoperated controls. Transplants of embryonic habenula cells placed near the denervated IPN in FR-lesioned animals restored levels of NE and EPI to normal, but did not attenuate elevated corticosterone levels. When plasma samples were obtained in conscious animals via indwelling arterial cannulae, FR-lesioned rats likewise exhibited increased basal levels of corticosterone but plasma levels of catecholamines were similar to those of unoperated controls. Differences in our results obtained using the two methods of blood sampling may be explained by the effects of anesthesia and stress associated with the eye-bleed method. Thus, the effect of FR lesions in increasing plasma levels of catecholamines may not reflect a difference in basal hormone levels, but a heightened sympathetic adrenomedullary response to stress. While these results indicate that the integrity of the habenular efferent pathway is important in modulating circulating levels of hormones associated with the stress response, two separate mechanisms appear to control its interactions with sympathetic-adrenal medullary and adrenocortical pathways.

Quantitative percussion diagnostics as an indicator of the level of the structural pathology of teeth: Retrospective follow-up investigation of high-risk sites that remained pathological after restorative treatment.

PubMed

Sheets, Cherilyn G; Wu, Jean C; Earthman, James C

2017-11-29

Structural damage may remain even after a tooth is restored. Conventional diagnostic aids do not quantify the severity of structural damage or allow the monitoring of structural changes after restoration. The purpose of this retrospective clinical study was to provide an in-depth analysis of 9 high-risk sites after restoration. The analysis followed structural defects found upon disassembly, restorative materials used, therapeutic procedures provided, current longevity, and long-term quantitative percussion diagnostics (QPD) to monitor results. The hypothesis was that QPD can be used to quantify positive and negative changes in structural stability. Sixty sites requiring restoration were part of an institutional review board-approved clinical study. Each participant was examined comprehensively, including QPD testing, at each follow-up. Long-term changes in normal fit error (NFE) values after restoration were evaluated according to a pathology rating system established in an earlier publication. Nine highly compromised sites were chosen for further analysis and monitored for an additional 6 years. Of the 9 high-risk sites (NFE>0.04), 7 sites improved and 2 sites deteriorated. Potential causes for each trend were documented. The data support the hypothesis that QPD can be used to monitor changes in structural stability after restoration. Knowledge of changes in advance of any symptoms allows further preventive or therapeutic intervention before serious structural damage can occur. Follow-up QPD indications of site improvement can also assure the clinician of the desired structural outcome. Copyright © 2017 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

A Bloody Mess: An Unusual Case of Diffuse Alveolar Hemorrhage Because of Warfarin Overdose.

PubMed

Heffler, Enrico; Campisi, Raffaele; Ferri, Sebastian; Crimi, Nunzio

2016-01-01

We herein present the case of a patient with frank hemoptysis and hematuria, dyspnea, and cough. The patient was known to be affected by Chronic Obstructive Pulmonary Disease (COPD) and dilated cardiomyopathy with atrial fibrillation. For this latter condition, he was supposed to take 1.25 mg warfarin daily. Laboratory findings revealed very high levels of International Normalized Ratio (INR) (16), and the patient referred that he self-increased warfarin dose to 5 mg daily since 8 days before the onset of symptoms. Computed tomography scan revealed diffuse bilateral signs of alveolar hemorrhage with hydroaerial levels within emphysematous cysts. Wafarin was immediately stopped and changed with 220 mg dabigatran daily, and he was properly treated to restore a normal coagulation status. We concluded for a case of diffuse alveolar hemorrhage because of warfarin overdose.

Protein C deficiency in insulin-dependent diabetes: a hyperglycemia-related phenomenon.

PubMed

Ceriello, A; Quatraro, A; Dello Russo, P; Marchi, E; Barbanti, M; Milani, M R; Giugliano, D

1990-08-13

In 30 insulin-dependent diabetic patients protein C (PC) antigen and PC activity were significantly lower than those of matched control healthy subjects. An inverse correlation between fasting plasma glucose and both PC concentration and activity was present in diabetics, while a direct correlation between PC concentration and PC activity was observed. Induced hyperglycemia in diabetic and normal subjects was able to decrease both PC antigen levels and PC activity, and heparin reversed in part this effect. In diabetic patients euglycemia obtained by insulin infusion restored to normal the depressed PC levels. Heparin did not alter both the basal PC concentration and activity in healthy controls. These data stress the major role of hyperglycemia in determining PC decrease in diabetics, and suggest that PC reduction is probably associated to hyperglycemia-enhanced thrombin formation.

Evidence for a hyperglycaemia-dependent decrease of antithrombin III-thrombin complex formation in humans.

PubMed

Ceriello, A; Giugliano, D; Quatraro, A; Marchi, E; Barbanti, M; Lefèbvre, P

1990-03-01

In the presence of increased levels of fibrinopeptide A, decreased antithrombin III biological activity, and thrombin-antithrombin III complex levels are seen in diabetic patients. Induced-hyperglycaemia in diabetic and normal subjects decreased antithrombin III activity and thrombin-antithrombin III levels, and increased fibrinopeptide A plasma levels, while antithrombin III concentration did not change; heparin was shown to reduced these phenomena. In diabetic patients, euglycaemia induced by insulin infusion restored antithrombin III activity, thrombin-antithrombin III complex and fibrinopeptide A concentrations; heparin administration had the same effects. These data stress the role of a hyperglycaemia-dependent decrease of antithrombin III activity in precipitating thrombin hyperactivity in diabetes mellitus.

Restoration of Cardiac Tissue Thyroid Hormone Status in Experimental Hypothyroidism: A Dose-Response Study in Female Rats

PubMed Central

Weltman, Nathan Y.; Ojamaa, Kaie; Savinova, Olga V.; Chen, Yue-Feng; Schlenker, Evelyn H.; Zucchi, Riccardo; Saba, Alessandro; Colligiani, Daria; Pol, Christine J.

2013-01-01

Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T3 (instead of T4) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T3 dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T3 and T4 levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T3 led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T3 levels was not associated with restoration of cardiac tissue T3 levels or cardiac function. In fact, a 3-fold higher T3 dosage was necessary to normalize cardiac tissue T3 levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states. PMID:23594789

Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology

PubMed Central

Yang, Sujeong; Cacquevel, Matthias; Saksida, Lisa M.; Bussey, Timothy J.; Schneider, Bernard L.; Aebischer, Patrick; Melani, Riccardo; Pizzorusso, Tommaso; Fawcett, James W.; Spillantini, Maria Grazia

2015-01-01

Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3 month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1 week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders. PMID:25483398

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

PubMed Central

Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

2017-01-01

Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats. PMID:28287621

Switch to restoration therapy in a testosterone treated central hypogonadism with erythrocytosis.

PubMed

Cangiano, B; Cacciatore, C; Persani, L; Bonomi, M

2017-01-01

We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic-pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion. Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.

Influence of boron supplementation on performance, immunity and antioxidant status of lambs fed diets with or without adequate level of calcium

PubMed Central

Mondal, S.; Pattanaik, A. K.; Verma, A. K.

2017-01-01

Little is known about biological significance of effects of dietary Boron (B) and Calcium (Ca) interaction on health and production of farm animals. This is a preliminary investigation to evaluate the effects of B supplementation in lambs fed diets with (normal) or without adequate (low) levels of Ca. Twenty-four crossbred ram lambs were randomly distributed into four groups with six animals each in a 2x2 factorial design namely, normal-Ca diet (NCa) and low-Ca diet (LCa) fed without or with 40 ppm B (NCaB-40 and LCaB-40). The lambs were fed paddy straw and hybrid napier hay-based total mixed ration (60 roughage: 40 concentrate) during 180 days experimental period. Compared to control, the LCa diet lowered (P<0.01) average daily gain of lambs, but B-supplementation (LCaB-40) of the same nullified the effect. The lowered (P<0.05) total antioxidant activity and humoral immune response in lambs fed LCa diet were restored (P>0.05) to become at par with the control (NCa) upon supplementation of B (LCaB-40). The mRNA expression of SOD1 was lowered (P<0.05) due to LCa diet feeding which too was normalized on B-supplementation to become at par (P>0.05) with the control (NCa). Further, B-supplementation restored lowered (P<0.05) SOD1 gene expression on LCa diet, but enhanced (P<0.05) that in NCaB-40 group, when compared to the control (NCa) diet fed animals. However, these variations were not reflected in the SOD activity in the erythrocytes. The cell-mediated immune response was higher (P<0.05) in lambs fed LCa and LCaB-40 groups and there was no significant interaction between the levels of either Ca or B in diets with the period of immune response measurement. B- supplementation of LCa diet ameliorated tissue degenerative changes in liver and kidney. It was concluded that feeding LCa diet to lambs resulted in reduced growth rate, total antioxidant activity, humoral immune response along with degenerative changes in liver and kidney tissues, but B-supplementation of such diet restored most of these changes and ameliorated histopathological alterations. PMID:29141035

Influence of immediate loading on provisional restoration in dental implant stability

NASA Astrophysics Data System (ADS)

Ikbal, M.; Odang, R. W.; Indrasari, M.; Dewi, R. S.

2017-08-01

The success of dental implant treatment is determined by the primary stability at placement. One factor that could influence this stability is occlusal loading through provisional restoration. Two types of loading protocols are usually used: immediate and delayed loading. However, some controversies remain about the influence of occlusal loading on implant stability. Therefore, the influence of immediate loading on implant stability must be studied. An animal study was conducted by placing nine dental implants in the mandibular jaw of three Macaca fascicularis. Provisional restorations with various occlusal contacts (no, light, and normal contact) were placed on the implant. The implant stability was measured using the Ostell ISQ three times: immediately (baseline) and at the first and second months after implant placement. The implant stability between implants with no and normal occlusal contact as well as light and normal occlusal contact showed significant differences (p < 0.05) at the first and second months after implant placement. However, no significant increase (p > 0.05) in implant stability was seen at the baseline and the first and second months after implant placement for all occlusal contact groups. Immediate loading influenced the implant stability, and provisional restoration of implant without occlusal contact showed the highest implant stability.

Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin★

PubMed Central

Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L.; Mosher, Christina; Berglund, Eric D.; Elmquist, Joel K.; Zigman, Jeffrey M.

2013-01-01

The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreERT2 transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia. PMID:24567905

Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin.

PubMed

Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L; Mosher, Christina; Berglund, Eric D; Elmquist, Joel K; Zigman, Jeffrey M

2014-02-01

The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.

Weight restoration therapy rapidly reverses cortical thinning in anorexia nervosa: A longitudinal study.

PubMed

Bernardoni, Fabio; King, Joseph A; Geisler, Daniel; Stein, Elisa; Jaite, Charlotte; Nätsch, Dagmar; Tam, Friederike I; Boehm, Ilka; Seidel, Maria; Roessner, Veit; Ehrlich, Stefan

2016-04-15

Structural magnetic resonance imaging studies have documented reduced gray matter in acutely ill patients with anorexia nervosa to be at least partially reversible following weight restoration. However, few longitudinal studies exist and the underlying mechanisms of these structural changes are elusive. In particular, the relative speed and completeness of brain structure normalization during realimentation remain unknown. Here we report from a structural neuroimaging study including a sample of adolescent/young adult female patients with acute anorexia nervosa (n=47), long-term recovered patients (n=34), and healthy controls (n=75). The majority of acutely ill patients were scanned longitudinally (n=35): at the beginning of standardized weight restoration therapy and again after partial weight normalization (>10% body mass index increase). High-resolution structural images were processed and analyzed with the longitudinal stream of FreeSurfer software to test for changes in cortical thickness and volumes of select subcortical regions of interest. We found globally reduced cortical thickness in acutely ill patients to increase rapidly (0.06 mm/month) during brief weight restoration therapy (≈3 months). This significant increase was predicted by weight restoration alone and could not be ascribed to potentially mediating factors such as duration of illness, hydration status, or symptom improvements. By comparing cortical thickness in partially weight-restored patients with that measured in healthy controls, we confirmed that cortical thickness had normalized already at follow-up. This pattern of thinning in illness and rapid normalization during weight rehabilitation was largely mirrored in subcortical volumes. Together, our findings indicate that structural brain insults inflicted by starvation in anorexia nervosa may be reversed at a rate much faster than previously thought if interventions are successful before the disorder becomes chronic. This provides evidence drawing previously speculated mechanisms such as (de-)hydration and neurogenesis into question and suggests that neuronal and/or glial remodeling including changes in macromolecular content may underlie the gray matter alterations observed in anorexia nervosa. Copyright © 2016 Elsevier Inc. All rights reserved.

Immediate and extended effects of sodium lauryl sulphate exposure on stratum corneum natural moisturizing factor.

PubMed

Hoffman, D R; Kroll, L M; Basehoar, A; Reece, B; Cunningham, C T; Koenig, D W

2014-02-01

Natural moisturizing factor (NMF) serves as the primary humectant of the stratum corneum (SC), principally comprised of hygroscopic amino acids and derivatives that absorb moisture. Barrier disruption has been shown to differentially affect the levels of specific NMF components, though the kinetics of NMF component restoration following disruption have not been examined. Here, we investigated the impact of barrier disruption caused by surfactant exposure on a subset of NMF components immediately following exposure and out to 10 days post-exposure. Volunteers wore patches containing either 1% w/v sodium lauryl sulphate (SLS) or distilled water on their forearms for 24 h. Measurements of transepidermal water loss, erythema, SC water content and a subset of SC NMF and lipid components were obtained at both sites before treatment, the day of patch removal, and 1, 2, 3, 6, and 10 days following treatment. Most measured NMF components decreased in response to SLS exposure. Exceptions were increases in lactate, ornithine and urea, and no difference in proline levels. In the days following exposure, reduced levels of several NMF components continued at the SLS site; however, all measured NMF components demonstrated equivalence to the vehicle control within 10 days. Histidine pH 7, lactate, ornithine and urea were the first to achieve levels equivalent to the vehicle control site, normalizing within 1 day after patch removal. Results imply that NMF components derived from sweat and urea cycling are least impacted by SLS exposure whereas NMF components derived from degradation of filaggrin and/or other S-100 proteins are most impacted. This implies the restoration of the processes responsible for S-100 protein processing into free amino acids takes several days to return to normal. Further examination of the enzymes involved in S-100 protein processing following barrier disruption would provide insight into the pathway(s) for NMF restoration during SC recovery. © 2013 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Dysfunction of protein kinase FA/GSK-3 alpha in lymphocytes of patients with schizophrenic disorder.

PubMed

Yang, S D; Yu, J S; Lee, T T; Yang, C C; Ni, M H; Yang, Y Y

1995-09-01

As compared to normal people, the lymphocytes of patients with schizophrenia were found to have an impairment of ATP.Mg-dependent protein phosphatase activation. More importantly, the impaired protein phosphatase activation in the lymphocytes of schizophrenic patients could be consistently and completely restored to normal by exogenous pure protein kinase FA/glycogen synthase kinase-3 alpha (kinase FA/GSK-3 alpha) (the activating factor of ATP.Mg-dependent protein phosphatase), indicating that the molecular mechanism for the impaired protein phosphatase activation in schizophrenic patients may be due to a functional loss of kinase FA/GSK-3 alpha. Immunoblotting and kinase activity analysis in an anti-kinase FA/GSK-3 alpha immunoprecipitate further demonstrate that both cellular activities and protein levels of kinase FA/GSK-3 alpha in the lymphocytes of schizophrenic patients were greatly impared as compared to normal controls. Statistical analysis revealed that the lymphocytes isolated from 37 normal people contain kinase FA/GSK-3 alpha activity in the high levels of 14.8 +/- 2.4 units/mg of cell protein, whereas the lymphocytes of 48 patients with schizophrenic disorder contain kinase FA/GSK-3 alpha activity in the low levels of 2.8 +/- 1.6 units/mg, indicating that the different levels of kinase FA/GSK-3 alpha activity between schizophrenic patients and normal people are statistically significant. Taken together, the results provide initial evidence that patients with schizophrenic disorder may have a common impairment in the protein levels and cellular activities of kinase FA/GSK-3 alpha, a multisubstrate protein kinase and a multisubstrate protein phosphatase activator in their lymphocytes.

Forest restoration and fuels reduction in ponderosa pine and dry mixed conifer in the Southwest

Treesearch

Marlin Johnson

2008-01-01

(Please note, this is an abstract only) Most people agree that ponderosa pine and dry mixed conifer stands need to be thinned and burned to move the stands to within a normal range of variability. Unfortunately, people are in disagreement beyond that point. To some, restoration and fuels reduction means restoring stands to more open, pre-European (pre-1880) conditions...

Extracellular vesicles from human liver stem cells restore argininosuccinate synthase deficiency.

PubMed

Herrera Sanchez, Maria Beatriz; Previdi, Sara; Bruno, Stefania; Fonsato, Valentina; Deregibus, Maria Chiara; Kholia, Sharad; Petrillo, Sara; Tolosano, Emanuela; Critelli, Rossana; Spada, Marco; Romagnoli, Renato; Salizzoni, Mauro; Tetta, Ciro; Camussi, Giovanni

2017-07-27

Argininosuccinate synthase (ASS)1 is a urea cycle enzyme that catalyzes the conversion of citrulline and aspartate to argininosuccinate. Mutations in the ASS1 gene cause citrullinemia type I, a rare autosomal recessive disorder characterized by neonatal hyperammonemia, elevated citrulline levels, and early neonatal death. Treatment for this disease is currently restricted to liver transplantation; however, due to limited organ availability, substitute therapies are required. Recently, extracellular vesicles (EVs) have been reported to act as intercellular transporters carrying genetic information responsible for cell reprogramming. In previous studies, we isolated a population of stem cell-like cells known as human liver stem cells (HLSCs) from healthy liver tissue. Moreover, EVs derived from HLSCs were reported to exhibit regenerative effects on the liver parenchyma in models of acute liver injury. The aim of this study was to evaluate whether EVs derived from normal HLSCs restored ASS1 enzymatic activity and urea production in hepatocytes differentiated from HLSCs derived from a patient with type I citrullinemia. HLSCs were isolated from the liver of a patient with type I citrullinemia (ASS1-HLSCs) and characterized by fluorescence-activated cell sorting (FACS), immunofluorescence, and DNA sequencing analysis. Furthermore, their differentiation capabilities in vitro were also assessed. Hepatocytes differentiated from ASS1-HLSCs were evaluated by the production of urea and ASS enzymatic activity. EVs derived from normal HLSCs were purified by differential ultracentrifugation followed by floating density gradient. The EV content was analyzed to identify the presence of ASS1 protein, mRNA, and ASS1 gene. In order to obtain ASS1-depleted EVs, a knockdown of the ASS1 gene in HLSCs was performed followed by EV isolation from these cells. Treating ASS1-HLSCs with EVs from HLSCs restored both ASS1 activity and urea production mainly through the transfer of ASS1 enzyme and mRNA. In fact, EVs from ASS1-knockdown HLSCs contained low amounts of ASS1 mRNA and protein, and were unable to restore urea production in hepatocytes differentiated from ASS1-HLSCs. Collectively, these results suggest that EVs derived from normal HLSCs may compensate the loss of ASS1 enzyme activity in hepatocytes differentiated from ASS1-HLSCs.

A Full Snow Season in Yellowstone: A Database of Restored Aqua Band 6

NASA Technical Reports Server (NTRS)

Gladkova, Irina; Grossberg, Michael; Bonev, George; Romanov, Peter; Riggs, George; Hall, Dorothy

2013-01-01

The algorithms for estimating snow extent for the Moderate Resolution Imaging Spectroradiometer (MODIS) optimally use the 1.6- m channel which is unavailable for MODIS on Aqua due to detector damage. As a test bed to demonstrate that Aqua band 6 can be restored, we chose the area surrounding Yellowstone and Grand Teton national parks. In such rugged and difficult-to-access terrain, satellite images are particularly important for providing an estimation of snow-cover extent. For the full 2010-2011 snow season covering the Yellowstone region, we have used quantitative image restoration to create a database of restored Aqua band 6. The database includes restored radiances, normalized vegetation index, normalized snow index, thermal data, and band-6-based snow-map products. The restored Aqua-band-6 data have also been regridded and combined with Terra data to produce a snow-cover map that utilizes both Terra and Aqua snow maps. Using this database, we show that the restored Aqua-band-6-based snow-cover extent has a comparable performance with respect to ground stations to the one based on Terra. The result of a restored band 6 from Aqua is that we have an additional band-6 image of the Yellowstone region each day. This image can be used to mitigate cloud occlusion, using the same algorithms used for band 6 on Terra. We show an application of this database of restored band-6 images to illustrate the value of creating a cloud gap filling using the National Aeronautics and Space Administration s operational cloud masks and data from both Aqua and Terra.

Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction.

PubMed

Joseph, Gregory; Soler, Amanda; Hutcheson, Rebecca; Hunter, Ian; Bradford, Chastity; Hutcheson, Brenda; Gotlinger, Katherine H; Jiang, Houli; Falck, John R; Proctor, Spencer; Schwartzman, Michal Laniado; Rocic, Petra

2017-03-01

Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of MetS (JCR) completely restored and neutrophil depletion significantly improved CCG. We determined whether low endogenous levels of miR-145 in MetS allowed for elevated production of 20-hydroxyeicosatetraenoic acid (20-HETE), which, in turn, resulted in excessive neutrophil accumulation and endothelial dysfunction leading to impaired CCG. Rats underwent 0-9 days of repetitive ischemia (RI). RI-induced cardiac CYP4F (neutrophil-specific 20-HETE synthase) expression and 20-HETE levels were increased (4-fold) in JCR vs. normal rats. miR-145-Adv and 20-HETE antagonists abolished and neutrophil depletion (blocking antibodies) reduced (~60%) RI-induced increases in CYP4F expression and 20-HETE production in JCR rats. Impaired CCG in JCR rats (collateral-dependent blood flow using microspheres) was completely restored by 20-HETE antagonists [collateral-dependent zone (CZ)/normal zone (NZ) flow ratio was 0.76 ± 0.07 in JCR + 20-SOLA, 0.84 ± 0.05 in JCR + 20-HEDGE vs. 0.11 ± 0.02 in JCR vs. 0.84 ± 0.03 in normal rats]. In JCR rats, elevated 20-HETE was associated with excessive expression of endothelial adhesion molecules and neutrophil infiltration, which were reversed by miR-145-Adv. Endothelium-dependent vasodilation of coronary arteries, endothelial nitric oxide synthase (eNOS) Ser1179 phosphorylation, eNOS-dependent NO ·- production and endothelial cell survival were compromised in JCR rats. These parameters of endothelial dysfunction were completely reversed by 20-HETE antagonism or miR-145-Adv delivery, whereas neutrophil depletion resulted in partial reversal (~70%). We conclude that low miR-145 in MetS allows for increased 20-HETE, mainly from neutrophils, which compromises endothelial cell survival and function leading to impaired CCG. 20-HETE antagonists could provide viable therapy for restoration of CCG in MetS. NEW & NOTEWORTHY Elevated 20-hydroxyeicosatetraenoic acid (20-HETE) impairs coronary collateral growth (CCG) in metabolic syndrome by eliciting endothelial dysfunction and apoptosis via excessive neutrophil infiltration. 20-HETE antagonists completely restore coronary collateral growth in metabolic syndrome. microRNA-145 (miR-145) is an upstream regulator of 20-HETE production in metabolic syndrome; low expression of miR-145 in metabolic syndrome promotes elevated production of 20-HETE. Copyright © 2017 the American Physiological Society.

Effect of zinc supplementation on the status of thyroid hormones and Na, K, And Ca levels in blood following ethanol feeding.

PubMed

Pathak, R; Dhawan, D; Pathak, A

2011-05-01

The influence of zinc (Zn) on the serum levels of triiodothyronine (T(3)), thyroxine (T(4)), thyroid-stimulating hormone (TSH) and sodium (Na), potassium (K), and calcium (Ca) was evaluated following ethanol toxicity to the rats. To achieve this, male Wistar rats (150-195 g) were given 3 ml of 30% ethanol orally, and zinc was given in the form of zinc sulfate (227 mg/l) in their drinking water daily for 8 weeks. Ethanol feeding resulted in a slight decrease in T(3) and T(4) levels and a significant increase in thyroid-stimulating hormone concentration, which may be due to the direct stimulatory effect of ethanol on thyroid. Interestingly, when zinc was given to these rats, all the above levels were brought quite close to their normal levels, thus indicating the positive role of zinc in thyroid hormone metabolism. Serum Zn and Ca levels were found to be reduced, but Na levels were raised upon ethanol feeding. Restoration of normal levels of these metals upon zinc supplementation to ethanol fed rats confirms that zinc has potential in alleviating some of the altered thyroid functions following ethanol administration.

Hypercorticism blunts circadian variations of osteocalcin regardless of nutritional status.

PubMed

Vergély, N; Lafage-Proust, M-H; Caillot-Augusseau, A; Millot, L; Lang, F; Estour, B

2002-02-01

Anorexia nervosa (AN) and Cushing's syndrome (CS) are both responsible for osteoporosis. The mechanisms leading to osteoporosis in AN include hypogonadism, nutritional depletion, and in some cases hypercorticism. Osteocalcin circulating level is a serum marker of osteoblastic activity that follows a circadian rhythm (OCR). Serum osteocalcin is decreased in both CS and AN and can be increased with treatment. In this study we analyzed the influence of combined cortisol and nutritional status on osteocalcin levels and its circadian rhythm in these two different models of hypercorticism, one nutritionally replete (CS) and one nutritionally deplete (AN), and we evaluated the effects of their treatment (surgical cure and weight gain, respectively). Before treatment, osteocalcin levels were lower in CS (n = 16) and AN (n = 42) than in controls and in the AN patient subgroup with hypercorticism (n = 13) compared to those without (n = 29). OCR was absent in CS and in AN patients with hypercorticism, whereas their circadian cortisol cycle was maintained. In CS, successful surgical treatment increased osteocalcin levels (n = 5) and restored OCR. In AN, weight gain (n = 13) induced a significant decrease in cortisol levels in hypercortisolic AN patients, and restored normal osteocalcin levels and OCR. In conclusion, we found that hypercorticism was associated with a decrease in osteocalcin levels in nutritionally replete or deplete patients and that OCR was more affected by cortisol levels than by cortisol cycle.

Albumin-induced apoptosis of glomerular parietal epithelial cells is modulated by extracellular signal-regulated kinase 1/2

PubMed Central

Ohse, Takamoto; Krofft, Ron D.; Wu, Jimmy S.; Eddy, Allison A.; Pippin, Jeffrey W.; Shankland, Stuart J.

2012-01-01

Background. The biological role(s) of glomerular parietal epithelial cells (PECs) is not fully understood in health or disease. Given its location, PECs are constantly exposed to low levels of filtered albumin, which is increased in nephrotic states. We tested the hypothesis that PECs internalize albumin and increased uptake results in apoptosis. Methods. Confocal microscopy of immunofluorescent staining and immunohistochemistry were used to demonstrate albumin internalization in PECs and to quantitate albumin uptake in normal mice and rats as well as experimental models of membranous nephropathy, minimal change disease/focal segmental glomerulosclerosis and protein overload nephropathy. Fluorescence-activated cell sorting analysis was performed on immortalized cultured PECs exposed to fluorescein isothiocyanate (FITC)-labeled albumin in the presence of an endosomal inhibitor or vehicle. Apoptosis was measured by Hoechst staining in cultured PECs exposed to bovine serum albumin. Levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) were restored by retroviral infection of mitogen-activated protein kinase (MEK) 1/2 and reduced by U0126 in PECs exposed to high albumin levels in culture and apoptosis measured by Hoechst staining. Results. PECs internalized albumin normally, and this was markedly increased in all of the experimental disease models (P < 0.05 versus controls). Cultured immortalized PECs also internalize FITC-labeled albumin, which was reduced by endosomal inhibition. A consequence of increased albumin internalization was PEC apoptosis in vitro and in vivo. Candidate signaling pathways underlying these events were examined. Data showed markedly reduced levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2) in PECs exposed to high albumin levels in nephropathy and in culture. A role for ERK1/2 in limiting albumin-induced apoptosis was shown by restoring p-ERK1/2 by retroviral infection, which reduced apoptosis in cultured PECs, while a forced decrease of p-ERK1/2 through inhibition of MEK 1/2 significantly increased albumin-induced PEC apoptosis. Conclusions. A normal role of PECs is to take up filtered albumin. However, this is increased in proteinuric glomerular diseases, leading to apoptosis through changes in ERK1/2. PMID:21896500

Rehydration beverage

NASA Technical Reports Server (NTRS)

Greenleaf, John E. (Inventor)

1995-01-01

A novel rehydration beverage containing sodium chloride, sodium citrate, and aspartame useful for rapid restoration of hydration homeostasis is disclosed. The beverage is particularly useful for restoration of normal body fluid volumes and their intracellular and extracellular distribution during a hypohydration state observed in astronauts and air passengers.

Circadian hormone profiles and insulin sensitivity in patients with Addison's disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy.

PubMed

Björnsdottir, Sigridur; Øksnes, Marianne; Isaksson, Magnus; Methlie, Paal; Nilsen, Roy M; Hustad, Steinar; Kämpe, Olle; Hulting, Anna-Lena; Husebye, Eystein S; Løvås, Kristian; Nyström, Thomas; Bensing, Sophie

2015-07-01

Conventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). The aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. An open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. Ten Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. Thrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. We measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. Continuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. Continuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD. © 2015 John Wiley & Sons Ltd.

In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation

PubMed Central

Coffee, R. Lane; Williamson, Ashley J.; Adkins, Christopher M.; Gray, Marisa C.; Page, Terry L.; Broadie, Kendal

2012-01-01

Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior. PMID:22080836

Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.

PubMed

Sippel, Trisha R; White, Jason; Nag, Kamalika; Tsvankin, Vadim; Klaassen, Marci; Kleinschmidt-DeMasters, B K; Waziri, Allen

2011-11-15

The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM. Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.

THE REGENERATIVE CYCLE OF MOTONEURONS, WITH SPECIAL REFERENCE TO PHOSPHATASE ACTIVITY.

PubMed

Bodian, D; Mellors, R C

1945-05-01

1. The regenerative cycle of motoneurons after axon amputation is described, and an attempt made to correlate morphological and chemical events in cell bodies with the growth requirements of regenerating axons. 2. The "normal" pattern of Nissl material in the cell is considered to be the resultant of a steady state in cytoplasmic nucleoprotein. Chromatol is then interpreted as a shift of the balance of nucleoprotein turnover in fa of degradation. The rapid early depletion of Nissl substance in chromatolysis is ascribed to the increased growth requirements created by the active early sprouting of the regenerating axon. Acid phosphatase activity begins to increase above normal levels during this period in the region of nucleopro degradation. 3. The recovery period of chromatolysis due to axon section coincide in time with the phase of gradual lengthening of the regenerating axon, and is thought to represent a gradual restoration of the balance of nucleoprotein degradation and synthesis. During this period acid phosphatase activity is at its height in the region of transformation of Nissl substance, later declines to normal levels when the original pattern of Nissl bodie is restored. 4. The transformation of cytoplasmic nucleoprotein which occurs in chromatolysis after axon section, with the probable liberation (46), and depletion (44), of nucleotides, associated with acid phosphatase activity, suggests the hypothesis that liberated nucleotides or nucleotide compounds may pass down the axon in which they take part in enzymatic activity associated with growth and organization of the newly formed axon. This type of activity would not be incompatible with the ideas previously expressed (30, 81) of a continual function of Nissl substance in maintaining the integrity of the large volume of cytoplasm represented by the axon, as well perhaps as the associated myelin sheath.

[Efficacy of highly active antiretroviral therapy for childhood acquired immunodeficiency syndrome].

PubMed

Hao, Jin-Li; Wang, Bao-Jin; Baptiste, Jean

2010-11-01

To investigate the efficacy of highly active antiretroviral therapy (HAART) for acquired immunodeficiency syndrome (AIDS) in children. The clinical data of 38 children (2-15 years old) with AIDS from a region of Rwanda and who had received HAART were retrospectively reviewed. All of 13 children with anemia showed improved anemia symptoms after HAART. The hemoglobin contents returned to normal levels in 12 children with mild or moderate anemia. CD4 T lymphocytes increased by 24%-1 181% in 5 out of 6 cases with severe immunodeficiency after HAART. During the HAART, the weight gain averaged 2.3 kg yearly. The growth and development in 5 out of 8 children with delayed growth restored the levels of normal children of the same age after HAART. HAART can improve the health status in children with AIDS and is effective for childhood AIDS.

Using motor behavior during an early critical period to restore skilled limb movement after damage to the corticospinal motor system during development

PubMed Central

Friel, KM; Chakrabarty, S; H-C, Kuo; Martin, JH

2012-01-01

This study investigated requirements for restoring motor function after corticospinal (CS) system damage during early postnatal development. Activity-dependent competition between the CS tracts (CST) of the two hemispheres is imperative for normal development. Blocking primary motor cortex (M1) activity unilaterally during a critical period (postnatal weeks-PW-5–7) produces permanent contralateral motor skill impairments, loss of M1 motor map, aberrant CS terminations, and decreases in CST presynaptic sites and spinal cholinergic interneuron numbers. To repair these motor systems impairments and restore function, we manipulated motor experience in three groups of cats after this CST injury produced by inactivation. One group wore a jacket restraining the limb ipsilateral to inactivation, forcing use of the contralateral, impaired, limb, for the month following M1 inactivation (PW8–13; “Restraint Alone”). A second group wore the restraint during PW8–13, and was also trained for 1 h/day in a reaching task with the contralateral forelimb (“Early Training”). To test the efficacy of intervention during adolescence, a third group wore the restraint and received reach training during PW20–24 (“Delayed Training”). Early training restored CST connections and the M1 motor map; increased cholinergic spinal interneurons numbers on the contralateral, relative to ipsilateral, side; and abrogated limb control impairments. Delayed training restored CST connectivity and the M1 motor map, but not contralateral spinal cholinergic cell counts or motor performance. Restraint alone only restored CST connectivity. Our findings stress the need to reestablish the integrated functions of the CS system at multiple hierarchical levels in restoring skilled motor function after developmental injury. PMID:22764234

Predicting strain using forward modelling of restored cross-sections: Application to rollover anticlines over listric normal faults

NASA Astrophysics Data System (ADS)

Poblet, Josep; Bulnes, Mayte

2007-12-01

A strategy to predict strain across geological structures, based on previous techniques, is modified and evaluated, and a practical application is shown. The technique, which employs cross-section restoration combined with kinematic forward modelling, consists of restoring a section, placing circular strain markers on different domains of the restoration, and forward modelling the restored section with strain markers until the present-day stage is reached. The restoration algorithm employed must be also used to forward model the structure. The ellipses in the forward modelled section allow determining the strain state of the structure and may indirectly predict orientation and distribution of minor structures such as small-scale fractures. The forward model may be frozen at different time steps (different growth stages) allowing prediction of both spatial and temporal variation of strain. The method is evaluated through its application to two stages of a clay experiment, that includes strain markers, and its geometry and deformation history are well documented, providing a strong control on the results. To demonstrate the method's potential, it is successfully applied to a depth-converted seismic profile in the Central Sumatra Basin, Indonesia. This allowed us to gain insight into the deformation undergone by rollover anticlines over listric normal faults.

Nephro-protective action of P. santalinus against alcohol-induced biochemical alterations and oxidative damage in rats.

PubMed

Bulle, Saradamma; Reddy, Vaddi Damodara; Hebbani, Ananda Vardhan; Padmavathi, Pannuru; Challa, Chandrasekhar; Puvvada, Pavan Kumar; Repalle, Elisha; Nayakanti, Devanna; Aluganti Narasimhulu, Chandrakala; Nallanchakravarthula, Varadacharyulu

2016-12-01

The present study investigated the antioxidant potential of P. santalinus heartwood methanolic extract (PSE) against alcohol-induced nephro-toxicity. The results indicated an increase in the concentration of kidney damage plasma markers, urea and creatinine with a concomitant decrease in the concentration of uric acid in alcohol-administered rats. A significant decrease in plasma electrolytes and mineral levels with increased kidney thiobarbituric acid reactive substances (TBARS) and nitric oxide (NOx) levels was also observed. PSE treatment to alcohol-administered rats effectively prevented the elevation in TBARS and NOx levels. Decreased activity of Na + /K + -ATPase in alcohol administered rats was brought to near normal levels with treatment of PSE. Chronic alcohol consumption affects antioxidant enzymatic activity and reabsorption function of the kidney which is evident from the decreased level of GSH as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione s-transferase (GST). However, treatment with PSE to alcohol-administered rats significantly enhanced these enzymatic activities and reduced glutathione (GSH) content close to normal level. Alcohol-induced organ damage was evident from morphological changes in the kidney. Nevertheless, administration of PSE effectively restored these morphological changes to normal. The flavonoid and tannoid compounds might have protective activity against alcohol-induced oxidative/nitrosative stress mediated kidney damage. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Lack of soluble TNF-receptors in women with recurrent spontaneous abortion and possibility for its correction.

PubMed

Chernyshov, Victor P; Vodyanik, Maxim A; Pisareva, Svetlana P

2005-11-01

Tumor necrosis factor (TNF) and soluble TNF receptors (sTNF-Rs) system related with Th1 and Th2 and activity of NF-kappaB/IkappaB regulatory system. This study was designed to compare sTNF-R1 and sTNF-R2 production (shedding) and levels of late activated CD8+ T-lymphocytes in non-pregnant (n = 30) and pregnant (n = 20) normal women and non-pregnant (n = 20) and pregnant (n = 30) RSA women. Effects of progesterone (natural structure) injections in RSA women were studied. Levels of sTNF-R1, sTNF-R2, TNF in peripheral blood serum were detected by enzyme-linked immunosorbent assay. Lymphocyte subsets were estimated by multicolor flow cytometry. NK cell cytotoxic activity of peripheral blood lymphocytes (PBL) in whole blood against K562 targets was determined using Europium-release cytotoxicity assay. Mitogen-induced proliferative response of PBL to PHA-P, Con A and PWM were determined by standard 3H-thymidine incorporation assay. Levels of soluble TNF-R1 and TNF-R2 in normal pregnancy were elevated when compared with non-pregnant normal women and pregnant RSA women. Levels of late activated CD8+ T-lymphocytes in normal pregnancy were decreased but no changes were detected in RSA women. After progesterone therapy (i.m. injections of 2.5% oil solution) in RSA women elevation of sTNF-R1 and sTNF-R2 to normal pregnancy ranges was observed. No changes in levels of late activated CD8+ T-lymphocytes after progesterone treatment were detected. Elevation of levels of sTNF-R1, sTNF-R2 and decrease of late activated cytotoxic T-lymphocytes are pronounce markers of normal human pregnancy. In RSA women there are no elevation of sTNF-R1 and sTNF-R2 levels during pregnancy. This deficiency may be restored by progesterone treatment.

Anti-stress effects of cilnidipine and nimodipine in immobilization subjected mice.

PubMed

Kumar, Naresh; Singh, Nirmal; Jaggi, Amteshwar Singh

2012-03-20

The present study was designed to investigate the ameliorative role of cilnidipine and nimodipine in immobilization stress-induced behavioral alterations and memory defects in the mice. Acute stress was induced by immobilizing the mice for 150 min and stress-induced behavioral changes were assessed using actophotometer, hole board, open field and social interaction tests. The learning and memory was evaluated using elevated plus maze tests and biochemically, the corticosterone levels were measured in the blood serum. Acute immobilization stress resulted in decrease in locomotor activity, frequency of head dips and rearings in hole board; line crossing and rearing in the open field; increase in avoidance in social behavior along with development of memory deficits assessed by an increased transfer latency time and elevation of the corticosterone levels. Administration of cilnidipine (10 mg/kg), an L and N-type dual calcium channel blocker, and nimodipine (10 mg/kg), an L-type calcium channel blocker, significantly attenuated the immobilized stress-induced behavioral changes and restored memory deficits along with normalization of the corticosterone levels. Cilnidipine and nimodipine produced comparable beneficial effects in restoring immobilization stress subjected mice. It may be concluded that cilnidipine and nimodipine mediated attenuation of corticosterone release by blockage of calcium channels (both L and N-type) on the HPA-axis is responsible for beneficial effects in restoration of behavioral alterations and memory deficits in immobilization-induced acute stress in mice. Copyright © 2011 Elsevier Inc. All rights reserved.

Oral administration of antioxidants improves skin wound healing in diabetic mice.

PubMed

Pessoa, Ana Flávia Marçal; Florim, Juliana Costa; Rodrigues, Hosana Gomes; Andrade-Oliveira, Vinicius; Teixeira, Simone A; Vitzel, Kaio Fernando; Curi, Rui; Saraiva Câmara, Niels Olsen; Muscará, Marcelo N; Lamers, Marcelo Lazzaron; Santos, Marinilce Fagundes

2016-11-01

Oxidative stress aggravates several long-term complications in diabetes mellitus. We evaluated the effectiveness of the oral administration of antioxidants (vitamins E and C, 40 and 100 mg/kg b.w., respectively) on skin wound healing acceleration in alloxan-induced diabetic mice. Mice were wounded 30 days after the induction of diabetes. Antioxidants were effective in preventing oxidative stress, as assessed by TBARS. The enzymes catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase were increased in diabetics on the 3rd day post-wounding; catalase and glutathione peroxidase remained still augmented in diabetics after 14th day postwounding, and the treatment with vitamins restored their activities to control. After 3 days, diabetic mice showed lower infiltration of inflammatory cells (including CD11b + and Ly6G + cells) and reduced levels of KC, TNF-α, IL-1β, and IL-12 p40 when compared with control mice. The treatment restored cytokine levels. After 14 days, diabetic mice showed late wound closure, persistent inflammation and delayed reepithelialization, accompanied by an increase in MIG + /CD206 - macrophages whereas CD206 + /MIG - macrophages were decreased. Cytokines IL-12p40, TNF-α, IL-1β, and KC were increased and normal levels were restored after treatment with antioxidants. These results suggest that oxidative stress plays a major role in diabetic wound healing impairment and the oral administration of antioxidants improves healing by modulating inflammation and the antioxidant system with no effect on glycemia. © 2016 by the Wound Healing Society.

Recycling energy to restore impaired ankle function during human walking.

PubMed

Collins, Steven H; Kuo, Arthur D

2010-02-17

Humans normally dissipate significant energy during walking, largely at the transitions between steps. The ankle then acts to restore energy during push-off, which may be the reason that ankle impairment nearly always leads to poorer walking economy. The replacement of lost energy is necessary for steady gait, in which mechanical energy is constant on average, external dissipation is negligible, and no net work is performed over a stride. However, dissipation and replacement by muscles might not be necessary if energy were instead captured and reused by an assistive device. We developed a microprocessor-controlled artificial foot that captures some of the energy that is normally dissipated by the leg and "recycles" it as positive ankle work. In tests on subjects walking with an artificially-impaired ankle, a conventional prosthesis reduced ankle push-off work and increased net metabolic energy expenditure by 23% compared to normal walking. Energy recycling restored ankle push-off to normal and reduced the net metabolic energy penalty to 14%. These results suggest that reduced ankle push-off contributes to the increased metabolic energy expenditure accompanying ankle impairments, and demonstrate that energy recycling can be used to reduce such cost.

On the effects of leaflet microstructure and constitutive model on the closing behavior of the mitral valve

PubMed Central

Lee, Chung-Hao; Rabbah, Jean-Pierre; Yoganathan, Ajit P.; Gorman, Robert C.; Gorman, Joseph H.

2016-01-01

Recent long-term studies showed an unsatisfactory recurrence rate of severe mitral regurgitation 3–5 years after surgical repair, suggesting that excessive tissue stresses and the resulting strain-induced tissue failure are potential etiological factors controlling the success of surgical repair for treating mitral valve (MV) diseases. We hypothesized that restoring normal MV tissue stresses in MV repair techniques would ultimately lead to improved repair durability through the restoration of MV normal homeostatic state. Therefore, we developed a micro- and macro- anatomically accurate MV finite element model by incorporating actual fiber microstructural architecture and a realistic structure-based constitutive model. We investigated MV closing behaviors, with extensive in vitro data used for validating the proposed model. Comparative and parametric studies were conducted to identify essential model fidelity and information for achieving desirable accuracy. More importantly, for the first time, the interrelationship between the local fiber ensemble behavior and the organ-level MV closing behavior was investigated using a computational simulation. These novel results indicated not only the appropriate parameter ranges, but also the importance of the microstructural tuning (i.e., straightening and re-orientation) of the collagen/elastin fiber networks at the macroscopic tissue level for facilitating the proper coaptation and natural functioning of the MV apparatus under physiological loading at the organ level. The proposed computational model would serve as a logical first step toward our long-term modeling goal—facilitating simulation-guided design of optimal surgical repair strategies for treating diseased MVs with significantly enhanced durability. PMID:25947879

Steam plant startup and control in system restoration

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

Mello, F.P. de; Westcott, J.C.

1994-02-01

The IEEE Working Group on Power System Restoration developed a panel session for the Summer Power Meeting on July 14, 1992 on Special Considerations in Power System Restoration. One of the contributions to this session is presented in this paper dealing with aspects of steam plant startup and control in scenarios of system restoration. The topics addressed include the complexity of a steam plant, the contrast between normal plant startups and shutdowns and those following major system blackouts including the effects of plant design, automatic controls, bypass valving and operator training.

Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors.

PubMed Central

Rana, B; Mischoulon, D; Xie, Y; Bucher, N L; Farmer, S R

1994-01-01

Previous investigations have shown that culture of freshly isolated hepatocytes under conventional conditions, i.e., on dried rat tail collagen in the presence of growth factors, facilitates cell growth but also causes an extensive down-regulation of most liver-specific functions. This dedifferentiation process can be prevented if the cells are cultured on a reconstituted basement membrane gel matrix derived from the Englebreth-Holm-Swarm mouse sarcoma tumor (EHS gel). To gain insight into the mechanisms regulating this response to extracellular matrix, we are analyzing the activities of two families of transcription factors, C/EBP and AP-1, which control the transcription of hepatic and growth-responsive genes, respectively. We demonstrate that isolation of hepatocytes from the normal quiescent rat liver by collagenase perfusion activates the immediate-early growth response program, as indicated by increased expression of c-jun, junB, c-fos, and c-myc mRNAs. Adhesion of these activated cells to dried rat tail collagen augments the elevated levels of these mRNAs for the initial 1 to 2 h postplating; junB and c-myc mRNA levels then drop steeply, with junB returning to normal quiescence and the c-myc level remaining slightly elevated during the 3-day culture period. Levels of c-jun mRNA and AP-1 DNA binding activity, however, remain elevated from the outset, while C/EBP alpha mRNA expression is down-regulated, resulting in a decrease in the steady-state levels of the 42- and 30-kDa C/EBP alpha polypeptides and C/EBP alpha DNA binding activity. In contrast, C/EBP beta mRNA production remains at near-normal hepatic levels for 5 to 8 days of culture, although its DNA binding activity decreases severalfold during this time. Adhesion of hepatocytes to the EHS gel for the same period of time dramatically alters this program: it arrests growth and inhibits AP-1 DNA binding activity and the expression of c-jun, junB, and c-myc mRNAs, but, in addition, it restores C/EBP alpha mRNA and protein as well as C/EBP alpha and C/EBP beta DNA binding activities to the abundant levels present in freshly isolated hepatocytes. These changes are not due merely to growth inhibition, because suppression of hepatocyte proliferation on collagen by epidermal growth factor starvation or addition of transforming growth factor beta does not inhibit AP-1 activity or restore C/EBP alpha DNA binding activity to normal hepatic levels. These data suggest that expression of the normal hepatic phenotype requires that hepatocytes exist in a G0 state of growth arrest, facilitated here by adhesion of cells to the EHS gel, in order to express high levels of hepatic transcription factors such as C/EBP alpha. Images PMID:8065319

Experience-Dependent Color Constancy in Guppies (Poecilia reticulata)

PubMed Central

Intskirveli, I. E.; Roinishvili, M. O.; Kezeli, A. R.

2002-01-01

We investigated the ability to recognize the color of surfaces in fish (Poecilia reticulata), bred from birth in conditions of artificial light with constant spectral content. The capacity for color constancy significantly deteriorated when compared that to the control group. Further alteration of lighting conditions and transfer into natural daylight conditions restored the suppressed function to its normal level. We suggest that the color constancy function belongs in the visual system-response functions, the full development of which requires the accumulation of individual visual experience. PMID:12757371

Experience-dependent color constancy in guppies (Poecilia reticulata).

PubMed

Intskirveli, I E; Roinishvili, M O; Kezeli, A R

2002-01-01

We investigated the ability to recognize the color of surfaces in fish (Poecilia reticulata), bred from birth in conditions of artificial light with constant spectral content. The capacity for color constancy significantly deteriorated when compared that to the control group. Further alteration of lighting conditions and transfer into natural daylight conditions restored the suppressed function to its normal level. We suggest that the color constancy function belongs in the visual system-response functions, the full development of which requires the accumulation of individual visual experience.

Association between neuroendocrinological parameters and learning and memory functions in adolescent anorexia nervosa before and after weight recovery.

PubMed

Buehren, Katharina; Konrad, Kerstin; Schaefer, Kerstin; Kratzsch, Juergen; Kahraman-Lanzerath, Berak; Lente, Christina; Herpertz-Dahlmann, Beate

2011-06-01

A growing body of evidence indicates that hormones play an important role in learning and memory functions as well as in mood modulation. During the acute stage of anorexia nervosa (AN), weight loss has a significant effect on serum levels of estrogen, thyroid hormones, and cortisol. Furthermore deficits in learning and memory functions are evident in patients with eating disorders during emaciation. Hormonal and neuropsychological alterations at least partly remit during weight restoration. We investigated the association between learning and memory functions as well as mood and neuroendocrinological parameters before and after weight gain in adolescent AN. Twenty-eight female subjects with AN, diagnosed according to DSM-IV, were examined before and after weight recovery. Both investigations took place while the patients were receiving hospital treatment, and the results were compared to a control group consisting of 18 age- and IQ-matched normal-weight female adolescents also tested twice within 4 months. Verbal memory and learning were assessed by a German paper-pencil-test (LGT). We performed correlation calculations between neuropsychological functions and depressive symptoms and estrogen, cortisol and free triiodothyronine (fT₃) in the plasma at both time points. Compared to normal controls adolescents with AN performed worse in one subtest of the LGT which requires the verbal reproduction of figural material across both time points. Verbal learning was positively correlated with estrogen levels after weight recovery. Depressive symptoms of AN patients significantly decreased during weight rehabilitation and correlated negatively with fT₃ at T₁. We did not find a relationship between cortisol levels and neuropsychological functions. We observed subtle memory impairments and depressive symptoms in subjects with adolescent AN associated with starvation-induced estrogen and triiodothyronine deficits, respectively. Normalization of body weight and resuming of menses is needed to restore learning and memory functions as well as to alleviate depressive symptoms.

Reverse Engineering Nature to Design Biomimetic Total Knee Implants.

PubMed

Varadarajan, Kartik Mangudi; Zumbrunn, Thomas; Rubash, Harry E; Malchau, Henrik; Muratoglu, Orhun K; Li, Guoan

2015-10-01

While contemporary total knee arthroplasty (TKA) provides tremendous clinical benefits, the normal feel and function of the knee is not fully restored. To address this, a novel design process was developed to reverse engineer "biomimetic" articular surfaces that are compatible with normal soft-tissue envelope and kinematics of the knee. The biomimetic articular surface is created by moving the TKA femoral component along in vivo kinematics of normal knees and carving out the tibial articular surface from a rectangular tibial block. Here, we describe the biomimetic design process. In addition, we utilize geometric comparisons and kinematic simulations to show that; (1) tibial articular surfaces of conventional implants are fundamentally incompatible with normal knee motion, and (2) the anatomic geometry of the biomimetic surface contributes directly to restoration of normal knee kinematics. Such biomimetic implants may enable us to achieve the long sought after goal of a "normal" knee post-TKA surgery. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Planning strategies for development of effective exercise and nutrition countermeasures for long-duration space flight

NASA Technical Reports Server (NTRS)

Convertino, Victor A.

2002-01-01

Exercise and nutrition represent primary countermeasures used during space flight to maintain or restore maximal aerobic capacity, musculoskeletal structure, and orthostatic function. However, no single exercise, dietary regimen, or combination of prescriptions has proven entirely effective in maintaining or restoring cardiovascular and musculoskeletal functions to preflight levels after prolonged space flight. As human space flight exposures increase in duration, identification, assessment, and development of various effective exercise- and nutrition-based protective procedures will become paramount. The application of adequate dietary intake in combination with effective exercise prescription will be based on identification of basic physiologic stimuli that maintain normal function in terrestrial gravity, and understanding how specific combinations of exercise characteristics (e.g., duration, frequency, intensity, and mode) can be combined with minimal nutritional requirements that mimic the stimuli normally produced by living in Earth's gravity environment. This can be accomplished only with greater emphasis of research on ground-based experiments targeted at understanding the interactions between caloric intake and expenditure during space flight. Future strategies for application of nutrition and exercise countermeasures for long-duration space missions must be directed to minimizing crew time and the impact on life-support resources.

Planning strategies for development of effective exercise and nutrition countermeasures for long-duration space flight.

PubMed

Convertino, Victor A

2002-10-01

Exercise and nutrition represent primary countermeasures used during space flight to maintain or restore maximal aerobic capacity, musculoskeletal structure, and orthostatic function. However, no single exercise, dietary regimen, or combination of prescriptions has proven entirely effective in maintaining or restoring cardiovascular and musculoskeletal functions to preflight levels after prolonged space flight. As human space flight exposures increase in duration, identification, assessment, and development of various effective exercise- and nutrition-based protective procedures will become paramount. The application of adequate dietary intake in combination with effective exercise prescription will be based on identification of basic physiologic stimuli that maintain normal function in terrestrial gravity, and understanding how specific combinations of exercise characteristics (e.g., duration, frequency, intensity, and mode) can be combined with minimal nutritional requirements that mimic the stimuli normally produced by living in Earth's gravity environment. This can be accomplished only with greater emphasis of research on ground-based experiments targeted at understanding the interactions between caloric intake and expenditure during space flight. Future strategies for application of nutrition and exercise countermeasures for long-duration space missions must be directed to minimizing crew time and the impact on life-support resources.

The Hypoglycemic and Antioxidant Activity of Cress Seed and Cinnamon on Streptozotocin Induced Diabetes in Male Rats.

PubMed

Qusti, Safaa; El Rabey, Haddad A; Balashram, Sarah A

2016-01-01

The present study aimed to estimate the stimulation of pancreas of rats with streptozotocin induced diabetes using 20% (w/w) garden cress seed (Lepidium sativum) and cinnamon methanol extracts. The positive control diabetic group showed a significant increase in fasting blood sugar, lipid peroxide, interleukin-6, carboxymethyl lysine, serum uric acid, urea, creatinine, immunoglobulins, and urine albumin and a significant decrease in antioxidant enzymes, sodium ions, potassium ions, and urine creatinine. Severe histopathological changes in the kidney and pancreas tissues in hyperglycemic rats were also shown in the positive control diabetic group. Meanwhile, the groups that were treated with 20% garden cress seed and cinnamon methanol extracts showed a significant decrease in fasting blood sugar and all elevated abovementioned biochemical parameters and an increase in the lowered ones restoring them nearly to the normal levels of G1. Kidney and pancreas tissues were also ameliorated and restored nearly to the normal status. Both garden cress seed and cinnamon methanol extracts succeeded in controlling hyperglycemia in rats with streptozotocin induced diabetes and ameliorated the biochemical and histopathological changes because of their antioxidant activity acquired by their possession of phenolic phytochemicals.

Wetland ecosystem health assessment through integrating remote sensing and inventory data with an assessment model for the Hangzhou Bay, China.

PubMed

Sun, Tengteng; Lin, Wenpeng; Chen, Guangsheng; Guo, Pupu; Zeng, Ying

2016-10-01

Due to rapid urbanization, industrialization and population growth, wetland area in China has shrunk rapidly and many wetland ecosystems have been reported to degrade during recent decades. Wetland health assessment could raise the public awareness of the wetland condition and guide policy makers to make reasonable and sustainable policies or strategies to protect and restore wetland ecosystems. This study assessed the health levels of wetland ecosystem at the Hangzhou Bay, China using the pressure-state-response (PSR) model through synthesizing remote sensing and statistical data. Ten ecological and social-economic indicators were selected to build the wetland health assessment system. Weights of these indicators and PSR model components as well as the normalized wetland health score were assigned and calculated based on the analytic hierarchy process (AHP) method. We analyzed the spatio-temporal changes in wetland ecosystem health status during the past 20years (1990-2010) from the perspectives of ecosystem pressure, state and response. The results showed that the overall wetland health score was in a fair health level, but displayed large spatial variability in 2010. The wetland health score declined from good health level to fair health level from 1990 to 2000, then restored slightly from 2000 to 2010. Overall, wetland health levels showed a decline from 1990 to 2010 for most administrative units. The temporal change patterns in wetland ecosystem health varied significantly among administrative units. Our results could help to clarify the administrative responsibilities and obligations and provide scientific guides not only for wetland protection but also for restoration and city development planning at the Hangzhou Bay area. Copyright © 2016 Elsevier B.V. All rights reserved.

Fracture resistance of structurally compromised and normal endodontically treated teeth restored with different post systems: An in vitro study

PubMed Central

Mortazavi, Vajihesadat; Fathi, Mohammadhossein; Katiraei, Najmeh; Shahnaseri, Shirin; Badrian, Hamid; Khalighinejad, Navid

2012-01-01

Background: With the aim of developing methods that could increase the fracture resistance of structurally compromised endodontically treated teeth, this study was conducted to compare the effect of three esthetic post systems on the fracture resistance and failure modes of structurally compromised and normal roots. Materials and Methods: Forty five extracted and endodontically treated maxillary central teeth were assigned to 5 experimental groups (n=9). In two groups, the post spaces were prepared with the corresponding drills of the post systems to be restored with double taper light posts (DT.Light-Post) (group DT.N) and zirconia posts (Cosmopost) (group Zr.N). In other 3 groups thin wall canals were simulated to be restored with Double taper Light posts (DT.W), double taper Light posts and Ribbond fibers (DT+R.W) and Zirconia posts (Zr.W). After access cavity restoration and thermocycling, compressive load was applied and the fracture strength values and failure modes were evaluated. Data were analyzed using two-way ANOVA, Tukey and Fisher exact tests (P<0.05). Results: The mean failure loads (N) were 678.56, 638.22, 732.44, 603.44 and 573.67 for groups DT.N, Zr.N, DT.W, DT+R.W and Zr.w respectively. Group DT+R.W exhibited significantly higher resistance to fracture compared to groups Zr.N, DT.W and Zr.w (P<0.05). A significant difference was detected between groups DT.N and Zr.W (P=0.027). Zirconia posts showed significantly higher root fracture compared to fiber posts (P=0.004). Conclusion: The structurally compromised teeth restored with double taper light posts and Ribbond fibers showed the most fracture resistance and their strengths were comparable to those of normal roots restored with double taper light posts. More desirable fracture patterns were observed in teeth restored with fiber posts. PMID:22623936

Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance.

PubMed

Nakajo, Aya; Khoshnoodi, Jamshid; Takenaka, Hitoshi; Hagiwara, Emi; Watanabe, Takashi; Kawakami, Hayato; Kurayama, Ryota; Sekine, Yuji; Bessho, Fumio; Takahashi, Shori; Swiatecka-Urban, Agnieszka; Tryggvason, Karl; Yan, Kunimasa

2007-09-01

Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.

Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

PubMed Central

Sheweita, Salah A.; El-Hosseiny, Lobna S.; Nashashibi, Munther A.

2016-01-01

Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn’t change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared to control group. In addition, treatment of mice with CP was found to induce the protein expression of CYP 3A4, 2B1/2, 2C6, 2C23. Moreover, the present study showed that essential oils reduced the expression of CYPs 2E1, 3A4 but could not restore the expression of CYP 2C6 and 2C23 compared to CP-treated mice. Interestingly, pretreatment of mice with essential oil of clove was found to restore activities of DMN-dI, AHH, and ECOD which were induced by CP to their normal control levels. It is concluded that EOs showed a marked hepatoprotective effect against hepatotoxicity induced by CP. In addition, co-administration of CP with any of these oils might be used as a new strategy for cancer treatment to alleviate the hepatotoxicity induced by CP. PMID:27802299

Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice.

PubMed

Sheweita, Salah A; El-Hosseiny, Lobna S; Nashashibi, Munther A

2016-01-01

Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn't change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared to control group. In addition, treatment of mice with CP was found to induce the protein expression of CYP 3A4, 2B1/2, 2C6, 2C23. Moreover, the present study showed that essential oils reduced the expression of CYPs 2E1, 3A4 but could not restore the expression of CYP 2C6 and 2C23 compared to CP-treated mice. Interestingly, pretreatment of mice with essential oil of clove was found to restore activities of DMN-dI, AHH, and ECOD which were induced by CP to their normal control levels. It is concluded that EOs showed a marked hepatoprotective effect against hepatotoxicity induced by CP. In addition, co-administration of CP with any of these oils might be used as a new strategy for cancer treatment to alleviate the hepatotoxicity induced by CP.

Functional movement impairment in dancers: An assessment and treatment approach utilizing the Biomechanical Asymmetry Corrector (BAC) to restore normal mechanics of the spine and pelvis.

PubMed

Keller, K; West, J C

1995-01-01

Musculoskeletal injuries to the spine and pelvis are common in dancers. These injuries are associated with mechanical dysfunctions that impair spinal adaptation to the movement demands of the art form. This article introduces the biomechanical asymmetry corrector (BAC), a dynamic assessment and treatment tool, designed to restore normal spinal mechanics and functional movement patterns in dancers. A discussion of lumbo-pelvic mechanics and dance injury provides a theoretical context for describing exercises on the BAC.

Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNΔ7 mouse model of SMA.

PubMed

Iyer, Chitra C; McGovern, Vicki L; Murray, Jason D; Gombash, Sara E; Zaworski, Phillip G; Foust, Kevin D; Janssen, Paul M L; Burghes, Arthur H M

2015-11-01

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by loss of lower motor neurons. SMA is caused by deletion or mutation of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The loss of SMN1 results in reduced levels of the SMN protein. SMN levels appear to be particularly important in motor neurons; however SMN levels above that produced by two copies of SMN2 have been suggested to be important in muscle. Studying the spatial requirement of SMN is important in both understanding how SMN deficiency causes SMA and in the development of effective therapies. Using Myf5-Cre, a muscle-specific Cre driver, and the Cre-loxP recombination system, we deleted mouse Smn in the muscle of mice with SMN2 and SMNΔ7 transgenes in the background, thus providing low level of SMN in the muscle. As a reciprocal experiment, we restored normal levels of SMN in the muscle with low SMN levels in all other tissues. We observed that decreasing SMN in the muscle has no phenotypic effect. This was corroborated by muscle physiology studies with twitch force, tetanic and eccentric contraction all being normal. In addition, electrocardiogram and muscle fiber size distribution were also normal. Replacement of Smn in muscle did not rescue SMA mice. Thus the muscle does not appear to require high levels of SMN above what is produced by two copies of SMN2 (and SMNΔ7). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A framework for rating environmental value of urban parks.

PubMed

Jabben, Jan; Weber, Miriam; Verheijen, Edwin

2015-03-01

In this study, indicators are proposed to characterize the intrinsic environmental properties and external value of urban parks. The intrinsic properties involve both acoustic factors and non-acoustic factors, such as visual aspects and size. To assess external value, the restoration level is defined, which measures the nearby presence of a quiet, 'green' area at residential areas outside parks. The restoration levels of green areas are based on intrinsic properties and the distances of each dwelling to urban park areas. The overall environmental value of a park, the group restoration level, is defined as a logarithmic summation of the restoration levels over its surrounding residential areas. Restoration levels were determined for sixteen public parks in the city of Rotterdam and compared with survey data from questionnaires. Results show that the investigated parks display a large variation in the group restoration level levels, mainly due to differences in size and average noise levels. To validate the proposed method, survey data from questionnaires are investigated as to correlation with restoration levels. Copyright © 2014 Elsevier B.V. All rights reserved.

Monosialotetrahexosylganglioside Inhibits the Expression of p-CREB and NR2B in the Auditory Cortex in Rats with Salicylate-Induced Tinnitus.

PubMed

Song, Rui-Biao; Lou, Wei-Hua

2015-01-01

This study investigated the effects of monosialotetrahexosylganglioside (GM1) on the expression of N-methyl-D-aspartate receptor subunit 2B (NR2B) and phosphorylated (p)-cyclic AMP response element-binding protein (CREB) in the auditory cortex of rats with tinnitus. Tinnitus-like behavior in rats was tested with the gap prepulse inhibition of acoustic startle paradigm. We then investigated the NR2B mRNA and protein and p-CREB protein levels in the auditory cortex of tinnitus rats compared with normal rats. Rats treated for 4 days with salicylate exhibited tinnitus. NR2B mRNA and protein and p-CREB protein levels were upregulated in these animals, with expression returning to normal levels 14 days after cessation of treatment; baseline levels of NR2B and p-CREB were also restored by GM1 administration. These data suggest that chronic salicylate administration induces tinnitus via upregulation of p-CREB and NR2B expression, and that GM1 can potentially be used to treat tinnitus.

Speech Restoration: An Interactive Process

ERIC Educational Resources Information Center

Grataloup, Claire; Hoen, Michael; Veuillet, Evelyne; Collet, Lionel; Pellegrino, Francois; Meunier, Fanny

2009-01-01

Purpose: This study investigates the ability to understand degraded speech signals and explores the correlation between this capacity and the functional characteristics of the peripheral auditory system. Method: The authors evaluated the capability of 50 normal-hearing native French speakers to restore time-reversed speech. The task required them…

High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase

PubMed Central

Wirth, Eva K.; Rijntjes, Eddy; Meyer, Franziska; Köhrle, Josef; Schweizer, Ulrich

2015-01-01

Background The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). Objective: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). Methods We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Results Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Conclusions Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated. PMID:26601078

High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase.

PubMed

Wirth, Eva K; Rijntjes, Eddy; Meyer, Franziska; Köhrle, Josef; Schweizer, Ulrich

2015-09-01

The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated.

Effects of the Administration of 25(OH) Vitamin D3 in an Experimental Model of Chronic Kidney Disease in Animals Null for 1-Alpha-Hydroxylase.

PubMed

Torremadé, Noelia; Bozic, Milica; Goltzman, David; Fernandez, Elvira; Valdivielso, José M

2017-01-01

The final step in vitamin D activation is catalyzed by 1-alpha-hydroxylase (CYP27B1). Chronic kidney disease (CKD) is characterized by low levels of both 25(OH)D3 and 1,25(OH)2D3 provoking secondary hyperparathyroidism (2HPT). Therefore, treatments with active or native vitamin D compounds are common in CKD to restore 25(OH)D3 levels and also to decrease PTH. This study evaluates the dose of 25(OH)D3 that restores parathyroid hormone (PTH) and calcium levels in a model of CKD in CYP27B1-/- mice. Furthermore, we compare the safety and efficacy of the same dose in CYP27B1+/+ animals. The dose needed to decrease PTH levels in CYP27B1-/- mice with CKD was 50 ng/g. That dose restored blood calcium levels without modifying phosphate levels, and increased the expression of genes responsible for calcium absorption (TRPV5 and calbindinD- 28K in the kidney, TRPV6 and calbindinD-9k in the intestine). The same dose of 25(OH)D3 did not modify PTH in CYP27B1+/+ animals with CKD. Blood calcium remained normal, while phosphate increased significantly. Blood levels of 25(OH)D3 in CYP27B1-/- mice were extremely high compared to those in CYP27B1+/+ animals. CYP27B1+/+ animals with CKD showed increases in TRPV5, TRPV6, calbindinD-28K and calbindinD-9K, which were not further elevated with the treatment. Furthermore, CYP27B1+/+ animals displayed an increase in vascular calcification. We conclude that the dose of 25(OH)D3 effective in decreasing PTH levels in CYP27B1-/- mice with CKD, has a potentially toxic effect in CYP27B1+/+ animals with CKD.

IGF-1 Restores Visual Cortex Plasticity in Adult Life by Reducing Local GABA Levels

PubMed Central

Maya-Vetencourt, José Fernando; Baroncelli, Laura; Viegi, Alessandro; Tiraboschi, Ettore; Castren, Eero; Cattaneo, Antonino; Maffei, Lamberto

2012-01-01

The central nervous system architecture is markedly modified by sensory experience during early life, but a decline of plasticity occurs with age. Recent studies have challenged this dogma providing evidence that both pharmacological treatments and paradigms based on the manipulation of environmental stimulation levels can be successfully employed as strategies for enhancing plasticity in the adult nervous system. Insulin-like growth factor 1 (IGF-1) is a peptide implicated in prenatal and postnatal phases of brain development such as neurogenesis, neuronal differentiation, synaptogenesis, and experience-dependent plasticity. Here, using the visual system as a paradigmatic model, we report that IGF-1 reactivates neural plasticity in the adult brain. Exogenous administration of IGF-1 in the adult visual cortex, indeed, restores the susceptibility of cortical neurons to monocular deprivation and promotes the recovery of normal visual functions in adult amblyopic animals. These effects were accompanied by a marked reduction of intracortical GABA levels. Moreover, we show that a transitory increase of IGF-1 expression is associated to the plasticity reinstatement induced by environmental enrichment (EE) and that blocking IGF-1 action by means of the IGF-1 receptor antagonist JB1 prevents EE effects on plasticity processes. PMID:22720172

Yi-gan san restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia.

PubMed

Makinodan, Manabu; Yamauchi, Takahira; Tatsumi, Kouko; Okuda, Hiroaki; Noriyama, Yoshinobu; Sadamatsu, Miyuki; Kishimoto, Toshifumi; Wanaka, Akio

2009-01-01

The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic-polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi-gan san may have ameliorating effects on the pathological symptoms of schizophrenia.

Biomechanics of Hybrid Anterior Cervical Fusion and Artificial Disc Replacement in 3-Level Constructs: An In Vitro Investigation

PubMed Central

Liao, Zhenhua; Fogel, Guy R.; Pu, Ting; Gu, Hongsheng; Liu, Weiqiang

2015-01-01

Background The ideal surgical approach for cervical disk disease remains controversial, especially for multilevel cervical disease. The purpose of this study was to investigate the biomechanics of the cervical spine after 3-level hybrid surgery compared with 3-level anterior cervical discectomy and fusion (ACDF). Material/Methods Eighteen human cadaveric spines (C2-T1) were evaluated under displacement-input protocol. After intact testing, a simulated hybrid construct or fusion construct was created between C3 to C6 and tested in the following 3 conditions: 3-level disc plate disc (3DPD), 3-level plate disc plate (3PDP), and 3-level plate (3P). Results Compared to intact, almost 65~80% of motion was successfully restricted at C3-C6 fusion levels (p<0.05). 3DPD construct resulted in slight increase at the 3 instrumented levels (p>0.05). 3PDP construct resulted in significant decrease of ROM at C3-C6 levels less than 3P (p<0.05). Both 3DPD and 3PDP caused significant reduction of ROM at the arthrodesis level and produced motion increase at the arthroplasty level. For adjacent levels, 3P resulted in markedly increased contribution of both upper and lower adjacent levels (p<0.05). Significant motion increases lower than 3P were only noted at partly adjacent levels in some conditions for 3DPD and 3PDP (p<0.05). Conclusions ACDF eliminated motion within the construct and greatly increased adjacent motion. Artificial cervical disc replacement normalized motion of its segment and adjacent segments. While hybrid conditions failed to restore normal motion within the construct, they significantly normalized motion in adjacent segments compared with the 3-level ACDF condition. The artificial disc in 3-level constructs has biomechanical advantages compared to fusion in normalizing motion. PMID:26529430

Biomechanics of Hybrid Anterior Cervical Fusion and Artificial Disc Replacement in 3-Level Constructs: An In Vitro Investigation.

PubMed

Liao, Zhenhua; Fogel, Guy R; Pu, Ting; Gu, Hongsheng; Liu, Weiqiang

2015-11-03

The ideal surgical approach for cervical disk disease remains controversial, especially for multilevel cervical disease. The purpose of this study was to investigate the biomechanics of the cervical spine after 3-level hybrid surgery compared with 3-level anterior cervical discectomy and fusion (ACDF). Eighteen human cadaveric spines (C2-T1) were evaluated under displacement-input protocol. After intact testing, a simulated hybrid construct or fusion construct was created between C3 to C6 and tested in the following 3 conditions: 3-level disc plate disc (3DPD), 3-level plate disc plate (3PDP), and 3-level plate (3P). Compared to intact, almost 65~80% of motion was successfully restricted at C3-C6 fusion levels (p<0.05). 3DPD construct resulted in slight increase at the 3 instrumented levels (p>0.05). 3PDP construct resulted in significant decrease of ROM at C3-C6 levels less than 3P (p<0.05). Both 3DPD and 3PDP caused significant reduction of ROM at the arthrodesis level and produced motion increase at the arthroplasty level. For adjacent levels, 3P resulted in markedly increased contribution of both upper and lower adjacent levels (p<0.05). Significant motion increases lower than 3P were only noted at partly adjacent levels in some conditions for 3DPD and 3PDP (p<0.05). ACDF eliminated motion within the construct and greatly increased adjacent motion. Artificial cervical disc replacement normalized motion of its segment and adjacent segments. While hybrid conditions failed to restore normal motion within the construct, they significantly normalized motion in adjacent segments compared with the 3-level ACDF condition. The artificial disc in 3-level constructs has biomechanical advantages compared to fusion in normalizing motion.

Impaired leptin expression and abnormal response to fasting in corticotropin-releasing hormone-deficient mice.

PubMed

Jeong, Kyeong-Hoon; Sakihara, Satoru; Widmaier, Eric P; Majzoub, Joseph A

2004-07-01

Leptin has been postulated to comprise part of an adipostat, whereby during states of excessive energy storage, elevated levels of the hormone prevent further weight gain by inhibiting appetite. A physiological role for leptin in this regard remains unclear because the presence of excessive food, and therefore the need to restrain overeating under natural conditions, is doubtful. We have previously shown that CRH-deficient (Crh(-/-)) mice have glucocorticoid insufficiency and lack the fasting-induced increase in glucocorticoid, a hormone important in stimulating leptin synthesis and secretion. We hypothesized that these mice might have low circulating leptin. Indeed, Crh(-/-) mice exhibited no diurnal variation of leptin, whereas normal littermates showed a clear rhythm, and their leptin levels were lower than their counterparts. A continuous peripheral CRH infusion to Crh(-/-) mice not only restored corticosterone levels, but it also increased leptin expression to normal. Surprisingly, 36 h of fasting elevated leptin levels in Crh(-/-) mice, rather than falling as in normal mice. This abnormal leptin change during fasting in Crh(-/-) mice was corrected by corticosterone replacement. Furthermore, Crh(-/-) mice lost less body weight during 24 h of fasting and ate less food during refeeding than normal littermates. Taken together, we conclude that glucocorticoid insufficiency in Crh(-/-) mice results in impaired leptin production as well as an abnormal increase in leptin during fasting, and propose that the fast-induced physiological reduction in leptin may play an important role to stimulate food intake during the recovery from fasting.

Hyperthyrotropinemia in newly diagnosed cystic fibrosis patients with pancreatic insufficiency reversed by enzyme therapy.

PubMed

Giannakopoulos, Aris; Katelaris, Anni; Noni, Maria; Karakonstantakis, Theodore; Kanaka-Gantenbein, Christina; Doudounakis, Stavros

2018-05-01

Patients with cystic fibrosis (CF) commonly present with an elevated TSH concentration, suggesting subclinical hypothyroidism. Its relation to concomitant pancreatic insufficiency and its natural course upon initiation of enzyme replacement have not been adequately studied. Herein, we investigated the thyroid function in newly diagnosed infants with CF and monitored the course of thyroid function response to pancreatic enzyme substitution treatment. Fourteen, newly diagnosed infants with CF and pancreatic insufficiency, were followed every 6-8 weeks for 6 months ensuing onset of pancreatic enzyme substitution therapy. All infants had normal TSH values on neonatal screening. Ten out of 14 (71%) had hyperthyrotropinemia and normal freeT4 values at presentation. No patient received thyroxine. Upon follow-up, after 6 months, TSH values normalized in 90% of infants with CF and hyperthyrotropinemia. Serum selenium levels were negatively correlated with TSH levels. Mild TSH elevation is a frequent finding in newly diagnosed cystic fibrosis patients with pancreatic insufficiency during infancy. TSH elevation resolves in most cases after initiation of enzyme substitution and improvement of nutritional status without any substitutive therapy with thyroxine. What is Known: • Newly diagnosed infants with cystic fibrosis often present with a state of hyperthyrotropinemia suggesting subclinical hypothyroidism. What is New: • Pancreatic enzyme substitution and improvement of nutrition restores normal TSH levels without the need of thyroxine therapy.

Zif268 mRNA Expression Patterns Reveal a Distinct Impact of Early Pattern Vision Deprivation on the Development of Primary Visual Cortical Areas in the Cat.

PubMed

Laskowska-Macios, Karolina; Zapasnik, Monika; Hu, Tjing-Tjing; Kossut, Malgorzata; Arckens, Lutgarde; Burnat, Kalina

2015-10-01

Pattern vision deprivation (BD) can induce permanent deficits in global motion perception. The impact of timing and duration of BD on the maturation of the central and peripheral visual field representations in cat primary visual areas 17 and 18 remains unknown. We compared early BD, from eye opening for 2, 4, or 6 months, with late onset BD, after 2 months of normal vision, using the expression pattern of the visually driven activity reporter gene zif268 as readout. Decreasing zif268 mRNA levels between months 2 and 4 characterized the normal maturation of the (supra)granular layers of the central and peripheral visual field representations in areas 17 and 18. In general, all BD conditions had higher than normal zif268 levels. In area 17, early BD induced a delayed decrease, beginning later in peripheral than in central area 17. In contrast, the decrease occurred between months 2 and 4 throughout area 18. Lack of pattern vision stimulation during the first 4 months of life therefore has a different impact on the development of areas 17 and 18. A high zif268 expression level at a time when normal vision is restored seems to predict the capacity of a visual area to compensate for BD. © The Author 2014. Published by Oxford University Press.

Constitutive expression of ftsZ overrides the whi developmental genes to initiate sporulation of Streptomyces coelicolor.

PubMed

Willemse, Joost; Mommaas, A Mieke; van Wezel, Gilles P

2012-03-01

The filamentous soil bacteria Streptomyces undergo a highly complex developmental programme. Before streptomycetes commit themselves to sporulation, distinct morphological checkpoints are passed in the aerial hyphae that are subject to multi-level control by the whi sporulation genes. Here we show that whi-independent expression of FtsZ restores sporulation to the early sporulation mutants whiA, whiB, whiG, whiH, whiI and whiJ. Viability, stress resistance and high-resolution electron microscopy underlined that viable spores were formed. However, spores from sporulation-restored whiA and whiG mutants showed defects in DNA segregation/condensation, while spores from the complemented whiB mutant had increased stress sensitivity, perhaps as a result of changes in the spore sheath. In contrast to the whi mutants, normal sporulation of ssgB null mutants-which fail to properly localise FtsZ-could not be restored by enhancing FtsZ protein levels, forming spore-like bodies that lack spore walls. Our data strongly suggest that the whi genes control a decisive event towards sporulation of streptomycetes, namely the correct timing of developmental ftsZ transcription. The biological significance may be to ensure that sporulation-specific cell division will only start once sufficient aerial mycelium biomass has been generated. Our data shed new light on the longstanding question as to how whi genes control sporulation, which has intrigued scientists for four decades.

Caffeine - rich infusion from Cola nitida (kola nut) inhibits major carbohydrate catabolic enzymes; abates redox imbalance; and modulates oxidative dysregulated metabolic pathways and metabolites in Fe2+-induced hepatic toxicity.

PubMed

Erukainure, Ochuko L; Oyebode, Olajumoke A; Sokhela, Mxolisi K; Koorbanally, Neil A; Islam, Md Shahidul

2017-12-01

The antioxidative and antidiabetic effects and toxicity of caffeine-rich infusion of Cola nitida were investigated using in vitro, ex vivo and in silico models. C. nitida was infused in boiling water and allowed to cool before concentrating at <50°C. HPLC analysis of the infusion revealed a caffeine content of 80.08%. The infusion showed potent in vitro antioxidant activity by significantly (p<0.05) scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH). It significantly (p<0.05) inhibited α-glucosidase and α-amylase activities. Treatment of Fe 2+ induced oxidative hepatic tissues with the infusion led to increase Superoxide Dismutase (SOD) and catalase activities, and glutathione (GSH) level as well as decreased malondialdehyde (MDA) level. FTIR spectroscopy of hepatic metabolite revealed restoration of oxidative-induced depleted functional groups by the infusion. LC-MS analysis of the metabolite also revealed restoration of most depleted metabolites with concomitant generation of 4-O-Methylgallic, (-)-Epicatechin sulfate, L-Arginine, L-tyrosine, Citric acid and Decanoic acid in infusion-treated tissues. Pathway analysis of the identified metabolites revealed the presence of 21 metabolic pathways involved in normal hepatic tissues, 12 in oxidative injured tissues and 17 in the treated tissues. Treatment with the infusion restored 4 metabolic pathways common to the normal tissue and further activated 4 additional pathways. Prediction of oral toxicity of caffeine showed it to belong to class 3, with a LD 50 of 127mg/kg. Its toxicity target was predicted as Adenosine Receptor A2a. It was also predicted to be an inhibitor of CYP1A2. These results suggest the antioxidative and antidiabetic properties of C. nitida infusion, with caffeine as the major constituent. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Contrasting Sleeve Gastrectomy with Lifestyle Modification Therapy in the Treatment of Polycystic Ovary Syndrome.

PubMed

Wang, Kaijing; Jiang, Qixin; Zhi, Yunqing; Zhu, Zhe; Zhou, Zhuqing; Xie, Yanting; Yin, Xiaoqi; Lu, Aiguo

2015-06-01

To explore the feasibility of sleeve gastrectomy (SG) as a treatment for polycystic ovary syndrome (PCOS) and its potential to improve clinical efficacy in PCOS patients with symptoms of oligomenorrhea. Twenty-four obese patients with PCOS underwent laparoscopic SG. Simultaneously, 24 obese patients with PCOS received lifestyle modification therapy (LMT). Follow-ups were conducted at 3-6 months. Weight loss, menstruation, and improvements in hirsutism and metabolic symptoms were compared. In the SG group, 20 patients were restored to normal menstrual cycles and ovulation at 3-6 months after surgery. Their average androgen levels decreased significantly following surgery (P=.012). Conversely, only 6 patients in the LMT group were restored to normal menstrual cycles and ovulation after receiving 3 months of treatment. Their average preoperative and postoperative androgen levels showed a nonstatistically significant decrease (P>.05). Compared with the LMT group, the SG group showed more pronounced improvements in menstruation. Additionally, body mass and body mass index were significantly reduced in patients in the SG group 3 months after the surgeries, with maximum weight loss observed at approximately 6 months after surgery. Patients who received LMT showed a gradual weight reduction such that body mass decreased significantly after 3 months (P<. 001). Compared with patients in the LMT group, patients in the SG group showed greater weight loss results (P<.0001). In patients with PCOS, SG resulted in more marked weight loss and better improvements in clinical symptoms compared with LMT.

Bovine milk oligosaccharides decrease gut permeability and improve inflammation and microbial dysbiosis in diet-induced obese mice

PubMed Central

Boudry, Gaëlle; Hamilton, M. Kristina; Chichlowski, Maciej; Wickramasinghe, Saumya; Barile, Daniela; Kalanetra, Karen M.; Mills, David A.; Raybould, Helen E.

2017-01-01

Obesity is characterized by altered gut homeostasis, including dysbiosis and increased gut permeability closely linked to the development of metabolic disorders. Milk oligosaccharides are complex sugars that selectively enhance the growth of specific beneficial bacteria in the gastrointestinal tract and could be used as prebiotics. The aim of the study was to demonstrate the effects of bovine milk oligosaccharides (BMO) and Bifidobacterium longum ssp. infantis (B. infantis) on restoring diet-induced obesity intestinal microbiota and barrier function defects in mice. Male C57/BL6 mice were fed a Western diet (WD, 40% fat/kcal) or normal chow (C, 14% fat/kcal) for 7 wk. During the final 2 wk of the study, the diet of a subgroup of WD-fed mice was supplemented with BMO (7% wt/wt). Weekly gavage of B. infantis was performed in all mice starting at wk 3, yet B. infantis could not be detected in any luminal contents when mice were killed. Supplementation of the WD with BMO normalized the cecal and colonic microbiota with increased abundance of Lactobacillus compared with both WD and C mice and restoration of Allobaculum and Ruminococcus levels to that of C mice. The BMO supplementation reduced WD-induced increase in paracellular and transcellular flux in the large intestine as well as mRNA levels of the inflammatory marker tumor necrosis factor α. In conclusion, BMO are promising prebiotics to modulate gut microbiota and intestinal barrier function for enhanced health. PMID:28131576

Effects of alendronate on restoration of biomechanical properties of periodontium in replanted rat molars.

PubMed

Shibata, T; Komatsu, K; Shimada, A; Shimoda, S; Oida, S; Kawasaki, K; Chiba, M

2004-12-01

We examined the effect of the pretreatment of roots with alendronate on the restoration of the support function of the healing periodontal ligament in replanted rat molars. The left maxillary first molars were extracted, placed in 0.9% NaCl containing 1 mm alendronate (alendronate group) or 0.9% NaCl (control group) for 5 min, and were replanted into their sockets. Groups of animals were killed at 7, 14, and 21 days after replantation. Normal control rats were also killed on the same days. The force required to extract the replanted or normal tooth from its socket was measured, and a load-deformation curve was developed and analyzed. Micro-computed tomography and histologic analyses were also made. The mechanical properties of the healing periodontal ligament in the alendronate group were gradually restored from 7 to 21 days. However, fractures of the roots and bones during mechanical testing occurred in most of the replanted teeth in the control group at 21 days. The rates of restoration of the mechanical strength, extensibility, stiffness, and toughness for the alendronate group at 21 days were 67, 98, 74, and 68% of the normal controls, respectively. Micro-computed tomography and histologic observations revealed that bone-like structures within the pulp and ankylosis between the roots and socket bones occurred commonly in the control group, but were uncommon in the alendronate group. Our findings suggest that the pretreatment with alendronate inhibits the formation of abnormal mineralized tissues and results in better restoration of the support function of the healing periodontal ligament in replanted teeth. (c)Blackwell Munksgaard 2004

Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas.

PubMed

Goncharova, N D; Vengerin, A A; Khavinson, V Kh; Lapin, B A

2005-01-01

The purpose of this research was to study age-related changes in functioning of pineal and pancreatic glands of non-human primates, rhesus monkeys, and to elucidate the possibility of their corrections with the help of epitalon, a synthetic analogue of the pharmacopoeia drug epithalamin. In old (20-27 years) animals, the basal plasma levels of glucose and insulin were found to be higher, while the night melatonin level was lower in comparison with (6-8 years) young animals. After the glucose administration to old monkeys, a larger area under the curve of the plasma glucose response, a reduced glucose 'disappearance' rate, and a reduced insulin peak (5 min after the glucose administration) were observed in comparison with young animals in similar experiments. The epitalon administration to old monkeys caused the decrease in the basal levels of glucose and insulin and the increase in the basal night melatonin level. Additionally, in the case of old monkeys, epitalon decreased the area under the plasma glucose response curve, markedly increased the glucose 'disappearance' rate and normalized the plasma insulin dynamics in response to glucose administration. Yet, it has not affected the hormonal and metabolic changes in young animals. Thus, epitalon is a promising factor for restoring the age-related endocrine dysfunctions of primates.

Radiographic Outcomes of Volar Locked Plating for Distal Radius Fractures

PubMed Central

Mignemi, Megan E.; Byram, Ian R.; Wolfe, Carmen C.; Fan, Kang-Hsien; Koehler, Elizabeth A.; Block, John J.; Jordanov, Martin I.; Watson, Jeffry T.; Weikert, Douglas R.; Lee, Donald H.

2013-01-01

Purpose To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures. Methods We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type. Results At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome. Conclusions Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types. PMID:23218558

Metal chaperones prevent zinc-mediated cognitive decline.

PubMed

Adlard, Paul A; Parncutt, Jacqui; Lal, Varsha; James, Simon; Hare, Dominic; Doble, Philip; Finkelstein, David I; Bush, Ashley I

2015-09-01

Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95; AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippocampus. While we demonstrated a small regional increase in hippocampal zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippocampal formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy

PubMed Central

Watkins, Crystal C.; Sawa, Akira; Jaffrey, Samie; Blackshaw, Seth; Barrow, Roxanne K.; Snyder, Solomon H.; Ferris, Christopher D.

2000-01-01

Gastrointestinal dysfunction is common in diabetic patients. In genetic (nonobese diabetic) and toxin-elicited (streptozotocin) models of diabetes in mice, we demonstrate defects in gastric emptying and nonadrenergic, noncholinergic relaxation of pyloric muscle, which resemble defects in mice harboring a deletion of the neuronal nitric oxide synthase gene (nNOS). The diabetic mice manifest pronounced reduction in pyloric nNOS protein and mRNA. The decline of nNOS in diabetic mice does not result from loss of myenteric neurons. nNOS expression and pyloric function are restored to normal levels by insulin treatment. Thus diabetic gastropathy in mice reflects an insulin-sensitive reversible loss of nNOS. In diabetic animals, delayed gastric emptying can be reversed with a phosphodiesterase inhibitor, sildenafil. These findings have implications for novel therapeutic approaches and may clarify the etiology of diabetic gastropathy. PMID:10930440

β-Lapachone attenuates mitochondrial dysfunction in MELAS cybrid cells.

PubMed

Jeong, Moon Hee; Kim, Jin Hwan; Seo, Kang-Sik; Kwak, Tae Hwan; Park, Woo Jin

2014-11-21

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease caused by mutations in the mitochondrial genome. This study investigated the efficacy of β-lapachone (β-lap), a natural quinone compound, in rescuing mitochondrial dysfunction in MELAS cybrid cells. β-Lap significantly restored energy production and mitochondrial membrane potential as well as normalized the elevated ROS level in MELAS cybrid cells. Additionally, β-lap reduced lactic acidosis and restored glucose uptake in the MELAS cybrid cells. Finally, β-lap activated Sirt1 by increasing the intracellular NAD(+)/NADH ratio, which was accompanied by increased mtDNA content. Two other quinone compounds (idebenone and CoQ10) that have rescued mitochondrial dysfunction in previous studies of MELAS cybrid cells had a minimal effect in the current study. Taken together, these results demonstrated that β-lap may provide a novel therapeutic modality for the treatment of MELAS. Copyright © 2014 Elsevier Inc. All rights reserved.

Epigenetics in prostate cancer.

PubMed

Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

2011-01-01

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice.

PubMed

de Theije, Caroline G M; van den Elsen, Lieke W J; Willemsen, Linette E M; Milosevic, Vanja; Korte-Bouws, Gerdien A H; Lopes da Silva, Sofia; Broersen, Laus M; Korte, S Mechiel; Olivier, Berend; Garssen, Johan; Kraneveld, Aletta D

2015-03-01

Allergy is suggested to exacerbate impaired behaviour in children with neurodevelopmental disorders. We have previously shown that food allergy impaired social behaviour in mice. Dietary fatty acid composition may affect both the immune and nervous system. The aim of this study was to assess the effect of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) on food allergy-induced impaired social behaviour and associated deficits in prefrontal dopamine (DA) in mice. Mice were fed either control or n-3 LCPUFA-enriched diet before and during sensitization with whey. Social behaviour, acute allergic skin response and serum immunoglobulins were assessed. Monoamine levels were measured in brain and intestine and fatty acid content in brain. N-3 LCPUFA prevented impaired social behaviour of allergic mice. Moreover, n-3 LCPUFA supplementation increased docosahexaenoic acid (DHA) incorporation into the brain and restored reduced levels of prefrontal DA and its metabolites 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine and homovanillic acid in allergic mice. In addition to these brain effects, n-3 LCPUFA supplementation reduced the allergic skin response and restored decreased intestinal levels of serotonin metabolite 5-hydroxyindoleacetic acid in allergic mice. N-3 LCPUFA may have beneficial effects on food allergy-induced deficits in social behaviour, either indirectly by reducing the allergic response and restoring intestinal 5-HT signalling, or directly by DHA incorporation into neuronal membranes, affecting the DA system. Therefore, it is of interest to further investigate the relevance of food allergy-enhanced impairments in social behaviour in humans and the potential benefits of dietary n-3 LCPUFA supplementation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

PubMed Central

Sobrevia, Luis; Salsoso, Rocío; Fuenzalida, Bárbara; Barros, Eric; Toledo, Lilian; Silva, Luis; Pizarro, Carolina; Subiabre, Mario; Villalobos, Roberto; Araos, Joaquín; Toledo, Fernando; González, Marcelo; Gutiérrez, Jaime; Farías, Marcelo; Chiarello, Delia I.; Pardo, Fabián; Leiva, Andrea

2016-01-01

Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies. PMID:27065887

Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response

PubMed Central

Raat, Nicolaas J.H.; Noguchi, Audrey C.; Liu, Virginia B.; Raghavachari, Nalini; Liu, Delong; Xu, Xiuli; Shiva, Sruti; Munson, Peter J.; Gladwin, Mark T.

2009-01-01

Dietary nitrate, found in abundance in green vegetables, can be converted to the cytoprotective molecule nitrite by oral bacteria, suggesting that nitrate and nitrite may represent active cardioprotective constituents of the Mediterranean diet. We therefore tested the hypothesis that dietary nitrate and nitrite levels modulate tissue damage and ischemic gene expression in a mouse liver ischemia-reperfusion model. We found that stomach content, plasma, heart and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion, and could be restored to normal levels with nitrite supplementation in water. Remarkably, we confirmed that basal nitrite levels significantly reduced liver injury after ischemia-reperfusion. Consistent with an effect of nitrite on the post-translational modification of complex I of the mitochondrial electron transport chain, the severity of liver infarction was inversely proportional to complex I activity after nitrite repletion in the diet. The transcriptional response of dietary nitrite after ischemia was more robust than after normoxia, suggesting a hypoxic potentiation of nitrite-dependent transcriptional signaling. Our studies indicate that normal dietary nitrate and nitrite levels modulate ischemic stress responses and hypoxic gene expression programs, supporting the hypothesis that dietary nitrate and nitrite are cytoprotective components of the diet. PMID:19464364

Treatment with Thyroxine Restores Myelination and Clinical Recovery after Intraventricular Hemorrhage

PubMed Central

Vose, Linnea R.; Vinukonda, Govindaiah; Jo, Sungro; Miry, Omid; Diamond, Daniel; Korumilli, Ritesh; Arshad, Arslan; Zia, Muhammad T. K.; Hu, Furong; Kayton, Robert J.; La Gamma, Edmund F.; Bansal, Rashmi; Bianco, Antonio C.

2013-01-01

Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor α (TRα) and TRβ. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TRα expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH. PMID:24174657

Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality.

PubMed

Kalathil, Suresh; Lugade, Amit A; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

2013-04-15

The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1(+)-exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-γ producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations. ©2013 AACR.

Ursolic acid improves podocyte injury caused by high glucose.

PubMed

Xu, Li; Fan, Qiuling; Wang, Xu; Li, Lin; Lu, Xinxing; Yue, Yuan; Cao, Xu; Liu, Jia; Zhao, Xue; Wang, Lining

2017-08-01

Autophagy plays an important role in the maintenance of podocyte homeostasis. Reduced autophagy may result in limited renal cell function during exposure to high glucose conditions. In this study we investigated the effects of ursolic acid (UA) on autophagy and podocyte injury, which were induced by high glucose. Conditionally immortalized murine podocytes were cultured in media supplemented with high glucose and the effects of the PI3K inhibitor LY294002 and UA on protein expression were determined. miR-21 expression was detected by real-time RT-PCR. Activation of the PTEN-PI3K/Akt/mTOR pathway, expression of autophagy-related proteins and expression of podocyte marker proteins were determined by western blot. Immunofluorescence was used to monitor the accumulation of LC3 puncta. Autophagosomes were also observed by transmission electron microscopy. During exposure to high glucose conditions, the normal level of autophagy was reduced in podocytes, and this defective autophagy induced podocyte injury. Increased miR-21 expression, decreased PTEN expression and abnormal activation of the PI3K/Akt/mTOR pathway were observed in cells that were cultured in high glucose conditions. UA and LY294002 reduced podocyte injury through the restoration of defective autophagy. Our data suggest that UA inhibits miR-21 expression and increases PTEN expression, which in turn inhibits Akt and mTOR and restores normal levels of autophagy. Our data suggest that podocyte injury is associated with reduced levels of autophagy during exposure to high glucose conditions, UA attenuated podocyte injury via an increase in autophagy through miR-21 inhibition and PTEN expression, which inhibit the abnormal activation of the PI3K/Akt/mTOR pathway. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Durability of bonds and clinical success of adhesive restorations

PubMed Central

Carvalho, Ricardo M.; Manso, Adriana P.; Geraldeli, Saulo; Tay, Franklin R.; Pashley, David H.

2013-01-01

Resin-dentin bond strength durability testing has been extensively used to evaluate the effectiveness of adhesive systems and the applicability of new strategies to improve that property. Clinical effectiveness is determined by the survival rates of restorations placed in non-carious cervical lesions (NCCL). While there is evidence that the bond strength data generated in laboratory studies somehow correlates with the clinical outcome of NCCL restorations, it is questionable whether the knowledge of bonding mechanisms obtained from laboratory testing can be used to justify clinical performance of resin-dentin bonds. There are significant morphological and structural differences between the bonding substrate used in in vitro testing versus the substrate encountered in NCCL. These differences qualify NCCL as a hostile substrate for bonding, yielding bond strengths that are usually lower than those obtained in normal dentin. However, clinical survival time of NCCL restorations often surpass the durability of normal dentin tested in the laboratory. Likewise, clinical reports on the long-term survival rates of posterior composite restorations defy the relatively rapid rate of degradation of adhesive interfaces reported in laboratory studies. This article critically analyzes how the effectiveness of adhesive systems is currently measured, to identify gaps in knowledge where new research could be encouraged. The morphological and chemical analysis of bonded interfaces of resin composite restorations in teeth that had been in clinical service for many years, but were extracted for periodontal reasons, could be a useful tool to observe the ultrastructural characteristics of restorations that are regarded as clinically acceptable. This could help determine how much degradation is acceptable for clinical success. PMID:22192252

Multi-scale modeling of APC and [Formula: see text]-catenin regulation in the human colonic crypt.

PubMed

Emerick, Brooks; Schleiniger, Gilberto; Boman, Bruce M

2018-06-01

Stem cell renewal and differentiation in the human colonic crypt are linked to the [Formula: see text]-catenin pathway. The spatial balance of Wnt factors in proliferative cells within the crypt maintain an appropriate level of cellular reproduction needed for normal crypt homeostasis. Mutational events at the gene level are responsible for deregulating the balance of Wnt factors along the crypt, causing an overpopulation of proliferative cells, a loss of structure of the crypt domain, and the initiation of colorectal carcinomas. We formulate a PDE model describing cell movement and reproduction in a static crypt domain. We consider a single cell population whose proliferative capabilities are determined by stemness, a quantity defined by intracellular levels of adenomatous polyposis coli (APC) scaffold protein and [Formula: see text]-catenin. We fit APC regulation parameters to biological data that describe normal protein gradients in the crypt. We also fit cell movement and protein flux parameters to normal crypt characteristics such as renewal time, total cell count, and proportion of proliferating cells. The model is used to investigate abnormal crypt dynamics when subjected to a diminished APC gradient, a scenario synonymous to mutations in the APC gene. We find that a 25% decrease in APC synthesis leads to a fraction of 0.88 proliferative, which is reflective of normal-appearing FAP crypts. A 50% drop in APC activity yields a fully proliferative crypt showing a doubling of the level of stemness, which characterizes the initial stages of colorectal cancer development. A sensitivity analysis of APC regulation parameters shows the perturbation of factors that is required to restore crypt dynamics to normal in the case of APC mutations.

A personal perspective and update on erosive tooth wear - 10 years on: Part 2 - Restorative management.

PubMed

Bartlett, D

2016-08-26

The management challenge with erosive tooth wear is that the condition involves erosion and contributions from attrition and abrasion, both of which impact on the longevity of restorations. Severe erosive tooth wear results in visibly shorter teeth, exposure of dentine and adaptive changes which complicate restorative management. There is increasing evidence to suggest if the risk factors, such as reducing the frequency of acidic foods and drinks, are reduced the progression of tooth wear slows and follows a normal pattern of wear. But once teeth become shorter patients often seek advice from dentists on restorative intervention. Composite restorations are successful in some patients but they often involve regular maintenance with repairs and rebuilds, which for some patients is unacceptable. Full coverage crowns, although destructive of tooth tissue, remain an option for restorations.

SICONID: a FORTRAN-77 program for conditional simulation in one dimension

NASA Astrophysics Data System (ADS)

Pardo-Igúzquiza, E.; Chica-Olmo, M.; Delgado-García, J.

1992-07-01

The SICONID program, written in FORTRAN 77 for the conditional simulation of geological variables in one dimension, is presented. The program permits all the necessary steps to obtain a simulated series of the experimental data to be carried out. These states are: acquisition of the experimental values, modelization of the anamorphosis function, variogram of the normal scores, conditional simulation, and restoration of the experimental histogram. A practical case of simulation of the evolution of the groundwater level in a survey to show the operation of the program is given.

Mechanisms of nephroprotective effect of mitochondria-targeted antioxidants under rhabdomyolysis and ischemia/reperfusion.

PubMed

Plotnikov, E Y; Chupyrkina, A A; Jankauskas, S S; Pevzner, I B; Silachev, D N; Skulachev, V P; Zorov, D B

2011-01-01

Oxidative stress-related renal pathologies apparently include rhabdomyolysis and ischemia/reperfusion phenomenon. These two pathologies were chosen for study in order to develop a proper strategy for protection of the kidney. Mitochondria were found to be a key player in these pathologies, being both the source and the target for excessive production of reactive oxygen species (ROS). A mitochondria-targeted compound which is a conjugate of a positively charged rhodamine molecule with plastoquinone (SkQR1) was found to rescue the kidney from the deleterious effect of both pathologies. Intraperitoneal injection of SkQR1 before the onset of pathology not only normalized the level of ROS and lipid peroxidized products in kidney mitochondria but also decreased the level of cytochrome c in the blood, restored normal renal excretory function and significantly lowered mortality among animals having a single kidney exposed to ischemia/reperfusion. The SkQR1-derivative missing plastoquinone (C12R1) possessed some, although limited nephroprotective properties and enhanced animal survival after ischemia/reperfusion. SkQR1 was found to induce some elements of nephroprotective pathways providing ischemic tolerance such as an increase in erythropoietin levels and phosphorylation of glycogen synthase kinase 3β in the kidney. SkQR1 also normalized renal erythropoietin level lowered after kidney ischemia/reperfusion and injection of a well-known nephrotoxic agent gentamicin. Copyright © 2010 Elsevier B.V. All rights reserved.

A Multidisciplinary Approach for Rehabilitation of Enucleated Sockets: Ocular Implants with Custom Ocular Prosthesis.

PubMed

Choudhury, Minati; Banu, Fathima; Natarajan, Shanmuganathan; Kumar, Anand; Tv, Padmanabhan

2018-02-16

Interdisciplinary prosthodontics goes beyond our imagination into fields that have a direct effect on our total body health and quality of life. Removal of an eye has a detrimental effect on the psychology of the patient. Enucleation involves removal of the eyeball proper and leads to an enophthalmic socket with a shrunken eye, which has a crippling effect on patient's emotional and social life. Custom-made eye prosthesis simulates the characteristics of the companion eye and helps in restoring the normal facial appearance. Restoration of saccadic eye movements occurring during speech is desirable because this greatly contributes to a normal facial expression. This can be achieved by an orbital implant, which helps in orbital volume replacement and restoration of prosthesis movement and comfort. This article describes prosthodontic rehabilitation of enucleated eye sockets with orbital implants for two patients.

[The use of acupuncture in combined balneotherapy of erectile dysfunction in patients with lumbosacral osteochondrosis].

PubMed

Zhuravlev, I E; Tereshin, A T

2010-01-01

The objective of the present study was to elucidate effects of therapeutic and preventive measures on restoration of compromised erectile function in patients with osteochondrosis of the lumbosacral spine segment (LSSS). The patients were treated using corporal and auricular acupuncture, Narzan mineral water baths, manual therapy, remedial gymnastics, and psychotherapeutic correction of sexual dysadaptation. This combined treatment resulted in the elimination of algic syndrome in 77.5% of the patients, restoration of sexual function in 62.5%, and normalization of hemodynamics in cavernous bodies in 65.2%. The functional activity of the hypothalamo-pituitary-testicular axis was normalized in 65% of the LSSS patients of strong and moderate sexual constitution. Introduction of acupuncture in the combined medicamentous therapy increased its efficiency by 15%. In 57.5% of the patients with strong and moderate sexual constitution, the restored sexual function persisted for at least 12 months.

Gravity and Skeletal Growth

NASA Technical Reports Server (NTRS)

Morey-Holton, Emily; Turner, Russell T.

1999-01-01

Two simultaneous experiments were performed using 5-week-old male Sprague Dawley rats; in one study, the rats were flown in low earth orbit; in the other study, the hindlimbs of the growing rats were elevated to prevent weight bearing. Following 9 d of unloading, weight bearing was restored for 4, 28, and 76 hrs. Afterwards, additional hindlimb unloading experiments were performed to evaluate the skeletal response to 0, 2, 4, 6, 8, 10, 12, 16, and 24 hrs of restored weight bearing following 7 d of unloading. Cancellous and cortical bone histomorphometry were evaluated in the left tibia at the proximal metaphysis and in the left femur at mid-diaphysis, respectively. Steady-state mRNA levels for bone matrix proteins and skeletal signaling peptides were determined in total cellular RNA extracted from trabeculae from the right proximal tibiametaphysis and periosteum from the right femur. Spaceflight and hindlimb unloading each resulted in cancellous osteopenia, as well as a tendency towards decreased periosteal bone formation. Both models for skeletal unloading resulted in site specific reductions in mRNA levels for transforming growth factor-beta (sub 1) (TGF-beta) osteocalcin (OC), and prepro-alpha (I) subunit of type 1 collagen (collagen) and little or no changes in mRNA levels for glyceraldehyde-3-phosphate dehydrogenase (GAP) and insulin-like growth factor I (IGF-I). Restoration of normal weight bearing resulted in transient increases in mRNA levels for the bone matrix proteins and TGF-beta in the proximal metaphysis and periosteum and no changes in either GAP or IGF-I mRNA levels. The timecourse for the response differed between the two skeletal compartments; the tibial metaphysis responded much more quickly to reloading. These results suggest that the skeletal adaptation to acute physiological changes in mechanical usage are mediated, in part, by changes in mRNA levels for bone matrix proteins and TGF-beta.

Levetiracetam Reverses Synaptic Deficits Produced by Overexpression of SV2A

PubMed Central

Yao, Jia; Bleckert, Adam; Hill, Jessica; Bajjalieh, Sandra M.

2011-01-01

Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions. PMID:22220214

DuCLOX-2/5 Inhibition Attenuates Inflammatory Response and Induces Mitochondrial Apoptosis for Mammary Gland Chemoprevention

PubMed Central

Gautam, Swetlana; Rawat, Atul K.; Sammi, Shreesh R.; Roy, Subhadeep; Singh, Manjari; Devi, Uma; Yadav, Rajnish K.; Singh, Lakhveer; Rawat, Jitendra K.; Ansari, Mohd N.; Saeedan, Abdulaziz S.; Kumar, Dinesh; Pandey, Rakesh; Kaithwas, Gaurav

2018-01-01

The present study is a pursuit to define implications of dual cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) (DuCLOX-2/5) inhibition on various aspects of cancer augmentation and chemoprevention. The monotherapy and combination therapy of zaltoprofen (COX-2 inhibitor) and zileuton (5-LOX inhibitor) were validated for their effect against methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. The combination therapy demarcated significant effect upon the cellular proliferation as evidenced through decreased in alveolar bud count and restoration of the histopathological architecture when compared to toxic control. DuCLOX-2/5 inhibition also upregulated levels of caspase-3 and caspase-8, and restored oxidative stress markers (GSH, TBARs, protein carbonyl, SOD and catalase). The immunoblotting and qRT-PCR studies revealed the participation of the mitochondrial mediated death apoptosis pathway along with favorable regulation of COX-2, 5-LOX. Aforementioned combination restored the metabolic changes to normal when scrutinized through 1H NMR studies. Henceforth, the DuCLOX-2/5 inhibition was recorded to import significant anticancer effects in comparison to either of the individual treatments. PMID:29681851

Functional dilatation and medial remodeling of the renal artery in response to chronic increased blood flow.

PubMed

Roan, Jun-Neng; Yeh, Chin-Yi; Chiu, Wen-Cheng; Lee, Chou-Hwei; Chang, Shih-Wei; Jiangshieh, Ya-Fen; Tsai, Yu-Chuan; Lam, Chen-Fuh

2011-01-01

Renal blood flow (RBF) is tightly regulated by several intrinsic pathways in maintaining optimal kidney blood supply. Using a rat model of aortocaval (AC) fistula, we investigated remodeling of the renal artery following prolonged increased blood flow. An AC fistula was created in the infrarenal aorta of anesthetized rats, and changes of blood flow in the renal artery were assessed using an ultrasonic flow probe. Morphological changes and expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 in the remodeled renal artery were analyzed. Blood flow in the renal artery increased immediately after creation of AC fistula, but normal RBF was restored 8 weeks later. The renal artery dilated significantly 8 weeks after operation. Expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 was upregulated shortly after blood flow increase, and returned to baseline levels after 3 weeks. Histological sections showed luminal dilatation with medial thickening and endothelial cell-to-smooth muscle cell attachments in the remodeled renal artery. Increased RBF was accommodated by functional dilatation and remodeling in the medial layer of the renal artery in order to restore normal blood flow. Our results provide important mechanistic insight into the intrinsic regulation of the renal artery in response to increased RBF. Copyright © 2011 S. Karger AG, Basel.

Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

PubMed Central

McBrayer, Mary Kate; Campbell, Jabbar; Kumar, Asok; Hashim, Audrey; Sershen, Henry; Stavrides, Philip H.; Ohno, Masuo; Hutton, Michael; Nixon, Ralph A.

2014-01-01

Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states. PMID:25009256

Astrocytes influence the severity of spinal muscular atrophy

PubMed Central

Rindt, Hansjörg; Feng, Zhihua; Mazzasette, Chiara; Glascock, Jacqueline J.; Valdivia, David; Pyles, Noah; Crawford, Thomas O.; Swoboda, Kathryn J.; Patitucci, Teresa N.; Ebert, Allison D.; Sumner, Charlotte J.; Ko, Chien-Ping; Lorson, Christian L.

2015-01-01

Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). α-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron-autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA. PMID:25911676

Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency.

PubMed

McGowan, Stephen E; Holmes, Amey Jo; Smith, Jennifer

2004-02-01

Airway hyperresponsiveness (AHR) is influenced by structural components of the bronchial wall, including the smooth muscle and connective tissue elements and the neuromuscular function. AHR is also influenced by parenchymally derived tethering forces on the bronchial wall, which maintain airway caliber by producing outward radial traction. Our previous work has shown that vitamin A-deficient (VAD) rats exhibit cholinergic hyperresponsiveness and a decrease in the expression and function of the muscarinic-2 receptors (M2R). We hypothesized that if decreases in radial traction from airway or parenchymal structures contributed to the VAD-related increase in AHR, then the radial traction would normalize more slowly than VAD-related alterations in neurotransmitter signaling. Rats remained vitamin A sufficient (VAS) or were rendered VAD and then maintained on the VAD diet in the presence or absence of supplementation with all-trans retinoic acid (RA). VAD was associated with an approximately twofold increase in respiratory resistance and elastance compared with VAS rats. Exposure to RA for 12 days but not 4 days restored resistance and elastance to control (VAS) levels. In VAD rats, AHR was accompanied by decreases in bronchial M2R gene expression and function, which were restored after 12 days of RA supplementation. Subepithelial bronchial elastic fibers were decreased by approximately 50% in VAD rats and were significantly restored by RA. The increase in AHR that is associated with VAD is accompanied by decreases in M2R expression and function that can be restored by RA and a reduction in airway elastic fibers that can be partially restored by RA.

Supplementation of α-Tocopherol Attenuates Minerals Disturbance, Oxidative Stress and Apoptosis Occurring in Favism.

PubMed

Koriem, Khaled M M; Arbid, Mahmoud S; Gomaa, Nawal E

2017-10-01

The favism is a metabolic disease that characterized with an acute hemolytic anemia where α-tocopherol is a type of tocopherol accumulated inside the human body. The objective of such a study was established to evaluate the effect of α-tocopherol in favism disorders. A total of 75 human cases were divided into 5 groups as follow; group 1 normal cases without any treatment and group 2 normal cases orally administrated α-tocopherol (200 mg/kg) once a day over 30 days period. Group 3 favism patients without any treatment. Groups 4 and 5 favism patients orally administrated 100 and 200 mg α-tocopherol/kg, respectively once a day over 30 days period. The results obtained revealed that oral administration of α-tocopherol into normal cases over 30 days period did not induce any biological change. In favism, hemoglobin, hematocrit, red and white blood cells, serum glucose, glucose-6-phosphate dehydrogenase, total protein, albumin, globulin, aspartate and alanine aminotransferases, blood glutathione, superoxide dismutase, glutathione peroxidase and serum calcium, phosphorous, sodium, potassium and chloride levels were significantly decreased. On the other hand, serum alkaline phosphatase, bilirubin, selenium, zinc, manganese, copper and iron, malondialdehyde levels showed significant increase in favism. Supplementation with α-tocopherol into favism restores all the above mentioned parameters to approach the normal levels. Also, α-tocopherol has anti-apoptotic effect in favism. In conclusion, α-tocopherol attenuates minerals disturbance, oxidative stress and apoptosis occurring in favism.

Effect of aqueous extracts of alligator pear seed (Persea americana mill) on blood glucose and histopathology of pancreas in alloxan-induced diabetic rats.

PubMed

Edem, Do; Ekanem, Is; Ebong, Pe

2009-07-01

Effects of aqueous extract of alligator pear seed on normal and alloxan-induced diabetic rats were investigated in 6 groups of rats (5 rats per group). Test groups were made diabetic with intra-peritoneal injection of alloxan and treated with 300 mg and 600 mg/kg body weight of alligator pear seed extract. Two non-diabetic groups were also administered with 300 mg and 600 mg/kg body weight extract. The levels of blood glucose were examined in all 6 experimental groups. In diabetic rats, blood glucose levels were significantly reduced (p<0.05) by 73.26-78.24% on consumption of the extracts, with greater effect exhibited by the 600 mg/kg extract. In normal rats, blood glucose levels were significantly reduced (p<0.05) by 34.68-38.9% on consumption of the seed extract. Histological studies showed a degenerative effect on the pancreatic islet cells of diabetic rats. The result suggested restorative (protective) effect of the extract on pancreatic islet cells. Administration of aqueous extract of alligator pear seed may contribute significantly to the reduction of blood glucose levels and can be useful in the treatment of diabetes.

Induction of plasma acetylcholinesterase activity in mice challenged with organophosphorus poisons

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

Duysen, Ellen G.; Lockridge, Oksana, E-mail: olockrid@unmc.edu

2011-09-01

The restoration of plasma acetylcholinesterase activity in mice following inhibition by organophosphorus pesticides and nerve agents has been attributed to synthesis of new enzyme. It is generally assumed that activity levels return to normal, are stable and do not exceed the normal level. We have observed over the past 10 years that recovery of acetylcholinesterase activity levels in mice treated with organophosphorus agents (OP) exceeds pretreatment levels and remains elevated for up to 2 months. The most dramatic case was in mice treated with tri-cresyl phosphate and tri-ortho-cresyl phosphate, where plasma acetylcholinesterase activity rebounded to a level 250% higher thanmore » the pretreatment activity. The present report summarizes our observations on plasma acetylcholinesterase activity in mice treated with chlorpyrifos, chlorpyrifos oxon, diazinon, tri-ortho-cresyl phosphate, tri-cresyl phosphate, tabun thiocholine, parathion, dichlorvos, and diisopropylfluorophosphate. We have developed a hypothesis to explain the excess acetylcholinesterase activity, based on published observations. We hypothesize that acetylcholinesterase activity is induced when cells undergo apoptosis and that consequently there is a rise in the level of plasma acetylcholinesterase. - Highlights: > Acetylcholinesterase activity is induced by organophosphorus agents. > AChE induction is related to apoptosis. > Induction of AChE activity by OP is independent of BChE.« less

Evaluation of antihyperglycemic activity of Cocos nucifera Linn. on streptozotocin induced type 2 diabetic rats.

PubMed

Naskar, Sagar; Mazumder, Upal K; Pramanik, Goutam; Gupta, Malaya; Kumar, R B Suresh; Bala, Asis; Islam, Aminul

2011-12-08

The plant Cocos nucifera Linn. (Arecaceae) is commonly known as coconut. Traditionally the juice of the young spadix when fresh is used in diarrhea and diabetes. The objective of the present study was to investigate the effect of antidiabetic activity and effect on lipid profile as well as cardioprotective effect of hydro-methanol extract of Cocos nucifera (HECN) on streptozotocin (STZ)-induced diabetic rats. After 72 h of STZ (50 mg/kg, b.w. i.p.) administration, animals showing plasma sugar level more than 250 mg/dl were considered as diabetic rat. Fasting blood glucose (FBG) levels were measured on 0th (after 72 h of STZ), 5th, 10th, and 15th day. On the 15th day all the animals were sacrificed and the serum biochemical parameters and antioxidant enzyme status were measured. HECN treated animals showed a significant reduction in FBG level as compared with diabetic control group. Serum enzyme level (SGOT, SGPT, SALP), lipid peroxidation and antioxidant enzyme level such as CAT, GSH, SOD and cholesterol and triglycerides in the HECN treated groups were restored towards normal level as compared to diabetic control groups and the values were comparable with the standard groups (glibenclamide). Improvement in the FBG and the restoration of all other biomarker as well as enzymes indicates that HECN has very good antidiabetic activity with very low side effects and provides a scientific rationale for the use as an antidiabetic agent. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Clearwater Focus Watershed; Nez Perce Tribe, 2002-2003 Annual Report.

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

Jones, Ira

2004-01-01

The Nez Perce Tribe Department of Fisheries Resource Management, Watershed Division, approaches watershed restoration with a goal to protect, restore, and enhance a connected network of functioning habitat types capable of supporting all fish life stages. Its goal is also to re-establish normal patters of production, dispersal, and exchange of genetic information within the 1855 Treaty Area. The Nez Perce Tribe began watershed restoration projects within the Clearwater River Subbasin in 1996. Progress has been made in restoring the sub-basin by excluding cattle from critical riparian areas through fencing, stabilizing streambanks, decommissioning roads, and upgrading culverts. Coordination of these projectsmore » is critical to the success of the restoration of the sub-basin. Coordination includes: within department coordination, sub-basin assessment and planning, and treaty area coordination.« less

Regulatory influence of germ cells on sertoli cell function in the pre-pubertal rat after acute irradiation of the testis.

PubMed

Guitton, N; Touzalin, A M; Sharpe, R M; Cheng, C Y; Pinon-Lataillade, G; Méritte, H; Chenal, C; Jégou, B

2000-12-01

While germ cell regulation of Sertoli cells has been extensively explored in adult rats in vivo, in contrast, very little is known about germ cell influence on Sertoli cell function at the time when spermatogenesis begins and develops. In the present study various Sertoli cell parameters (number, testicular androgen binding protein (ABP) and testin, serum inhibin-B and, indirectly, follicle-stimulating hormone (FSH)) were investigated after the exposure of 19-day-old rats to a low dose of 3 Grays of gamma-rays. Differentiated spermatogonia were the primary testicular targets of the gamma-rays, which resulted in progressive maturation depletion, sequentially and reversibly affecting all germ cell classes. Testicular weight declined to a nadir when pachytene spermatocytes and spermatids were depleted from the seminiferous epithelium and complete or near complete recovery of spermatogenesis and testicular weight was observed at the end of the experiment. Blood levels of FSH and ABP were normal during the first 11 days after irradiation, when spermatogonia and early spermatocytes were depleted. While the number of Sertoli cells was not significantly affected by the irradiation, from days 11-66 after gamma-irradiation, ABP production declined and FSH levels increased when pachytene spermatocytes and spermatids were depleted and the recovery of these parameters was only observed when spermatogenesis was fully restored. Comparison of the pattern of change in serum levels of inhibin-B and testicular levels of testin and of germ cell numbers strongly suggest a relationship between the disappearance of spermatocytes and spermatids from the seminiferous epithelium and the decrease in levels of inhibin-B and increase in levels of testin from 7 to 36 days post-irradiation. Levels of testin and inhibin-B were restored before spermatogenesis had totally returned to normal. In conclusion, this in vivo study shows that pre-pubertal Sertoli cell function is under the complex control of various germ cell classes. This control presents clear differences when compared with that previously observed in adult animals and depends on the Sertoli cell parameter of interest, as well as on the germ cell type.

Fructo-oligosaccharides and intestinal barrier function in a methionine-choline-deficient mouse model of nonalcoholic steatohepatitis.

PubMed

Matsumoto, Kotaro; Ichimura, Mayuko; Tsuneyama, Koichi; Moritoki, Yuki; Tsunashima, Hiromichi; Omagari, Katsuhisa; Hara, Masumi; Yasuda, Ichiro; Miyakawa, Hiroshi; Kikuchi, Kentaro

2017-01-01

Impairments in intestinal barrier function, epithelial mucins, and tight junction proteins have been reported to be associated with nonalcoholic steatohepatitis. Prebiotic fructo-oligosaccharides restore balance in the gastrointestinal microbiome. This study was conducted to determine the effects of dietary fructo-oligosaccharides on intestinal barrier function and steatohepatitis in methionine-choline-deficient mice. Three groups of 12-week-old male C57BL/6J mice were studied for 3 weeks; specifically, mice were fed a methionine-choline-deficient diet, a methionine-choline-deficient diet plus 5% fructo-oligosaccharides in water, or a normal control diet. Fecal bacteria, short-chain fatty acids, and immunoglobulin A (IgA) levels were investigated. Histological and immunohistochemical examinations were performed using mice livers for CD14 and Toll-like receptor-4 (TLR4) expression and intestinal tissue samples for IgA and zonula occludens-1 expression in epithelial tight junctions. The methionine-choline-deficient mice administered 5% fructo-oligosaccharides maintained a normal gastrointestinal microbiome, whereas methionine-choline-deficient mice without prebiotic supplementation displayed increases in Clostridium cluster XI and subcluster XIVa populations and a reduction in Lactobacillales spp. counts. Methionine-choline-deficient mice given 5% fructo-oligosaccharides exhibited significantly decreased hepatic steatosis (p = 0.003), decreased liver inflammation (p = 0.005), a decreased proportion of CD14-positive Kupffer cells (p = 0.01), decreased expression of TLR4 (p = 0.04), and increases in fecal short-chain fatty acid and IgA concentrations (p < 0.04) compared with the findings in methionine-choline-deficient mice that were not administered this prebiotic. This study illustrated that in the methionine-choline-deficient mouse model, dietary fructo-oligosaccharides can restore normal gastrointestinal microflora and normal intestinal epithelial barrier function, and decrease steatohepatitis. The findings support the role of prebiotics, such as fructo-oligosaccharides, in maintaining a normal gastrointestinal microbiome; they also support the need for further studies on preventing or treating nonalcoholic steatohepatitis using dietary fructo-oligosaccharides.

Chronic alcoholism in rats induces a compensatory response, preserving brain thiamine diphosphate, but the brain 2-oxo acid dehydrogenases are inactivated despite unchanged coenzyme levels.

PubMed

Parkhomenko, Yulia M; Kudryavtsev, Pavel A; Pylypchuk, Svetlana Yu; Chekhivska, Lilia I; Stepanenko, Svetlana P; Sergiichuk, Andrej A; Bunik, Victoria I

2011-06-01

Thiamine-dependent changes in alcoholic brain were studied using a rat model. Brain thiamine and its mono- and diphosphates were not reduced after 20 weeks of alcohol exposure. However, alcoholism increased both synaptosomal thiamine uptake and thiamine diphosphate synthesis in brain, pointing to mechanisms preserving thiamine diphosphate in the alcoholic brain. In spite of the unchanged level of the coenzyme thiamine diphosphate, activities of the mitochondrial 2-oxoglutarate and pyruvate dehydrogenase complexes decreased in alcoholic brain. The inactivation of pyruvate dehydrogenase complex was caused by its increased phosphorylation. The inactivation of 2-oxoglutarate dehydrogenase complex (OGDHC) correlated with a decrease in free thiols resulting from an elevation of reactive oxygen species. Abstinence from alcohol following exposure to alcohol reactivated OGDHC along with restoration of the free thiol content. However, restoration of enzyme activity occurred before normalization of reactive oxygen species levels. Hence, the redox status of cellular thiols mediates the action of oxidative stress on OGDHC in alcoholic brain. As a result, upon chronic alcohol consumption, physiological mechanisms to counteract the thiamine deficiency and silence pyruvate dehydrogenase are activated in rat brain, whereas OGDHC is inactivated due to impaired antioxidant ability. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Vertebral reconstruction using the telescopic plate spacer-thoracolumbar (TPS-TL) device.

PubMed

Atalay, Basar; Riesenburger, Ron I; Schirmer, Clemens M; Bhadelia, Rafeeque A; Weller, Simcha J

2010-07-01

Retrospective study of surgical technique and outcome. The authors conducted a study to evaluate the ability of the TPS-TL (telescopic plate spacer-thoracolumbar) implant to correct kyphotic deformity and restore vertebral body height after vertebrectomy in the thoracolumbar spine. TPS-TL is a novel vertebral body replacement device that consists of an expandable cage with an integrated plate component for transvertebral screw fixation. This is a retrospective study of 20 patients who underwent anterior column reconstruction with TPS-TL after a 1 or 2 level thoracolumbar vertebrectomy. Preoperative and postoperative sagittal alignment and vertebral body heights were radiologically analyzed in all patients. The mean follow-up was 14 months. Preoperative and postoperative Cobb angles were measured to assess sagittal alignment. The average preoperative Cobb angle was 16.0 + or - 7 degrees. This was reduced to 9.8 + or - 10 degrees at the final follow-up (P<0.001). Percent of ideal vertebral body height was used to assess postoperative restoration of vertebral body height. This value was obtained by creating a ratio of the height of the effected vertebral levels to the height of the adjacent normal vertebral bodies. The mean percent of ideal vertebral body height improved from a preoperative value from 86.2 + or - 2% to 93.1 + or - 6% at the final follow-up (P<0.001). The TPS-TL implant is effective in restoring vertebral body height and correcting kyphotic deformity after thoracolumbar vertebrectomy.

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

Kajimoto, Masaki; Ledee, Dolena R.; Xu, Chun

Background: Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. We previously showed that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study was focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. Methods: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 hours) and wean: normal circulation (Group-C);transient coronary occlusion (10 minutes) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon labeled lactate, medium-chain and long-chain FAs were infused as oxidative substrates. Substrate fractional contribution to the citricmore » acid cycle (FC) was analyzed by 13-Carbon nuclear magnetic resonance. Results: ECMO depressed circulating T3 levels to 40% baseline at 4 hours and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [ATP]/[ADP] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. Conclusions: T3 releases inhibition of lactate oxidation following ischemia-reperfusion injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.« less

Total hip arthroplasty using a short-stem prosthesis: restoration of hip anatomy.

PubMed

Amenabar, Tomas; Marimuthu, Kanniraj; Hawdon, Gabrielle; Gildone, Alessandro; McMahon, Stephen

2015-04-01

To evaluate hip parameters such as vertical centre of rotation (VCR), horizontal centre of rotation (HCR), femoral offset, and leg length after total hip arthroplasty (THA) using the Nanos short-stem prosthesis. Medical records of 73 men and 74 women aged 25 to 92 (mean, 63) years who underwent THA using the Nanos short-stem prosthesis by a single surgeon were reviewed. Prior to the surgery, the optimal cup and stem size, head length, and level of the neck osteotomy were determined using radiographs. Intra-operatively, the leg length and femoral offset were checked, and the level of neck resection and head length were adjusted. VCR, HCR, femoral offset, and leg length of the operated and contralateral sides were compared. Functional outcomes were assessed using the Harris Hip Score (HHS). Compared with the normal contralateral hips, the operated hips had a mean increase of 0.4 mm in VCR (p=0.032), a mean decrease of 1.4 mm in HCR (p=0.027), a mean increase of 0.6 mm in femoral offset (p=0.043), and a mean increase of 0.36 mm in leg length (p=0.035). For these respective parameters, the difference between the normal contralateral side and the operated side was within 5 mm in 89%, 80%, 71%, and 96% of patients. The HHS improved from a mean of 53 to 91 at one year (p<0.001). THA using the Nanos short-stem prosthesis enabled restoration of hip anatomy (VCR, HCR, femoral offset, and leg length).

Involvement of oxidative stress in the impairment in biliary secretory function induced by intraperitoneal administration of aluminum to rats.

PubMed

Gonzalez, Marcela A; Alvarez, Maria Del Lujan; Pisani, Gerardo B; Bernal, Claudio A; Roma, Marcelo G; Carrillo, María C

2007-06-01

We have shown that aluminum (Al) induces cholestasis associated with multiple alterations in hepatocellular transporters involved in bile secretory function, like Mrp2. This work aims to investigate whether these harmful effects are mediated by the oxidative stress caused by the metal. For this purpose, the capability of the antioxidant agent, vitamin E, to counteract these alterations was studied in male Wistar rats. Aluminum hydroxide (or saline in controls) was administered ip (27 mg/kg body weight, three times a week, for 90 d). Vitamin E (600 mg/kg body weight) was coadministered, sc. Al increased lipid peroxidation (+50%) and decreased hepatic glutation levels (-43%) and the activity of glutation peroxidase (-50%) and catalase (-88%). Vitamin E counteracted these effects total or partially. Both plasma and hepatic Al levels reached at the end of the treatment were significantly reduced by vitamin E (-40% and -44%, respectively; p<0.05). Al increased 4 times the hepatic apoptotic index, and this effect was fully counteracted by vitamin E. Bile flow was decreased in Altreated rats (-37%) and restored to normality by vitamin E. The antioxidant normalized the hepatic handling of the Mrp2 substrates, rose bengal, and dinitrophenyl-S-glutathione, which was causally associated with restoration of Mrp2 expression. Our data indicate that oxidative stress has a crucial role in cholestasis, apoptotic/necrotic hepatocellular damage, and the impairment in liver transport function induced by Al and that vitamin E counteracts these harmful effects not only by preventing free-radical formation but also by favoring Al disposal.

Immediate provisional restoration of a single-tooth implant in the esthetic zone: a case report.

PubMed

Fu, Po-Sung; Wu, Yi-Min; Tsai, Ching-Fang; Huang, Ta-Ko; Chen, Wen-Cheng; Hung, Chun-Cheng

2011-02-01

Immediate implant restoration of single implants may demonstrate a positive effect on peri-implant soft tissue. Placement of a provisional restoration following implant surgery can create soft tissue contours that resemble normal gingival topography before placement of the definitive prosthesis. This article describes a staged approach of the mandibular permanent right central incisor, which was congenital missing. The proper space for restoration of the missing incisor was created through orthodontic treatment. The scheduled implant site was reconstructed using autogenous bone harvested from the chin region. After a healing period of four months, an implant was installed with the connection of a fixed provisional crown to a prefabricated temporary abutment. The soft tissue around the implant healed according to the contours of the provisional restoration and the emergence profile was used to duplicate the definitive restoration. Peri-implant esthetics was achieved through the staged approach and immediate restoration of the implant. Copyright © 2011. Published by Elsevier B.V.

Hope for Restoration of Dead Valuable Bulls through Cloning Using Donor Somatic Cells Isolated from Cryopreserved Semen

PubMed Central

Selokar, Naresh L.; Saini, Monika; Palta, Prabhat; Chauhan, Manmohan S.; Manik, Radheysham; Singla, Suresh K.

2014-01-01

Somatic cells were isolated from cryopreserved semen of 4 buffalo bulls, 3 of which had died over 10 years earlier, and were established in culture. The cells expressed cytokeratin-18, keratin and vimentin indicating that they were of epithelial origin. The cells were used as nuclear donors for hand-made cloning for producing buffalo embryos. The blastocyst rate and quality, as indicated by apoptotic index, were comparable among embryos produced using cells obtained from fresh or frozen-thawed semen or those obtained from conventional cell sources such as skin. Examination of the epigenetic status revealed that the global level of H3K27me3 but not that of H3K9/14ac and H4K5ac differed significantly (P<0.05) among cloned embryos from different bulls. The relative mRNA abundance of HDAC1, DNMT1, P53 and CASPASE 3 but not that of DNMT3a differed in cells and in cloned embryos. Following transfer of 24 cloned embryos produced from fresh semen-derived cells to 12 recipients, one calf weighing 55 kg, which is now 6 months of age and is normal, was born through normal parturition. Following transfer of 20 embryos produced from frozen-thawed semen-derived cells to 10 recipients, 2 became pregnant, one of which aborted in the first trimester; the calf born was severely underweight (17 kg), and died 12 h after birth. The ability of cells derived from fresh and frozen-thawed semen to produce live offspring confirms the ability of these cells to be reprogrammed. Our findings pave the way for restoration of highly precious progeny-tested bulls, which has immense economic importance, and can also be used for restoration of endangered species. PMID:24614586

Hope for restoration of dead valuable bulls through cloning using donor somatic cells isolated from cryopreserved semen.

PubMed

Selokar, Naresh L; Saini, Monika; Palta, Prabhat; Chauhan, Manmohan S; Manik, Radheysham; Singla, Suresh K

2014-01-01

Somatic cells were isolated from cryopreserved semen of 4 buffalo bulls, 3 of which had died over 10 years earlier, and were established in culture. The cells expressed cytokeratin-18, keratin and vimentin indicating that they were of epithelial origin. The cells were used as nuclear donors for hand-made cloning for producing buffalo embryos. The blastocyst rate and quality, as indicated by apoptotic index, were comparable among embryos produced using cells obtained from fresh or frozen-thawed semen or those obtained from conventional cell sources such as skin. Examination of the epigenetic status revealed that the global level of H3K27me3 but not that of H3K9/14ac and H4K5ac differed significantly (P<0.05) among cloned embryos from different bulls. The relative mRNA abundance of HDAC1, DNMT1, P53 and CASPASE 3 but not that of DNMT3a differed in cells and in cloned embryos. Following transfer of 24 cloned embryos produced from fresh semen-derived cells to 12 recipients, one calf weighing 55 kg, which is now 6 months of age and is normal, was born through normal parturition. Following transfer of 20 embryos produced from frozen-thawed semen-derived cells to 10 recipients, 2 became pregnant, one of which aborted in the first trimester; the calf born was severely underweight (17 kg), and died 12 h after birth. The ability of cells derived from fresh and frozen-thawed semen to produce live offspring confirms the ability of these cells to be reprogrammed. Our findings pave the way for restoration of highly precious progeny-tested bulls, which has immense economic importance, and can also be used for restoration of endangered species.

Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1G93A Rats

PubMed Central

Satriotomo, Irawan; Grebe, Ashley M.

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease, causing muscle paralysis and death from respiratory failure. Effective means to preserve/restore ventilation are necessary to increase the quality and duration of life in ALS patients. At disease end-stage in a rat ALS model (SOD1G93A), acute intermittent hypoxia (AIH) restores phrenic nerve activity to normal levels via enhanced phrenic long-term facilitation (pLTF). Mechanisms enhancing pLTF in end-stage SOD1G93A rats are not known. Moderate AIH-induced pLTF is normally elicited via cellular mechanisms that require the following: Gq-protein-coupled 5-HT2 receptor activation, new BDNF synthesis, and MEK/ERK signaling (the Q pathway). In contrast, severe AIH elicits pLTF via a distinct mechanism that requires the following: Gs-protein-coupled adenosine 2A receptor activation, new TrkB synthesis, and PI3K/Akt signaling (the S pathway). In end-stage male SOD1G93A rats and wild-type littermates, we investigated relative Q versus S pathway contributions to enhanced pLTF via intrathecal (C4) delivery of small interfering RNAs targeting BDNF or TrkB mRNA, and MEK/ERK (U0126) or PI3 kinase/Akt (PI828) inhibitors. In anesthetized, paralyzed and ventilated rats, moderate AIH-induced pLTF was abolished by siBDNF and UO126, but not siTrkB or PI828, demonstrating that enhanced pLTF occurs via the Q pathway. Although phrenic motor neuron numbers were decreased in end-stage SOD1G93A rats (∼30% survival; p < 0.001), BDNF and phosphorylated ERK expression were increased in spared phrenic motor neurons (p < 0.05), consistent with increased Q-pathway contributions to pLTF. Our results increase understanding of respiratory plasticity and its potential to preserve/restore breathing capacity in ALS. SIGNIFICANCE STATEMENT Since neuromuscular disorders, such as amyotrophic lateral sclerosis (ALS), end life via respiratory failure, the ability to harness respiratory motor plasticity to improve breathing capacity could increase the quality and duration of life. In a rat ALS model (SOD1G93A) we previously demonstrated that spinal respiratory motor plasticity elicited by acute intermittent hypoxia is enhanced at disease end-stage, suggesting greater potential to preserve/restore breathing capacity. Here we demonstrate that enhanced intermittent hypoxia-induced phrenic motor plasticity results from amplification of normal cellular mechanisms versus addition/substitution of alternative mechanisms. Greater understanding of mechanisms underlying phrenic motor plasticity in ALS may guide development of new therapies to preserve and/or restore breathing in ALS patients. PMID:28500219

Estimation of the risk of failure for an endodontically treated maxillary premolar with MODP preparation and CAD/CAM ceramic restorations.

PubMed

Lin, Chun-Li; Chang, Yen-Hsiang; Pa, Che-An

2009-10-01

This study evaluated the risk of failure for an endodontically treated premolar with mesio occlusodistal palatal (MODP) preparation and 3 different computer-aided design/computer-aided manufacturing (CAD/CAM) ceramic restoration configurations. Three 3-dimensional finite element (FE) models designed with CAD/CAM ceramic onlay, endocrown, and conventional crown restorations were constructed to perform simulations. The Weibull function was incorporated with FE analysis to calculate the long-term failure probability relative to different load conditions. The results indicated that the stress values on the enamel, dentin, and luting cement for endocrown restoration were the lowest values relative to the other 2 restorations. Weibull analysis revealed that the individual failure probability in the endocrown enamel, dentin, and luting cement obviously diminished more than those for onlay and conventional crown restorations. The overall failure probabilities were 27.5%, 1%, and 1% for onlay, endocrown, and conventional crown restorations, respectively, in normal occlusal condition. This numeric investigation suggests that endocrown and conventional crown restorations for endodontically treated premolars with MODP preparation present similar longevity.

Cortical motor activity and reorganization following upper-limb amputation and subsequent targeted reinnervation.

PubMed

Chen, Albert; Yao, Jun; Kuiken, Todd; Dewald, Julius P A

2013-01-01

Previous studies have postulated that the amount of brain reorganization following peripheral injuries may be correlated with negative symptoms or consequences. However, it is unknown whether restoring effective limb function may then be associated with further changes in the expression of this reorganization. Recently, targeted reinnervation (TR), a surgical technique that restores a direct neural connection from amputated sensorimotor nerves to new peripheral targets such as muscle, has been successfully applied to upper-limb amputees. It has been shown to be effective in restoring both peripheral motor and sensory functions via the reinnervated nerves as soon as a few months after the surgery. However, it was unclear whether TR could also restore normal cortical motor representations for control of the missing limb. To answer this question, we used high-density electroencephalography (EEG) to localize cortical activity related to cued motor tasks generated by the intact and missing limb. Using a case study of 3 upper-limb amputees, 2 of whom went through pre and post-TR experiments, we present unique quantitative evidence for the re-mapping of motor representations for the missing limb closer to their original locations following TR. This provides evidence that an effective restoration of peripheral function from TR can be linked to the return of more normal cortical expression for the missing limb. Therefore, cortical mapping may be used as a potential guide for monitoring rehabilitation following peripheral injuries.

A Simplified Technique for Implant-Abutment Level Impression after Soft Tissue Adaptation around Provisional Restoration

PubMed Central

Kutkut, Ahmad; Abu-Hammad, Osama; Frazer, Robert

2016-01-01

Impression techniques for implant restorations can be implant level or abutment level impressions with open tray or closed tray techniques. Conventional implant-abutment level impression techniques are predictable for maximizing esthetic outcomes. Restoration of the implant traditionally requires the use of the metal or plastic impression copings, analogs, and laboratory components. Simplifying the dental implant restoration by reducing armamentarium through incorporating conventional techniques used daily for crowns and bridges will allow more general dentists to restore implants in their practices. The demonstrated technique is useful when modifications to implant abutments are required to correct the angulation of malpositioned implants. This technique utilizes conventional crown and bridge impression techniques. As an added benefit, it reduces costs by utilizing techniques used daily for crowns and bridges. The aim of this report is to describe a simplified conventional impression technique for custom abutments and modified prefabricated solid abutments for definitive restorations. PMID:29563457

Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice.

PubMed

Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G; Smokvina, Tamara; Langella, Philippe

2016-01-01

Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4(+) lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4(+) Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability.

Prospective multicenter study of marginal bone level and soft tissue health of a one-piece implant after two years.

PubMed

Finne, Kaj; Rompen, Eric; Toljanic, Joseph

2007-06-01

A novel 1-piece implant purported to provide for stable tissue support, immediate function, and immediate placement in extraction sockets has been developed. Stabilization of the marginal bone level over time requires documentation. The aim of this study was to evaluate marginal bone level differences and soft tissue health between the 1- and 2-year follow-up of a 1-piece implant design. Eighty-two implants, restoring both single teeth and multiple edentulous situations, in 56 consecutively treated patients, were included. Marginal bone level was evaluated on radiographs made at implant insertion, 6-month follow-up, and annually thereafter. At 3-, 6-month, and 1-year follow-ups, presence of plaque and the soft tissue response were evaluated using plaque and bleeding on probing indexes. The papilla index was used to determine papilla size at implant insertion with the provisional restoration in place and at the insertion of the definitive restoration. The change over time in marginal bone level was analyzed with a 1-way analysis of variance (ANOVA) paired design with time as main effect (1 to 2 years) and subjects as block effect (alpha=.05). One implant failure occurred, resulting in a 98.8% cumulative survival rate (CSR) for the follow-up time of 2 years. The mean (SD) change in bone level between years 1 and 2 was 0.08 mm (1.19) (95% CI-0.30 to 0.46) (P=.68), demonstrating a stable marginal bone level. Normal implant mucosa was noted for approximately 90% of the sites at the 1-year follow-up. The mean (SD) papilla score at placement was 1.3 (0.66) and increased to 1.7 (0.67) at insertion of the definitive prosthesis. The stable marginal bone level and soft tissue health observed indicate that the 1-piece implant tested has the ability to preserve both hard and soft tissue. Based on the high implant survival rate and favorable tissue response, the 1-piece implant can be recommended for clinical use.

Behavioral and Electrophysiological Characterization of Dyt1 Heterozygous Knockout Mice

PubMed Central

Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C.; Campbell, Susan L.; Roper, Steven N.; Sweatt, J. David; Li, Yuqing

2015-01-01

DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinAΔE). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinAΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia. PMID:25799505

Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

PubMed

Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C; Campbell, Susan L; Roper, Steven N; Sweatt, J David; Li, Yuqing

2015-01-01

DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin.

PubMed

Siddiqui, Almas; Bhaumik, Dipa; Chinta, Shankar J; Rane, Anand; Rajagopalan, Subramanian; Lieu, Christopher A; Lithgow, Gordon J; Andersen, Julie K

2015-09-16

Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson's disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1α-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1α-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via upregulation of TFEB function. Mutations in PARK2 are generally associated with loss in ability to interact with PINK1, impacting on autophagic initiation. Our data suggest that, in the case of at least one parkin mutation, Q311X, detrimental effects are due to inhibition at the level of downstream lysosomal function. Mechanistically, this involves elevations in PARIS protein levels and subsequent effects on PGC1α-TFEB signaling that normally regulates mitochondrial quality control. Treatment with rapamycin independently restores PGC1α-TFEB signaling in a manner not requiring parkin activity and abrogates subsequent mitochondrial impairment and neuronal cell loss. Taken in total, our data suggest that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via rapamycin. Copyright © 2015 the authors 0270-6474/15/3512833-12$15.00/0.

Assessment of Coronal Leakage of Temporary Restorations in Root Canal-treated Teeth: An in vitro Study.

PubMed

Srivastava, Pankaj K; Nagpal, Ajay; Setya, Gaurav; Kumar, Sunil; Chaudhary, Alankrita; Dhanker, Kuldeep

2017-02-01

Coronal leakage is one of the constant concerns in routine dental practice. It is one of the factors responsible for the failure of root canal therapy. Permanent restorations should be given as soon as possible after the completion of root canal therapy. If unavoidable, provisional restoration should be given in such a way that it maximally reduced the leakage of microorganisms and fluids from the external environment into the canal space. Hence, we evaluated the effect of saliva on the coronal leakage of temporary restorations. Biomechanical preparation of the root canals of 204 fresh mandibular first premolar teeth was done using endodontic files with intermittent irrigation of sodium hypochlorite solution and ethylenediaminetetraacetic acid. Alternate irrigation with normal saline was done periodically. After preparation, drying of the canals was done using paper points followed by sealing of the apical foramen. For the assessment of the microleakage, Siqueira et al apparatus and method was used. All the specimens were divided into four groups based on the provisional restorative material used. All the groups were further divided into three subgroups based on the presence and absence of intracanal medicaments. Verissimo et al's criteria were used to check the turbidity at 1-, 2-, 3-, and 4-week interval respectively. All the results were analyzed by Statistical Package for the Social Sciences (SPSS) software. Chi-square test was used to measure the level of significance, and p < 0.05 was considered to be significant. In group I, all the subgroups' specimens showed significant difference at 1 week's time. Only the subgroup with no intracanal medicaments in Cavit-containing provisional restoration showed nonsignificant alterations. Statistically significant alterations were seen at 1, 2, and 3 weeks' interval in all the subgroups except for one with intracanal medicaments. All the temporary restorative materials were not able to prevent microleakage after 1 week's time, with worst bacterial resistance shown by Ketac Molar and ionomer restorative material. Future studies are advocated for better prognosis of root canal therapy.

EFFECT OF HYPOTHYROIDISM AND THYROID GRAFTS ON LYMPHOID TUMOR DEVELOPMENT IN IRRADIATED C57BL MICE

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

Nagareda, C.S.; Kaplan, H.S.

1959-04-01

Studies on the effect of radiothyroidectomy and thyroid grafts on the incidence of thymic implant lymphomas in thymectomized-irradiated CS7BL mice are reported. Hypothyroidism significantly inhibited thymic implant tumor development in females. A similar reduction of lymphoma incidence in hypothyroid males was not statistically significant. When thyroid activity was restored by grafting normal thyroids to radiothyroidectomized animals, lymphoma incidence returned to the level seen in euthyroid animals. I/sup 131/ uptake measurements were made on a representative number of thyroids and thyroid grafts. There was no significant uptake by the I/sup 131/-treated thyroids. Thyroid grafts were just as active as thyroids frommore » control animals. Body weight decreased significantiy in hypothyroid animals and was restored to control euthyroid levels in radiothyroidectomized animals by thyroid grafts. The possible influence of secondary nutritional and endocrine disturbances on leukemogenesis are discussed; it seems likely that the observed inhibition is attributable to hypothyroidism per se, rather than to secondary influences on nutrition or other endocrine imbalances. Incidental observations on pituitary tumor development in lymphoma- free radiothyroldectomized animals are also reported. Pituitary tumor development was completely prevented by thyroid grafts after radiothyroidectomy. (auth)« less

Homogeneous antibodies in lethally irradiated and autologous bone marrow reconstituted Rhesus monkeys

PubMed Central

Van Den Berg, Pleuntje; Radl, J.; Löwenberg, B.; Swart, A. C. W.

1976-01-01

Ten Rhesus monkeys were lethally irradiated and reconstituted with autologous bone marrow. During the restoration period, the animals were immunized with DNP–Rhesus albumin and IgA1λ-10S human paraprotein. One or more transient homogeneous immunoglobulin components appeared in sera of all experimental monkeys. In four animals, these homogeneous immunoglobulins were shown to be specific antibodies against DNP–Rhesus albumin. They gradually became as heterogeneous as those in control monkeys which were immunized but not irradiated and transplanted. The onset of the specific antibody response after immunization was slightly delayed in the experimental group. On determining the time necessary to reach normalization of the overall immunoglobulin levels and the normal heterogeneity of the immunoglobulin spectrum, it was found to be more than 1 year in most of the animals. ImagesFig. 1

Verification of watershed vegetation restoration policies, arid China

PubMed Central

Zhang, Chengqi; Li, Yu

2016-01-01

Verification of restoration policies that have been implemented is of significance to simultaneously reduce global environmental risks while also meeting economic development goals. This paper proposed a novel method according to the idea of multiple time scales to verify ecological restoration policies in the Shiyang River drainage basin, arid China. We integrated modern pollen transport characteristics of the entire basin and pollen records from 8 Holocene sedimentary sections, and quantitatively reconstructed the millennial-scale changes of watershed vegetation zones by defining a new pollen-precipitation index. Meanwhile, Empirical Orthogonal Function method was used to quantitatively analyze spatial and temporal variations of Normalized Difference Vegetation Index in summer (June to August) of 2000–2014. By contrasting the vegetation changes that mainly controlled by millennial-scale natural ecological evolution with that under conditions of modern ecological restoration measures, we found that vegetation changes of the entire Shiyang River drainage basin are synchronous in both two time scales, and the current ecological restoration policies met the requirements of long-term restoration objectives and showed promising early results on ecological environmental restoration. Our findings present an innovative method to verify river ecological restoration policies, and also provide the scientific basis to propose future emphasizes of ecological restoration strategies. PMID:27470948

Verification of watershed vegetation restoration policies, arid China

NASA Astrophysics Data System (ADS)

Zhang, Chengqi; Li, Yu

2016-07-01

Verification of restoration policies that have been implemented is of significance to simultaneously reduce global environmental risks while also meeting economic development goals. This paper proposed a novel method according to the idea of multiple time scales to verify ecological restoration policies in the Shiyang River drainage basin, arid China. We integrated modern pollen transport characteristics of the entire basin and pollen records from 8 Holocene sedimentary sections, and quantitatively reconstructed the millennial-scale changes of watershed vegetation zones by defining a new pollen-precipitation index. Meanwhile, Empirical Orthogonal Function method was used to quantitatively analyze spatial and temporal variations of Normalized Difference Vegetation Index in summer (June to August) of 2000-2014. By contrasting the vegetation changes that mainly controlled by millennial-scale natural ecological evolution with that under conditions of modern ecological restoration measures, we found that vegetation changes of the entire Shiyang River drainage basin are synchronous in both two time scales, and the current ecological restoration policies met the requirements of long-term restoration objectives and showed promising early results on ecological environmental restoration. Our findings present an innovative method to verify river ecological restoration policies, and also provide the scientific basis to propose future emphasizes of ecological restoration strategies.

Fault-Tolerant Algorithms for Connectivity Restoration in Wireless Sensor Networks.

PubMed

Zeng, Yali; Xu, Li; Chen, Zhide

2015-12-22

As wireless sensor network (WSN) is often deployed in a hostile environment, nodes in the networks are prone to large-scale failures, resulting in the network not working normally. In this case, an effective restoration scheme is needed to restore the faulty network timely. Most of existing restoration schemes consider more about the number of deployed nodes or fault tolerance alone, but fail to take into account the fact that network coverage and topology quality are also important to a network. To address this issue, we present two algorithms named Full 2-Connectivity Restoration Algorithm (F2CRA) and Partial 3-Connectivity Restoration Algorithm (P3CRA), which restore a faulty WSN in different aspects. F2CRA constructs the fan-shaped topology structure to reduce the number of deployed nodes, while P3CRA constructs the dual-ring topology structure to improve the fault tolerance of the network. F2CRA is suitable when the restoration cost is given the priority, and P3CRA is suitable when the network quality is considered first. Compared with other algorithms, these two algorithms ensure that the network has stronger fault-tolerant function, larger coverage area and better balanced load after the restoration.

Tall stature without growth hormone: four male patients with aromatase deficiency.

PubMed

Rochira, Vincenzo; Zirilli, Lucia; Maffei, Laura; Premrou, Valeria; Aranda, Claudio; Baldi, Matteo; Ghigo, Ezio; Aimaretti, Gianluca; Carani, Cesare; Lanfranco, Fabio

2010-04-01

From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency. The GH deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome. To evaluate the GH secretion in aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in aromatase-deficient men was evaluated before and during therapy. A case-control study was conducted. Four adult men with aromatase deficiency were compared with 12 normal subjects. We measured the GH response to GHRH-ARG in aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls. The response of GH to GHRH-ARG was severely impaired in men with aromatase deficiency and resulted in significantly lower (P < 0.001) levels than in normal subjects. Although normal, serum IGF-I levels were also significantly lower (P < 0.001) than in normal subjects. Both GH peak and IGF-I concentrations were not modified by estrogen therapy in men with aromatase deficiency. In aromatase-deficient men, GH response to potent provocative stimuli is impaired and is not restored by exogenous estrogens. Furthermore, a tall stature may be reached, notwithstanding the coexistence of GHD, if a prolonged time for growth is available due to a delay in bone maturation, and other growth factors different from GH (mainly insulin) promote growth.

When walking in nature is not restorative-the role of prospect and refuge.

PubMed

Gatersleben, Birgitta; Andrews, Matthew

2013-03-01

People tend to recover more quickly from stress and mental fatigue in natural than in urban environments. But natural environments may not always be restorative. Dense wooded areas may evoke fear and stress and require directed attention to avoid getting lost or tripping over. Little is known about the restorative potential of such environments. Two experiments were conducted to examine restoration in natural settings with different levels of accessibility, prospect (clear field of vision) and refuge (places to hide). An on-line survey (n=269) examined perceived restoration of environments presented in a slide show. An experiment examined actual restoration in response to walks in a real outdoor setting (n=17) and in response to videos of the same walks (in a laboratory; n=17). The findings demonstrate that exposure to natural environments with high levels of prospect and low levels of refuge, is indeed restorative. However, exposure to natural environments low in prospect and high in refuge is not, and may even further increase levels of stress and attention fatigue. These findings demonstrate that natural places may not always be restorative places. Copyright © 2013 Elsevier Ltd. All rights reserved.

Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats

PubMed Central

Abdul Nasir, Nurul Alimah; Agarwal, Renu; Sheikh Abdul Kadir, Siti Hamimah; Vasudevan, Sushil; Tripathy, Minaketan; Iezhitsa, Igor; Mohammad Daher, Aqil; Ibrahim, Mohd Ikraam; Mohd Ismail, Nafeeza

2017-01-01

Cataract, a leading cause of blindness, is of special concern in diabetics as it occurs at earlier onset. Polyol accumulation and increased oxidative-nitrosative stress in cataractogenesis are associated with NFκB activation, iNOS expression, ATP depletion, loss of ATPase functions, calpain activation and proteolysis of soluble to insoluble proteins. Tocotrienol was previously shown to reduce lens oxidative stress and inhibit cataractogenesis in galactose-fed rats. In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Diabetic rats were treated with vehicle (DV) or tocotrienol (DT). A third group consists of normal, non-diabetic rats were treated with vehicle (NV). All treatments were given topically, bilaterally, twice daily for 8 weeks with weekly slit lamp monitoring. Subsequently, rats were euthanized and lenses were subjected to estimation of polyol accumulation, oxidative-nitrosative stress, NFκB activation, iNOS expression, ATP levels, ATPase activities, calpain activity and total protein levels. Cataract progression was delayed from the fifth week onwards in DT with lower mean of cataract stages compared to DV group (p<0.01) despite persistent hyperglycemia. Reduced cataractogenesis in DT group was accompanied with lower aldose reductase activity and sorbitol level compared to DV group (p<0.01). DT group also showed reduced NFκB activation, lower iNOS expression and reduced oxidative-nitrosative stress compared to DV group. Lenticular ATP and ATPase and calpain 2 activities in DT group were restored to normal. Consequently, soluble to insoluble protein ratio in DT group was higher compared to DV (p<0.05). In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative-nitrosative stress. These effects of tocotrienol invlove reduced NFκB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels. PMID:28350848

Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats.

PubMed

Abdul Nasir, Nurul Alimah; Agarwal, Renu; Sheikh Abdul Kadir, Siti Hamimah; Vasudevan, Sushil; Tripathy, Minaketan; Iezhitsa, Igor; Mohammad Daher, Aqil; Ibrahim, Mohd Ikraam; Mohd Ismail, Nafeeza

2017-01-01

Cataract, a leading cause of blindness, is of special concern in diabetics as it occurs at earlier onset. Polyol accumulation and increased oxidative-nitrosative stress in cataractogenesis are associated with NFκB activation, iNOS expression, ATP depletion, loss of ATPase functions, calpain activation and proteolysis of soluble to insoluble proteins. Tocotrienol was previously shown to reduce lens oxidative stress and inhibit cataractogenesis in galactose-fed rats. In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Diabetic rats were treated with vehicle (DV) or tocotrienol (DT). A third group consists of normal, non-diabetic rats were treated with vehicle (NV). All treatments were given topically, bilaterally, twice daily for 8 weeks with weekly slit lamp monitoring. Subsequently, rats were euthanized and lenses were subjected to estimation of polyol accumulation, oxidative-nitrosative stress, NFκB activation, iNOS expression, ATP levels, ATPase activities, calpain activity and total protein levels. Cataract progression was delayed from the fifth week onwards in DT with lower mean of cataract stages compared to DV group (p<0.01) despite persistent hyperglycemia. Reduced cataractogenesis in DT group was accompanied with lower aldose reductase activity and sorbitol level compared to DV group (p<0.01). DT group also showed reduced NFκB activation, lower iNOS expression and reduced oxidative-nitrosative stress compared to DV group. Lenticular ATP and ATPase and calpain 2 activities in DT group were restored to normal. Consequently, soluble to insoluble protein ratio in DT group was higher compared to DV (p<0.05). In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative-nitrosative stress. These effects of tocotrienol invlove reduced NFκB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels.

Sediment dynamics in the restored reach of the Kissimmee River Basin, Florida: A vast subtropical riparian wetland

USGS Publications Warehouse

Schenk, E.R.; Hupp, C.R.; Gellis, A.

2012-01-01

Historically, the Kissimmee River Basin consisted of a broad nearly annually inundated riparian wetland similar in character to tropical Southern Hemisphere large rivers. The river was channelized in the 1960s and 1970s, draining the wetland. The river is currently being restored with over 10 000 hectares of wetlands being reconnected to 70 river km of naturalized channel. We monitored riparian wetland sediment dynamics between 2007 and 2010 at 87 sites in the restored reach and 14 sites in an unrestored reference reach. Discharge and sediment transport were measured at the downstream end of the restored reach. There were three flooding events during the study, two as annual flood events and a third as a greater than a 5-year flood event. Restoration has returned periodic flood flow to the riparian wetland and provides a mean sedimentation rate of 11.3 mm per year over the study period in the restored reach compared with 1.7 mm per year in an unrestored channelized reach. Sedimentation from the two annual floods was within the normal range for alluvial Coastal Plain rivers. Sediment deposits consisted of over 20% organics, similar to eastern blackwater rivers. The Kissimmee River is unique in North America for its hybrid alluvial/blackwater nature. Fluvial suspended-sediment measurements for the three flood events indicate that a majority of the sediment (70%) was sand, which is important for natural levee construction. Of the total suspended sediment load for the three flood events, 3%–16% was organic and important in floodplain deposition. Sediment yield is similar to low-gradient rivers draining to the Chesapeake Bay and alluvial rivers of the southeastern USA. Continued monitoring should determine whether observed sediment transport and floodplain deposition rates are normal for this river and determine the relationship between historic vegetation community restoration, hydroperiod restoration, and sedimentation.

Neutralization of Schwann Cell-Secreted VEGF Is Protective to In Vitro and In Vivo Experimental Diabetic Neuropathy

PubMed Central

Taiana, Michela M.; Lombardi, Raffaella; Porretta-Serapiglia, Carla; Ciusani, Emilio; Oggioni, Norberto; Sassone, Jenny; Bianchi, Roberto; Lauria, Giuseppe

2014-01-01

The pathogenetic role of vascular endothelial growth factor (VEGF) in long-term retinal and kidney complications of diabetes has been demonstrated. Conversely, little is known in diabetic neuropathy. We examined the modulation of VEGF pathway at mRNA and protein level on dorsal root ganglion (DRG) neurons and Schwann cells (SC) induced by hyperglycaemia. Moreover, we studied the effects of VEGF neutralization on hyperglycemic DRG neurons and streptozotocin-induced diabetic neuropathy. Our findings demonstrated that DRG neurons were not affected by the direct exposition to hyperglycaemia, whereas showed an impairment of neurite outgrowth ability when exposed to the medium of SC cultured in hyperglycaemia. This was mediated by an altered regulation of VEGF and FLT-1 receptors. Hyperglycaemia increased VEGF and FLT-1 mRNA without changing their intracellular protein levels in DRG neurons, decreased intracellular and secreted protein levels without changing mRNA level in SC, while reduced the expression of the soluble receptor sFLT-1 both in DRG neurons and SC. Bevacizumab, a molecule that inhibits VEGF activity preventing the interaction with its receptors, restored neurite outgrowth and normalized FLT-1 mRNA and protein levels in co-cultures. In diabetic rats, it both prevented and restored nerve conduction velocity and nociceptive thresholds. We demonstrated that hyperglycaemia early affected neurite outgrowth through the impairment of SC-derived VEGF/FLT-1 signaling and that the neutralization of SC-secreted VEGF was protective both in vitro and in vivo models of diabetic neuropathy. PMID:25268360

Anti-Műllerian hormone – a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome

PubMed Central

Neagu, M; Cristescu, C

2012-01-01

Background: The anti- Műllerian hormone (AMH) is secreted in women exclusively by the granulosa cells of the ovarian follicles. The serum level of AMH is a precise marker of follicle pool size. In recent clinical studies of polycystic ovary syndrome (PCOS), the serum levels of AMH were elevated about two to threefold. The use of metformin in women with infertility and PCOS has proved to be efficient: restoring ovulation and reducing metabolic dysfunctions. The aim of our study is to assess AMH as a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome (PCOS). Methods: Eleven patients with infertility and PCOS were enrolled; PCOS was diagnosed according to the criteria of Androgen Excess and Polycystic Ovarian Syndrome Society 2006 (AE/PCOS). All patients have received metformin therapy. Serum AMH was recorded before and after 2 months of treatment; the normal laboratory values were 2.0-6.8 ng/ml. Results: The primary serum AMH level of all women in study was very high: 8.99±0.99 ng/ml. After 2 months of treatment with metformin ovulation was restored in all the patients and the serum AMH levels were significantly decreased. Conclusions: In clinical practice, serum AMH levels of women with infertility and PCOS receiving metformin are a useful predictive marker for the treatment efficiency. PMID:23346251

Nutrition beyond nutrition: plausibility of immunotrophic nutrition for space travel.

PubMed

Kulkarni, A D; Yamauchi, K; Hales, N W; Ramesh, V; Ramesh, G T; Sundaresan, A; Andrassy, R J; Pellis, N R

2002-06-01

Microgravity has adverse effects on the immune system. We examined the effects of supplemental dietary nucleotides on immune function in ground-based in vivo anti-orthostatic tail-suspended (AOS) mice and in vitro (bioreactor-BIO) analogs of microgravity. BALB/c mice were divided into the following three groups: group housed, single isolation, and AOS. Mice were fed either control chow or chow supplemented with RNA or uracil. Immune function was assessed by in vivo popliteal lymph node proliferation (PLN), in vitro PHA-stimulated proliferation of splenocytes and cytokine production. BIO splenocytes were cultured in vitro with/without PHA, a nucleoside-nucleotide mixture (NS/NT) or uridine. The cell proliferation and scanning electron microscopic examination for cells were carried out. PLN response was significantly suppressed in AOS mice (P<0.05) and was restored by RNA and uracil diets. Splenocytes from AOS mice had decreased phytohemagglutinin (PHA)-stimulated proliferation, decreased IL-2 and IFN-gamma cytokine levels (P<0.05). These responses were restored by RNA and uracil diets. In BIO cultures, PHA response was suppressed significantly, and uridine and NS/NT restored the proliferative responses. Scanning electron microscopic analysis of cells cultured in BIO revealed cells with pinched, distorted and eroded membranes. Nucleotide supplementation especially uridine restored normal activated cell surface appearance and ruffling. In the microgravity analog environment of AOS and BIO, supplemental nucleotides and especially uracil/uridine have up-regulating and immunoprotective effects with potential as a countermeasure to the observed immune dysfunction in true microgravity.

A novel male sterility-fertility restoration system in plants for hybrid seed production

PubMed Central

Singh, Surendra Pratap; Singh, Sudhir P.; Pandey, Tripti; Singh, Ram Rakshpal; Sawant, Samir V.

2015-01-01

Hybrid seeds are used for stimulated crop production, as they harness heterosis. The achievement of complete male-sterility in the female-parent and the restored-fertility in F1-hybrids are the major bottlenecks in the commercial hybrid seed production. Here, we report a male sterility–fertility restoration system by engineering the inmost nutritive anther wall layer tapetum of female and male parents. In the female parent, high–level, and stringent expression of Arabidopsis autophagy–related gene BECLIN1 was achieved in the tapetum, which altered the tapetal degeneration program, leading to male sterility. This works on our previously demonstrated expression cassette based on functional complementation of TATA-box mutant (TGTA) promoter and TATA-binding protein mutant3 (TBPm3), with modification by conjugating Long Hypocotyle in Far-Red1 fragment (HFR1NT131) with TBPm3 (HFR1NT131-TBPm3) to exercise regulatory control over it. In the male parent, tapetum–specific Constitutive photo-morphogenesis1 (COP1) was expressed. The F1 obtained by crossing these engineered parents showed decreased BECLIN1 expression, which was further completely abolished when COP1-mutant (COP1L105A) was used as a male parent, leading to normal tapetal development and restored fertility. The system works on COP1-HFR1 interaction and COP1–mediated degradation of TBPm3 pool (HFR1NT131-TBPm3). The system can be deployed for hybrid seed production in agricultural crops. PMID:26073981

A novel male sterility-fertility restoration system in plants for hybrid seed production.

PubMed

Singh, Surendra Pratap; Singh, Sudhir P; Pandey, Tripti; Singh, Ram Rakshpal; Sawant, Samir V

2015-06-15

Hybrid seeds are used for stimulated crop production, as they harness heterosis. The achievement of complete male-sterility in the female-parent and the restored-fertility in F1-hybrids are the major bottlenecks in the commercial hybrid seed production. Here, we report a male sterility-fertility restoration system by engineering the in most nutritive anther wall layer tapetum of female and male parents. In the female parent, high-level, and stringent expression of Arabidopsis autophagy-related gene BECLIN1 was achieved in the tapetum, which altered the tapetal degeneration program, leading to male sterility. This works on our previously demonstrated expression cassette based on functional complementation of TATA-box mutant (TGTA) promoter and TATA-binding protein mutant3 (TBPm3), with modification by conjugating Long Hypocotyle in Far-Red1 fragment (HFR1(NT131)) with TBPm3 (HFR1(NT131)-TBPm3) to exercise regulatory control over it. In the male parent, tapetum-specific Constitutive photo-morphogenesis1 (COP1) was expressed. The F1 obtained by crossing these engineered parents showed decreased BECLIN1 expression, which was further completely abolished when COP1-mutant (COP1(L105A)) was used as a male parent, leading to normal tapetal development and restored fertility. The system works on COP1-HFR1 interaction and COP1-mediated degradation of TBPm3 pool (HFR1(NT131)-TBPm3). The system can be deployed for hybrid seed production in agricultural crops.

Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation

PubMed Central

Chakravarty, Debyani; Santos, Elmer; Ryder, Mabel; Knauf, Jeffrey A.; Liao, Xiao-Hui; West, Brian L.; Bollag, Gideon; Kolesnick, Richard; Thin, Tin Htwe; Rosen, Neal; Zanzonico, Pat; Larson, Steven M.; Refetoff, Samuel; Ghossein, Ronald; Fagin, James A.

2011-01-01

Advanced human thyroid cancers, particularly those that are refractory to treatment with radioiodine (RAI), have a high prevalence of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations. However, the degree to which these cancers are dependent on BRAF expression is still unclear. To address this question, we generated mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas (BRAFV600E) in thyroid follicular cells in a doxycycline-inducible (dox-inducible) manner. Upon dox induction of BRAFV600E, the mice developed highly penetrant and poorly differentiated thyroid tumors. Discontinuation of dox extinguished BRAFV600E expression and reestablished thyroid follicular architecture and normal thyroid histology. Switching on BRAFV600E rapidly induced hypothyroidism and virtually abolished thyroid-specific gene expression and RAI incorporation, all of which were restored to near basal levels upon discontinuation of dox. Treatment of mice with these cancers with small molecule inhibitors of either MEK or mutant BRAF reduced their proliferative index and partially restored thyroid-specific gene expression. Strikingly, treatment with the MAPK pathway inhibitors rendered the tumor cells susceptible to a therapeutic dose of RAI. Our data show that thyroid tumors carrying BRAFV600E mutations are exquisitely dependent on the oncoprotein for viability and that genetic or pharmacological inhibition of its expression or activity is associated with tumor regression and restoration of RAI uptake in vivo in mice. These findings have potentially significant clinical ramifications. PMID:22105174

Restoration of G1 chemo/radioresistance and double-strand-break repair proficiency by wild-type but not endonuclease-deficient Artemis.

PubMed

Mohapatra, Susovan; Kawahara, Misako; Khan, Imran S; Yannone, Steven M; Povirk, Lawrence F

2011-08-01

Deficiency in Artemis is associated with lack of V(D)J recombination, sensitivity to radiation and radiomimetic drugs, and failure to repair a subset of DNA double-strand breaks (DSBs). Artemis harbors an endonuclease activity that trims both 5'- and 3'-ends of DSBs. To examine whether endonucleolytic trimming of terminally blocked DSBs by Artemis is a biologically relevant function, Artemis-deficient fibroblasts were stably complemented with either wild-type Artemis or an endonuclease-deficient D165N mutant. Wild-type Artemis completely restored resistance to γ-rays, bleomycin and neocarzinostatin, and also restored DSB-repair proficiency in G0/G1 phase as measured by pulsed-field gel electrophoresis and repair focus resolution. In contrast, cells expressing the D165N mutant, even at very high levels, remained as chemo/radiosensitive and repair deficient as the parental cells, as evidenced by persistent γ-H2AX, 53BP1 and Mre11 foci that slowly increased in size and ultimately became juxtaposed with promyelocytic leukemia protein nuclear bodies. In normal fibroblasts, overexpression of wild-type Artemis increased radioresistance, while D165N overexpression conferred partial repair deficiency following high-dose radiation. Restoration of chemo/radioresistance by wild-type, but not D165N Artemis suggests that the lack of endonucleolytic trimming of DNA ends is the principal cause of sensitivity to double-strand cleaving agents in Artemis-deficient cells.

In vivo study of the effectiveness of quantitative percussion diagnostics as an indicator of the level of the structural pathology of teeth.

PubMed

Sheets, Cherilyn G; Wu, Jean C; Rashad, Samer; Phelan, Michael; Earthman, James C

2016-08-01

Conventional dental diagnostic aids based upon imagery and patient symptoms are at best only partially effective for the detection of fine structural defects such as cracks in teeth. The purpose of this clinical study was to determine whether quantitative percussion diagnostics (QPD) provided knowledge of the structural instability of teeth before restorative work begins. QPD is a mechanics-based methodology that tests the structural integrity of teeth noninvasively. Eight human participants with 60 sites needing restoration were enrolled in an institutional review board-approved clinical study. Comprehensive examinations were performed in each human participant, including QPD testing. Each site was disassembled and microscopically video documented, and the results were recorded on a defect assessment sheet. Each restored site was then tested using QPD. The normal fit error (NFE), which corresponds to the localized defect severity, was correlated with any pretreatment structural pathology. QPD agreed with clinical disassembly in 55 of 60 comparisons (92% agreement). Moreover, the method achieved 98% specificity and 100% sensitivity for detecting structural pathologies found later upon clinical disassembly. Overall, the NFE was found to be highly predictive of advanced structural pathology. The data from the present in vivo study support the hypothesis that QPD can provide the clinician with advance knowledge of the structural instability of teeth before restorative work begins. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Central exogenous nitric oxide decreases cardiac sympathetic drive and improves baroreflex control of heart rate in ovine heart failure.

PubMed

Ramchandra, Rohit; Hood, Sally G; May, Clive N

2014-08-01

Heart failure (HF) is associated with increased cardiac and renal sympathetic drive, which are both independent predictors of poor prognosis. A candidate mechanism for the centrally mediated sympathoexcitation in HF is reduced synthesis of the inhibitory neuromodulator nitric oxide (NO), resulting from downregulation of neuronal NO synthase (nNOS). Therefore, we investigated the effects of increasing the levels of NO in the brain, or selectively in the paraventricular nucleus of the hypothalamus (PVN), on cardiac sympathetic nerve activity (CSNA) and baroreflex control of CSNA and heart rate in ovine pacing-induced HF. The resting level of CSNA was significantly higher in the HF than in the normal group, but the resting level of RSNA was unchanged. Intracerebroventricular infusion of the NO donor sodium nitroprusside (SNP; 500 μg · ml(-1)· h(-1)) in conscious normal sheep and sheep in HF inhibited CSNA and restored baroreflex control of heart rate, but there was no change in RSNA. Microinjection of SNP into the PVN did not cause a similar cardiac sympathoinhibition in either group, although the number of nNOS-positive cells was decreased in the PVN of sheep in HF. Reduction of endogenous NO with intracerebroventricular infusion of N(ω)-nitro-l-arginine methyl ester decreased CSNA in normal but not in HF sheep and caused no change in RSNA in either group. These findings indicate that endogenous NO in the brain provides tonic excitatory drive to increase resting CSNA in the normal state, but not in HF. In contrast, exogenously administered NO inhibited CSNA in both the normal and HF groups via an action on sites other than the PVN. Copyright © 2014 the American Physiological Society.

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion

PubMed Central

Carbonaro, Denise A.; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao-Jin; Skelton, Dianne C.; Dorey, Frederick; Kellems, Rodney E.; Blackburn, Michael R.

2008-01-01

Adenosine deaminase (ADA)–deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose–dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy. PMID:18356486

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion.

PubMed

Carbonaro, Denise A; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao-Jin; Skelton, Dianne C; Dorey, Frederick; Kellems, Rodney E; Blackburn, Michael R; Kohn, Donald B

2008-06-15

Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose-dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy.

Circulating levels of IGF-1 directly regulate bone growth and density

PubMed Central

Yakar, Shoshana; Rosen, Clifford J.; Beamer, Wesley G.; Ackert-Bicknell, Cheryl L.; Wu, Yiping; Liu, Jun-Li; Ooi, Guck T.; Setser, Jennifer; Frystyk, Jan; Boisclair, Yves R.; LeRoith, Derek

2002-01-01

IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1–deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis. PMID:12235108

An Individual’s Connection to Nature Can Affect Perceived Restorativeness of Natural Environments. Some Observations about Biophilia

PubMed Central

Berto, Rita; Barbiero, Giuseppe; Barbiero, Pietro

2018-01-01

This study investigates the relationship between the level to which a person feels connected to Nature and that person’s ability to perceive the restorative value of a natural environment. We assume that perceived restorativeness may depend on an individual’s connection to Nature and this relationship may also vary with the biophilic quality of the environment, i.e., the functional and aesthetic value of the natural environment which presumably gave an evolutionary advantage to our species. To this end, the level of connection to Nature and the perceived restorativeness of the environment were assessed in individuals visiting three parks characterized by their high level of “naturalness” and high or low biophilic quality. The results show that the perceived level of restorativeness is associated with the sense of connection to Nature, as well as the biophilic quality of the environment: individuals with different degrees of connection to Nature seek settings with different degrees of restorativeness and biophilic quality. This means that perceived restorativeness can also depend on an individual’s “inclination” towards Nature. PMID:29510581

Drug screens based on the newly found role of dystroglycan proteolysis and restoration of dystroglycan function thereof

DOEpatents

Bissell, Mina J.; Muschler, John L.

2010-02-23

The present invention provides methods and compositions for the diagnosis and treatment of cells lacking normal growth arresting characteristic. The present invention demonstrates that many tumor cells lack normal cell surface .alpha.-dystroglycan and thereby lack dystroglycan function. Dystroglycan can be lost from the cell surface by proteolytic shedding of a fragment of .alpha.-dystroglycan into the surrounding medium. Upon restoration of dystroglycan function and over-expression of the dystroglycan gene, the once tumorigenic cells revert to non-tumorigenic cells which polarize and arrest cell growth in the presence of basement membrane proteins, demonstrating that dystroglycan functions as a tumor marker and suppressor.

Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice.

PubMed

Sengupta, Anshuman; Patel, Peysh A; Yuldasheva, Nadira Y; Mughal, Romana S; Galloway, Stacey; Viswambharan, Hema; Walker, Andrew M N; Aziz, Amir; Smith, Jessica; Ali, Noman; Mercer, Ben N; Imrie, Helen; Sukumar, Piruthivi; Wheatcroft, Stephen B; Kearney, Mark T; Cubbon, Richard M

2018-05-15

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We asked whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor haploinsufficient mice (IRKO) were crossed with mice expressing a human insulin receptor transgene in the endothelium (hIRECO), to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO in glucose- and insulin-tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild-type littermates. These phenotypic changes were associated with enhanced basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro, but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

Therapeutic targeting of the p53 pathway in cancer stem cells

PubMed Central

Prabhu, Varun V.; Allen, Joshua E.; Hong, Bo; Zhang, Shengliang; Cheng, Hairong; El-Deiry, Wafik S.

2013-01-01

Introduction Cancer stem cells are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance, and therapeutic resistance. Restoring wild-type p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target cancer stem cells. Areas covered Therapeutic approaches to restore the function of wild-type p53, cancer and normal stem cell biology in relation to p53, and the downstream effects of p53 on cancer stem cells. Expert opinion The restoration of wild-type p53 function by targeting p53 directly, its interacting proteins, or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and cancer stem cells based on the current evidence linking p53 signaling with these populations. PMID:22998602

[Metabolic activity of neutrophilic granulocytes and possible ways of its correction in patients with acute coronary syndrome].

PubMed

Ryzhkova, N A; Havrylenko, T I; Parkhomenko, O M; Kozhukhov, S M

2011-01-01

The present study aimed to investigate the metabolic activity of neutrocytes and the action of corvitin on the level of superoxide anion and myeloperoxidases of cells in vitro with the calculation of index of consumption of myeloperoxidase in patients with ST-elevation acute coronary syndrome. Patient were divided into 2 groups according to the level of superoxide anion. Group 1 included the patients (68%) with the initially low level of superoxide anion, and adding of corvitin to the cells of such patients promoted normalization of this index. In this group we observed also neutrocytosis, low index of consumption of myeloperoxidase and a high level of this enzyme in general population of neutrocytes. Group 2 included patients (32%) with initially normal level of superoxide anion. In this group, corvitin did not influence substantially this factor. Such patients had a level ofmyeloperoxidase within control values and the index of consumption of this enzyme was also within control values. The analysis of hospital period showed that the patients of group 1 had a higher frequency of ventricular tachycardia/ventricular fibrillation, paroxysms of atrial fibrillation, bundle-branch blocks and worsening of the kidney function. We suppose that a low level of superoxide anion in neutrocytes play a major role in the development of complications in patients with acute coronary syndrome. An intravenous administration of corvitin was effective in restoring the metabolic activity of neutrocytes.

Glial-derived neurotrophic factor is essential for blood-nerve barrier functional recovery in an experimental murine model of traumatic peripheral neuropathy.

PubMed

Dong, Chaoling; Helton, E Scott; Zhou, Ping; Ouyang, Xuan; d'Anglemont de Tassigny, Xavier; Pascual, Alberto; López-Barneo, José; Ubogu, Eroboghene E

2018-06-18

There is emerging evidence that glial-derived neurotrophic factor (GDNF) is a potent inducer of restrictive barrier function in tight junction-forming microvascular endothelium and epithelium, including the human blood-nerve barrier (BNB) in vitro. We sought to determine the role of GDNF in restoring BNB function in vivo by evaluating sciatic nerve horseradish peroxidase (HRP) permeability in tamoxifen-inducible GDNF conditional knockout (CKO) adult mice following non-transecting crush injury via electron microscopy, with appropriate wildtype (WT) and heterozygous (HET) littermate controls. A total of 24 age-, genotype- and sex-matched mice >12 weeks of age were injected with 30 mg/kg HRP via tail vein injection 7 or 14 days following unilateral sciatic nerve crush, and both sciatic nerves were harvested 30 minutes later for morphometric assessment by light and electron microscopy. The number and percentage of HRP-permeable endoneurial microvessels were ascertained to determine the effect of GDNF in restoring barrier function in vivo. Following sciatic nerve crush, there was significant upregulation in GDNF protein expression in WT and HET mice that was abrogated in CKO mice. GDNF significantly restored sciatic nerve BNB HRP impermeability to near normal levels by day 7, with complete restoration seen by day 14 in WT and HET mice. A significant recovery lag was observed in CKO mice. This effect was independent on VE-Cadherin or claudin-5 expression on endoneurial microvessels. These results imply an important role of GDNF in restoring restrictive BNB function in vivo, suggesting a potential strategy to re-establish the restrictive endoneurial microenvironment following traumatic peripheral neuropathies.

Effects of Vernonia cinerea on reproductive performance in streptozotocin-induced diabetic rats.

PubMed

Pomjunya, Atchariya; Ratthanophart, Jasada; Fungfuang, Wirasak

2017-03-23

The present study investigated the effects of Vernonia cinerea (VC) on the reproductive function in streptozotocin (STZ)-induced diabetic male rats. Six-week-old male Sprague-Dawley rats were randomly divided into four groups: group 1, normal control rats; group 2, diabetic untreated rats; group 3, diabetic rats treated with VC (10 mg/kg); and group 4, diabetic rats treated with VC (40 mg/kg). Diabetes mellitus (DM) was induced by intraperitoneal injection of STZ (60 mg/kg). All animals were treated for 30 consecutive days. Body weight, blood glucose, food intake, epididymal sperm parameters, testicular microstructure and serum testosterone levels were evaluated. VC treatment significantly restored the sperm motility and testosterone concentration, and decreased the testicular histopathological changes in DM rats. Moreover, high-dose VC exhibited an antidibetic activity and significantly improved the sperm count. In conclusion, we found, for the first time, that administration of VC significantly restored the testicular function and testosterone concentration in diabetic male rats.

Effects of Vernonia cinerea on reproductive performance in streptozotocin-induced diabetic rats

PubMed Central

POMJUNYA, Atchariya; RATTHANOPHART, Jasada; FUNGFUANG, Wirasak

2017-01-01

The present study investigated the effects of Vernonia cinerea (VC) on the reproductive function in streptozotocin (STZ)-induced diabetic male rats. Six-week-old male Sprague-Dawley rats were randomly divided into four groups: group 1, normal control rats; group 2, diabetic untreated rats; group 3, diabetic rats treated with VC (10 mg/kg); and group 4, diabetic rats treated with VC (40 mg/kg). Diabetes mellitus (DM) was induced by intraperitoneal injection of STZ (60 mg/kg). All animals were treated for 30 consecutive days. Body weight, blood glucose, food intake, epididymal sperm parameters, testicular microstructure and serum testosterone levels were evaluated. VC treatment significantly restored the sperm motility and testosterone concentration, and decreased the testicular histopathological changes in DM rats. Moreover, high-dose VC exhibited an antidibetic activity and significantly improved the sperm count. In conclusion, we found, for the first time, that administration of VC significantly restored the testicular function and testosterone concentration in diabetic male rats. PMID:28190818

Effect of lateral hypothalamic lesion on brown adipose tissue of Zucker lean and obese rats.

PubMed

Holt, S J; York, D A

1988-01-01

Acute (10-day) lateral hypothalamic (LH) lesion induced a reduction of food intake in both lean and obese Zucker rats which averaged about 50% over the course of the first 10 days. The aphagia associated with a fall in body weight in both genotypes which was greater than their respective pair-fed controls, indicating a change in energetic efficiency. The reduced level of BAT protein, mitochondria and GDP binding observed in the obese rat was restored after LH lesion, suggesting the reestablishment of a normal sympathetic drive to the tissue. The markedly lower plasma insulin concentration in the LH lesioned obese rat is consistent with a reduction in parasympathetic activity in these animals. Food restriction in the sham lean rat reduced BAT protein content and mitochondrial GDP binding, whereas no such changes were observed in the food restricted obese rat. This demonstrates the insensitivity of the obese rat to dietary signals and may imply that LH lesion restores diet-induced BAT thermogenesis in the obese rat.

Application of bifurcation theory and siRNA-based control signal to restore the proper response of cancer cells to DNA damage.

PubMed

Kozłowska, Emilia; Puszynski, Krzysztof

2016-11-07

Many diseases with a genetic background such as some types of cancer are caused by damage in the p53 signaling pathway. The damage changes the system dynamics providing cancer cells with resistance to therapy such as radiation therapy. The change can be observed as the difference in bifurcation diagrams and equilibria type and location between normal and damaged cells, and summarized as the changes of the mathematical model parameters and following changes of the eigenvalues of Jacobian matrix. Therefore a change in other model parameters, such as mRNA degradation rates, may restore the proper eigenvalues and by that proper system dynamics. From the biological point of view, the change of mRNA degradation rate can be achieved by application of the small interfering RNA (siRNA). Here, we propose a general mathematical framework based on the bifurcation theory and siRNA-based control signal in order to study how to restore the proper response of cells with damaged p53 signaling pathway to therapy by using ionizing radiation (IR) therapy as an example. We show the difference between the cells with normal p53 signaling pathway and cells with abnormalities in the negative (as observed in SJSA-1 cell line) or positive (as observed in MCF-7 or PNT1a cell lines) feedback loop. Then we show how the dynamics of these cells can be restored to normal cell dynamics by using selected siRNA. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

NADPH oxidase-2 inhibition restores contractility and intracellular calcium handling and reduces arrhythmogenicity in dystrophic cardiomyopathy

PubMed Central

Gonzalez, Daniel R.; Treuer, Adriana V.; Lamirault, Guillaume; Mayo, Vera; Cao, Yenong; Dulce, Raul A.

2014-01-01

Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in humans and the mdx mouse. We tested the hypothesis that oxidative stress participates in disrupting calcium handling and contractility in the mdx mouse with established cardiomyopathy. We found increased expression (fivefold) of the NADPH oxidase (NOX) 2 in the mdx hearts compared with wild type, along with increased superoxide production. Next, we tested the impact of NOX2 inhibition on contractility and calcium handling in isolated cardiomyocytes. Contractility was decreased in mdx myocytes compared with wild type, and this was restored toward normal by pretreating with apocynin. In addition, the amplitude of evoked intracellular Ca2+ concentration transients that was diminished in mdx myocytes was also restored with NOX2 inhibition. Total sarcoplasmic reticulum (SR) Ca2+ content was reduced in mdx hearts and normalized by apocynin treatment. Additionally, NOX2 inhibition decreased the production of spontaneous diastolic calcium release events and decreased the SR calcium leak in mdx myocytes. In addition, nitric oxide (NO) synthase 1 (NOS-1) expression was increased eightfold in mdx hearts compared with wild type. Nevertheless, cardiac NO production was reduced. To test whether this paradox implied NOS-1 uncoupling, we treated cardiac myocytes with exogenous tetrahydrobioterin, along with the NOX inhibitor VAS2870. These agents restored NO production and phospholamban phosphorylation in mdx toward normal. Together, these results demonstrate that, in mdx hearts, NOX2 inhibition improves the SR calcium handling and contractility, partially by recoupling NOS-1. These findings reveal a new layer of nitroso-redox imbalance in dystrophic cardiomyopathy. PMID:25015966

Prevention of hyperphagia prevents ovariectomy-induced triacylglycerol accumulation in liver, but not plasma.

PubMed

Kitson, Alex P; Marks, Kristin A; Aristizabal Henao, Juan J; Tupling, A Russell; Stark, Ken D

2015-12-01

Menopause is associated with higher plasma and liver triacylglycerol (TAG) and increased risk for cardiovascular disease. Lowering TAG in menopause may be beneficial; however, the mechanism underlying menopause-induced TAG accumulation is not clear. Ovariectomy is a model for menopause and is associated with metabolic alterations and hyperphagia. This study investigated the role of hyperphagia in ovariectomy-induced increases in blood and tissue TAG, as well as differences in lipid metabolism enzymes and resting metabolic measures. It was hypothesized that prevention of hyperphagia would restore blood and tissue TAG, enzyme expression, and metabolic measures to eugonadal levels. Ovariectomized rats were fed ad libitum (OVX + AL) or pair-fed (OVX + PF) relative to sham-operated rats (SHAM) to prevent hyperphagia. OVX + AL had higher TAG concentrations in liver and plasma than SHAM (60% and 50%, respectively), and prevention of hyperphagia in OVX + PF normalized TAG concentrations to SHAM levels in liver, but not plasma. OVX + AL also had 141% higher hepatic stearoyl-CoA desaturase 1 which was almost completely normalized to SHAM levels by pair-feeding, suggesting normalization of hepatic lipid storage. In contrast, skeletal muscle carnitine palmitoyl transferase 1 was 40% lower in OVX + AL than SHAM and was intermediate in OVX + PF, suggesting lower muscle fatty acid oxidation that may underlie the higher plasma TAG in OVX. No differences were seen in energy expenditure, VO2, or VCO2. Overall, this study indicates that prevention of hyperphagia resulting from ovarian hormone withdrawal normalizes hepatic TAG to eugonadal levels but has no effect on ovariectomy-induced increases in plasma TAG. Copyright © 2015 Elsevier Inc. All rights reserved.

Mice with chimeric livers are an improved model for human lipoprotein metabolism.

PubMed

Ellis, Ewa C S; Naugler, Willscott Edward; Nauglers, Scott; Parini, Paolo; Mörk, Lisa-Mari; Jorns, Carl; Zemack, Helen; Sandblom, Anita Lövgren; Björkhem, Ingemar; Ericzon, Bo-Göran; Wilson, Elizabeth M; Strom, Stephen C; Grompe, Markus

2013-01-01

Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism. FRG [ F ah(-/-) R ag2(-/-)Il2r g (-/-)]) mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL) was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR. Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA). Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal. Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.

A general framework for regularized, similarity-based image restoration.

PubMed

Kheradmand, Amin; Milanfar, Peyman

2014-12-01

Any image can be represented as a function defined on a weighted graph, in which the underlying structure of the image is encoded in kernel similarity and associated Laplacian matrices. In this paper, we develop an iterative graph-based framework for image restoration based on a new definition of the normalized graph Laplacian. We propose a cost function, which consists of a new data fidelity term and regularization term derived from the specific definition of the normalized graph Laplacian. The normalizing coefficients used in the definition of the Laplacian and associated regularization term are obtained using fast symmetry preserving matrix balancing. This results in some desired spectral properties for the normalized Laplacian such as being symmetric, positive semidefinite, and returning zero vector when applied to a constant image. Our algorithm comprises of outer and inner iterations, where in each outer iteration, the similarity weights are recomputed using the previous estimate and the updated objective function is minimized using inner conjugate gradient iterations. This procedure improves the performance of the algorithm for image deblurring, where we do not have access to a good initial estimate of the underlying image. In addition, the specific form of the cost function allows us to render the spectral analysis for the solutions of the corresponding linear equations. In addition, the proposed approach is general in the sense that we have shown its effectiveness for different restoration problems, including deblurring, denoising, and sharpening. Experimental results verify the effectiveness of the proposed algorithm on both synthetic and real examples.

Hepatic gene expression profiling of 5'-AMP-induced hypometabolism in mice.

PubMed

Zhao, Zhaoyang; Miki, Takao; Van Oort-Jansen, Anita; Matsumoto, Tomoko; Loose, David S; Lee, Cheng Chi

2011-04-12

There is currently much interest in clinical applications of therapeutic hypothermia. Hypothermia can be a consequence of hypometabolism. We have recently established a procedure for the induction of a reversible deep hypometabolic state in mice using 5'-adenosine monophosphate (5'-AMP) in conjunction with moderate ambient temperature. The current study aims at investigating the impact of this technology at the gene expression level in a major metabolic organ, the liver. Our findings reveal that expression levels of the majority of genes in liver are not significantly altered by deep hypometabolism. However, among those affected by hypometabolism, more genes are differentially upregulated than downregulated both in a deep hypometabolic state and in the early arousal state. These altered gene expression levels during 5'-AMP induced hypometabolism are largely restored to normal levels within 2 days of the treatment. Our data also suggest that temporal control of circadian genes is largely stalled during deep hypometabolism.

Management and surgical treatment of parathyroid crisis secondary to parathyroid tumors: report of four cases.

PubMed

Ameerudden, Shakil; He, Xianghui

2011-01-01

Parathyroid crisis, also known as a parathyroid storm, is a rare and serious complication of primary hyperparathyroidism. Four cases are reported here in which patients presented to hospital with general complaints due to hypercalcemia secondary to hyperparathyroidism. Blood test results upon admission showed high levels of serum calcium and parathyroid hormone, and medical treatment initiated to lower the calcium level was ineffective. After relevant investigations, each patient underwent surgical exploration of the parathyroid glands, followed by excision of a pathological parathyroid tumor. There was a prompt decrease in parathyroid hormone level immediately after surgery. Histology reports revealed that patients had parathyroid adenoma. All patients recovered after surgery, with serum calcium levels restored back to normal and with resolution of all symptoms of hypercalcemia. This report illustrates how often this disease is initially misdiagnosed, and how prompt appropriate surgical treatment provides the best outcome for the patient.

Kinetochore localized Mad2 and Cdc20 is itself insufficient for triggering the mitotic checkpoint when Mps1 is low in Drosophila melanogaster neuroblasts.

PubMed

Herriott, Ashleigh; Sweeney, Michele; Whitaker, Michael; Taggart, Michael; Huang, Jun-Yong

2012-12-15

The relationships between the kinetochore and checkpoint control remain unresolved. Here, we report the characterization of the in vivo behavior of Cdc20 and Mad2 and the relevant spindle assembly checkpoint (SAC) functions in the neuroblasts of a Drosophila Mps1 weak allele (ald (B4-2) ). ald (B4-2) third instar larvae brain samples contain only around 16% endogenous Mps1 protein, and the SAC function is abolished. However, this does not lead to rapid anaphase onset and mitotic exit, in contrast to the loss of Mad2 alone in a mad2 (EY) mutant. The level of GFP-Cdc20 recruitment to the kinetochore is unaffected in ald (B4-2) neuroblasts, while the level of GFP-Mad2 is reduced to just about 20%. Cdc20 and Mad2 display only monophasic exponential kinetics at the kinetochores. The ald (B4-2) heterozygotes expressed approximately 65% of normal Mps1 protein levels, and this is enough to restore the SAC function. The kinetochore recruitment of GFP-Mad2 in response to SAC activation increases by around 80% in heterozygotes, compared with just about 20% in ald (B4-2) mutant. This suggests a correlation between Mps1 levels and Mad2 kinetochore localization and perhaps the existence of a threshold level at which Mps1 is fully functional. The failure to arrest the mitotic progression in ald (B4-2) neuroblasts in response to colchicine treatment suggests that when Mps1 levels are low, approximately 20% of normal GFP-Mad2, alongside normal levels of GFP-Cdc20 kinetochore recruitments, is insufficient for triggering SAC signal propagation.

Restoration Enhances Wetland Biodiversity and Ecosystem Service Supply, but Results Are Context-Dependent: A Meta-Analysis

PubMed Central

Meli, Paula; Rey Benayas, José María; Balvanera, Patricia; Martínez Ramos, Miguel

2014-01-01

Wetlands are valuable ecosystems because they harbor a huge biodiversity and provide key services to societies. When natural or human factors degrade wetlands, ecological restoration is often carried out to recover biodiversity and ecosystem services (ES). Although such restorations are routinely performed, we lack systematic, evidence-based assessments of their effectiveness on the recovery of biodiversity and ES. Here we performed a meta-analysis of 70 experimental studies in order to assess the effectiveness of ecological restoration and identify what factors affect it. We compared selected ecosystem performance variables between degraded and restored wetlands and between restored and natural wetlands using response ratios and random-effects categorical modeling. We assessed how context factors such as ecosystem type, main agent of degradation, restoration action, experimental design, and restoration age influenced post-restoration biodiversity and ES. Biodiversity showed excellent recovery, though the precise recovery depended strongly on the type of organisms involved. Restored wetlands showed 36% higher levels of provisioning, regulating and supporting ES than did degraded wetlands. In fact, wetlands showed levels of provisioning and cultural ES similar to those of natural wetlands; however, their levels of supporting and regulating ES were, respectively, 16% and 22% lower than in natural wetlands. Recovery of biodiversity and of ES were positively correlated, indicating a win-win restoration outcome. The extent to which restoration increased biodiversity and ES in degraded wetlands depended primarily on the main agent of degradation, restoration actions, experimental design, and ecosystem type. In contrast, the choice of specific restoration actions alone explained most differences between restored and natural wetlands. These results highlight the importance of comprehensive, multi-factorial assessment to determine the ecological status of degraded, restored and natural wetlands and thereby evaluate the effectiveness of ecological restorations. Future research on wetland restoration should also seek to identify which restoration actions work best for specific habitats. PMID:24743348

Levothyroxine treatment restored the decreased circulating fibroblast growth factor 21 levels in patients with hypothyroidism.

PubMed

Wang, Guang; Liu, Jia; Yang, Ning; Hu, Yanjin; Zhang, Heng; Miao, Li; Yao, Zhi; Xu, Yuan

2016-06-01

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator of energy metabolism. Thyroid hormone has been shown to regulate hepatic FGF21 expression in rodents. The goal of this study was to evaluate the plasma FGF21 levels in participants with normal thyroid function, subclinical hypothyroidism, or overt hypothyroidism and to investigate the change of plasma FGF21 levels in patients with overt hypothyroidism after levothyroxine treatment. A total of 473 drug-naive participants were recruited, including 250 healthy control subjects, 116 patients with subclinical hypothyroidism, and 107 patients with overt hypothyroidism. Thirty-eight patients with overt hypothyroidism were assigned to receive levothyroxine treatment. The overt hypothyroidism group had decreased FGF21 levels compared with the control and subclinical hypothyroidism groups (P<0.01). Levothyroxine treatment markedly attenuated the increased circulating levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hsCRP), and homeostasis model assessment index of insulin resistance (HOMA-IR) in patients with overt hypothyroidism. A significant increase in plasma FGF21 levels was observed after levothyroxine treatment (P<0.01). The change in FGF21 levels was correlated with the increase of FT3 and FT4 after levothyroxine treatment (FT3: r=0.44; FT4: r=0.53; all P<0.05). Levothyroxine treatment ameliorated metabolic disorders and restored the decreased circulating FGF21 levels in patients with overt hypothyroidism. The increase in FGF21 levels after levothyroxine treatment might be partly associated with the amelioration of metabolic disorders in patients with hypothyroidism. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Insulin Rescues Impaired Spermatogenesis via the Hypothalamic-Pituitary-Gonadal Axis in Akita Diabetic Mice and Restores Male Fertility

PubMed Central

Schoeller, Erica L.; Albanna, Gabriella; Frolova, Antonina I.; Moley, Kelle H.

2012-01-01

The mechanism responsible for poor reproductive outcomes in type 1 diabetic males is not well understood. In light of new evidence that the Sertoli cells of the testis secrete insulin, it is currently unclear whether diabetic subfertility is the result of deficiency of pancreatic insulin, testicular insulin, or both. In this study, the Akita mouse diabetic model, which expresses a mutant, nonfunctional form of ins2 in testes and pancreas, was used to distinguish between systemic and local effects of insulin deficiency on the process of spermatogenesis and fertility. We determined that Akita homozygous male mice are infertile and have reduced testis size and abnormal morphology. Spermatogonial germ cells are still present but are unable to mature into spermatocytes and spermatids. Exogenous insulin treatment regenerates testes and restores fertility, but this plasma insulin cannot pass through the blood-testis barrier. We conclude that insulin does not rescue fertility through direct interaction with the testis; instead, it restores function of the hypothalamic-pituitary-gonadal axis and, thus, normalizes hormone levels of luteinizing hormone and testosterone. Although we show that the Sertoli cells of the testis secrete insulin protein, this insulin does not appear to be critical for fertility. PMID:22522616

Beneficial effect of zinc chloride and zinc ionophore pyrithione on attenuated cardioprotective potential of preconditioning phenomenon in STZ-induced diabetic rat heart.

PubMed

Jamwal, Sumit; Kumar, Kushal; Reddy, B V Krishna

2016-05-01

Ischemic preconditioning (IPC) is well demonstrated to produce cardioprotection by phosphorylation and subsequent inactivation of glycogen synthase kinase-3β (GSk-3β) in the normal rat heart, but its effect is attenuated in the diabetic rat heart. This study was designed to investigate the effect of zinc chloride and zinc ionophore pyrithione (ZIP) on the attenuated cardioprotective potential of IPC in the diabetic rat heart. Diabetes mellitus (DM) was induced by a single intraperitoneal administration of streptozotocin (STZ) (50 mg/kg; i.p). The isolated perfused rat heart was subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and cardiac injury was measured by estimating lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the coronary effluent. Also, GSK-3β was measured and neutrophil accumulation was measured by estimating myeloperoxidase (MPO) levels. IPC significantly decreased the myocardial infarct size, the release of LDH and CK-MB, the GSK-3β levels and the MPO levels in the normal rat heart. Pre- and post-ischemic treatment with zinc chloride and zinc ionophore pyrithione (ZIP) in the normal and diabetic rat hearts significantly decreased the myocardial infarct size, the level of CK-MB and LDH in the coronary effluent and GSK-3β and MPO levels. Our results suggest that pharmacological preconditioning with zinc chloride and ZIP significantly restored the attenuated cardioprotective potential of IPC in the diabetic rat heart. © The Author(s) 2015.

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

PubMed Central

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

2014-01-01

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.

PubMed

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J; Isenberg, David A; Magee, Anthony I; Butters, Terry; Jury, Elizabeth C

2014-02-01

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

Connexin43 synthesis, phosphorylation, and degradation in regulation of transient inhibition of gap junction intercellular communication by the phorbol ester TPA in rat liver epithelial cells.

PubMed

Rivedal, Edgar; Leithe, Edward

2005-01-15

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces transient inhibition of gap junction intercellular communication (GJIC) in several cell types. The initial block in GJIC has been attributed to protein kinase C (PKC) mediated phosphorylation of connexin gap junction proteins, including connexin43 (Cx43). Restoration of GJIC, associated with normalization of the Cx43 phosphorylation status, has been ascribed to different events, including dephosphorylation of Cx43 and de novo synthesis of Cx43 or other, non-gap junctional, proteins. The data presented suggest that restoration of GJIC during continuous TPA exposure in normal and transformed rat liver epithelial cells is dependent on synthesis of Cx43 protein, as well as the transport of already synthesized Cx43 from intracellular pools to the plasma membrane. Reactivation of inactivated Cx43 by dephosphorylation does not appear to be involved in the recovery of GJIC. Both PKC and MAP kinase is involved in TPA-induced degradation of Cx43 and inhibition of GJIC. We show that coincubation of TPA with the protein synthesis inhibitor cycloheximide or the transcription inhibitor actinomycin D results in synergistic enhancement of the level of activated ERK1/2. Together, the present data highlight Cx43 degradation and synthesis as critical determinants in TPA-induced modifications of cell-cell communication via gap junctions.

Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle protein α-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy.

PubMed

Custer, Sara K; Todd, Adrian G; Singh, Natalia N; Androphy, Elliot J

2013-10-15

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that stems from low levels of survival of motor neuron (SMN) protein. The processes that cause motor neurons and muscle cells to become dysfunctional are incompletely understood. We are interested in neuromuscular homeostasis and the stresses put upon that system by loss of SMN. We recently reported that α-COP, a member of the coatomer complex of coat protein I (COPI) vesicles, is an SMN-binding partner, implicating this protein complex in normal SMN function. To investigate the functional significance of the interaction between α-COP and SMN, we constructed an inducible NSC-34 cell culture system to model the consequences of SMN depletion and find that depletion of SMN protein results in shortened neurites. Heterologous expression of human SMN, and interestingly over-expression of α-COP, restores normal neurite length and morphology. Mutagenesis of the canonical COPI dilysine motifs in exon 2b results in failure to bind to α-COP and abrogates the ability of human SMN to restore neurite outgrowth in SMN-depleted motor neuron-like NSC-34 cells. We conclude that the interaction between SMN and α-COP serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA.

Protein A Sepharose immunoadsorption can restore the efficacy of platelet concentrates in patients with Glanzmann's thrombasthenia and anti-glycoprotein IIb-IIIa antibodies.

PubMed

Martin, Isabelle; Kriaa, Fayçal; Proulle, Valérie; Guillet, Benoît; Kaplan, Cécile; D'Oiron, Roseline; Debré, Marianne; Fressinaud, Edith; Laurian, Yyes; Tchernia, Gil; Charpentier, Bernard; Lambert, Thierry; Dreyfus, Marie

2002-12-01

Type I Glanzmann's thrombasthenia is a rare congenital platelet function disorder, characterized by undetectable platelet membrane glycoprotein IIb-IIIa (GPIIb-IIIa). Severe bleeding is controlled by transfusion of normal platelets, leading in some cases to the occurrence of anti-GPIIb-IIIa isoantibodies, which induces a loss of transfused platelet efficacy. We used immunoadsorption on protein A Sepharose (IA-PA), which has been shown to be efficient in decreasing the titre of antibodies in several immune diseases, in three patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa isoantibodies on five different occasions. IA-PA was well tolerated with no deleterious side-effects reported. It induced a dramatic decrease of total immunoglobulin (Ig)G, including anti-GPIIb-IIIa isoantibody levels, as assessed by the monoclonal antibody-specific immobilization of platelet antigens test and the ex vivo inhibition of normal platelet aggregation induced by the patient's platelet-rich or platelet-poor plasma. Elimination of the antibody was associated with a correction of the bleeding time following platelet transfusion. IA-PA combined with platelet transfusion made it possible to control two life-threatening haemorrhages, and allowed two surgical procedures and one bone marrow transplantation to be performed safely. Our experience suggests that IA-PA, which restores the haemostatic efficacy of platelet transfusion, is a valuable therapeutic strategy in patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa isoantibodies.

Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1.

PubMed

Papadopoulos, Panayiota; Tong, Xin-Kang; Imboden, Hans; Hamel, Edith

2017-06-01

Alterations of the renin-angiotensin system have been implicated in the pathogenesis of Alzheimer's disease. We tested the efficacy of losartan (10 mg/kg/day for three months), a selective angiotensin II type 1 receptor antagonist, in alleviating cerebrovascular and cognitive deficits in double-transgenic mice (six months at endpoint) that overexpress a mutated form of the human amyloid precursor protein (APP Swe,Ind ) and a constitutively active form of the transforming growth factor-β1, thereafter named A/T mice. Losartan rescued cerebrovascular reactivity, particularly the dilatory responses, but failed to attenuate astroglial activation and to normalize the neurovascular uncoupling response to sensory stimulation. The cognitive deficits of A/T mice were not restored by losartan nor were the increased brain levels of soluble and insoluble Aβ 1-40 and Aβ 1-42 peptides normalized. Our results are the first to demonstrate the capacity of losartan to improve cerebrovascular reactivity in an Alzheimer's disease mouse model of combined Aβ-induced vascular oxidative stress and transforming growth factor-β1-mediated vascular fibrosis. These data suggest that losartan may be promising for restoring cerebrovascular function in patients with vascular diseases at risk for vascular dementia or Alzheimer's disease. However, a combined therapy may be warranted for rescuing both vascular and cognitive deficits in a multifaceted pathology like Alzheimer's disease.

Inactivating hepatic follistatin alleviates hyperglycemia.

PubMed

Tao, Rongya; Wang, Caixia; Stöhr, Oliver; Qiu, Wei; Hu, Yue; Miao, Ji; Dong, X Charlie; Leng, Sining; Stefater, Margaret; Stylopoulos, Nicholas; Lin, Lin; Copps, Kyle D; White, Morris F

2018-06-04

Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines-including excess follistatin (Fst)-that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.

Chronic administration of ellagic acid improved the cognition in middle-aged overweight men.

PubMed

Liu, Ying; Yu, Shuyi; Wang, Fen; Yu, Haitao; Li, Xueli; Dong, Wanru; Lin, Ruichao; Liu, Qingshan

2018-03-01

This study aimed to investigate if ellagic acid has beneficial effects on cognitive deficits in middle-aged overweight individuals and to propose a possible mechanism. A total of 150 middle-aged male participants, including 76 normal-weight and 74 overweight men, aged between 45 to 55 years, were recruited for this study. Both normal-weight and overweight participants were administered either 50 mg ellagic acid or placebo cellulose daily for 12 weeks. Blood lipids, peripheral brain-derived neurotrophic factor (BDNF), and saliva cortisol were assessed on the last day of the procedure to investigate the effects induced by ellagic acid. The results revealed that ellagic acid treatment improved the levels of blood lipid metabolism with a 4.7% decline in total cholesterol, 7.3% decline in triglycerides, 26.5% increase in high-density lipoprotein, and 6.5% decline in low-density lipoprotein. Additionally, ellagic acid increased plasma BDNF by 21.2% in the overweight group and showed no effects on normal-weight participants. Moreover, the increased saliva cortisol level in overweight individuals was inhibited by 22.7% in a 12-week ellagic acid treatment. Also, compared with placebo, overweight individuals who consumed ellagic acid showed enhanced cognitive function as measured by the Wechsler Adult Intelligence Scale-Revised and the Montreal Cognitive Assessment. To the best of our knowledge, this is the first report showing that ellagic acid prevents cognitive deficits through normalization of lipid metabolism, increase in plasma BDNF level, and reduction of saliva cortisol concentration. These results indicate that ellagic acid has a potential to restore cognitive performance related to mild age-related declines.

Ocimum gratissmum aqueous extract reduces plasma lipid in hypercholesterol-fed hamsters

PubMed Central

Chao, Pei-Yu; Lin, James A.; Ting, Wei-Jen; Lee, Hsueh-Hui; Hsieh, Kuanghui; Chiu, Yung-Wei; Lai, Te-Jen; Hwang, Jin-Ming; Liu, Je-rYuh; Huang, Chih-Yang

2016-01-01

Objectives: Hyperlipidemia is a significant risk factor in the development of atherosclerosis and related diseases which are major health problem in many developed and developing countries that can lead to fatality due to the changes in lifestyle and dietary habits in this modern age. Methods: In the present study, the Ocimum gratissimum aqueous extract (OGE) was tested for the lowering effect on the serum lipid level of male hamsters on a high-fat (12%) and high-cholesterol (0.2%) diet (HFCD). Results: The results showed that the levels of serum high-density-lipoprotein-cholesterol (HDL-C) low-density-lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and triglycerols (TG) were increased in the HFCD group (113±11, 259±87, 629±175 and 625±262, respectively), as compared to the control normal diet group (51±8, 19±5, 77±16 and 101±44, respectively). When co-treated with various doses (10 and 20 mg/kg) of the OGE or rosuvastatin, the rats exhibited the restoration of normal serum LDL-C, TC, and TG levels. Conclusion: Therefore, we suggest that the Ocimum gratissimum aqueous extract may have the potential function of lowering serum lipid in rats. PMID:27877073

Clearwater Focus Watershed; Nez Perce Tribe, 2003-2004 Annual Report.

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

Jones, Ira

2004-06-01

The Nez Perce Tribe Department of Fisheries Resource Management, Watershed Division, approaches watershed restoration with a goal to protect, restore, and enhance a connected network of functioning habitat types capable of supporting all fish life stages. Its goal is also to re-establish normal patterns of production, dispersal, and exchange of genetic information within the 1855 Treaty Area. The Nez Perce Tribe began watershed restoration projects within the Clearwater River Subbasin in 1996. Progress has been made in restoring the sub-basin by excluding cattle from critical riparian areas through fencing, stabilizing stream banks, decommissioning roads, and upgrading culverts. Coordination of thesemore » projects is critical to the success of the restoration of the sub-basin. Coordination activities also includes: inter and intra-department coordination, sub-basin assessment and planning, involving government and private organizations, and treaty area coordination.« less

Effects of kidney or kidney-pancreas transplantation on plasma pentosidine.

PubMed

Hricik, D E; Schulak, J A; Sell, D R; Fogarty, J F; Monnier, V M

1993-02-01

Tissue and plasma concentrations of pentose-derived glycation end-products ("pentosidine") are elevated in diabetic patients with normal renal function and in both diabetic and nondiabetic patients with end-stage renal disease. To determine the effects of correcting hyperglycemia and/or renal failure on the accumulation of pentosidine, we used reverse phase and ion exchange high performance liquid chromatography to measure this advanced glycation end-product in plasma proteins of diabetic and nondiabetic transplant recipients at various time intervals after kidney-pancreas or kidney transplantation. Changes in plasma pentosidine levels after transplantation were compared to changes in simultaneously obtained glycohemoglobin levels. Both kidney and kidney-pancreas transplantation were accompanied by a dramatic, but incomplete, reduction of plasma pentosidine concentrations within three months of transplantation. Kidney-pancreas transplantation resulted in normal glycohemoglobin levels within three months but offered no advantage over kidney transplantation alone in the partial correction of plasma pentosidine levels. There was no correlation between posttransplant plasma pentosidine and glycohemoglobin levels in either diabetic or nondiabetic transplant recipients. We conclude that renal failure is the major factor accounting for the accumulation of pentosidine in both diabetic and nondiabetic patients with end-stage renal disease. Restoration of euglycemia after kidney-pancreas transplantation provides no additional benefit in reducing plasma pentosidine levels to that achieved by correction of renal failure after kidney transplantation alone.

Triiodothyronine activates lactate oxidation without impairing fatty acid oxidation and improves weaning from extracorporeal membrane oxygenation.

PubMed

Kajimoto, Masaki; Ledee, Dolena R; Xu, Chun; Kajimoto, Hidemi; Isern, Nancy G; Portman, Michael A

2014-01-01

Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. It has previously been shown that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. METHODS AND RESULTS: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 h) and wean: normal circulation (Group-C); transient coronary occlusion (10 min) for ischemia-reperfusion (IR) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon ((13)C)-labeled lactate, medium-chain and long-chain FAs, was infused as oxidative substrates. Substrate fractional contribution (FC) to the citric acid cycle was analyzed by(13)C-nuclear magnetic resonance. ECMO depressed circulating T3 levels to 40% of the baseline at 4 h and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [adenosine triphosphate]/[adenosine diphosphate] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. T3 releases inhibition of lactate oxidation following IR injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.

Restoration handbook for sagebrush steppe ecosystems with emphasis on greater sage-grouse habitat—Part 2. Landscape level restoration decisions

USGS Publications Warehouse

Pyke, David A.; Knick, Steven T.; Chambers, Jeanne C.; Pellant, Mike; Miller, Richard F.; Beck, Jeffrey L.; Doescher, Paul S.; Schupp, Eugene W.; Roundy, Bruce A.; Brunson, Mark; McIver, James D.

2015-12-07

Land managers do not have resources to restore all locations because of the extent of the restoration need and because some land uses are not likely to change, therefore, restoration decisions made at the landscape to regional scale may improve the effectiveness of restoration to achieve landscape and local restoration objectives. We present a landscape restoration decision tool intended to assist decision makers in determining landscape objectives, to identify and prioritize landscape areas where sites for priority restoration projects might be located, and to aid in ultimately selecting restoration sites guided by criteria used to define the landscape objectives. The landscape restoration decision tool is structured in five sections that should be addressed sequentially. Each section has a primary question or statement followed by related questions and statements to assist the user in addressing the primary question or statement. This handbook will guide decision makers through the important process steps of identifying appropriate questions, gathering appropriate data, developing landscape objectives, and prioritizing landscape patches where potential sites for restoration projects may be located. Once potential sites are selected, land managers can move to the site-specific decision tool to guide restoration decisions at the site level.

Infection of Female BWF1 Lupus Mice with Malaria Parasite Attenuates B Cell Autoreactivity by Modulating the CXCL12/CXCR4 Axis and Its Downstream Signals PI3K/AKT, NFκB and ERK

PubMed Central

Badr, Gamal; Sayed, Ayat; Abdel-Maksoud, Mostafa A.; Mohamed, Amany O.; El-Amir, Azza; Abdel-Ghaffar, Fathy A.; Al-Quraishy, Saleh; Mahmoud, Mohamed H.

2015-01-01

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormal autoreactivity in B cells. Lymphocytes and their soluble mediators contribute to the disease pathogenesis. We recently demonstrated that infecting lupus mice with malaria confers protection against lupus nephritis by attenuating oxidative stress in both liver and kidney tissues. In the current study, we further investigated B cell autoreactivity in female BWF1 lupus mice after infection with either live or gamma-irradiated malaria, using ELISA, flow cytometry and Western blot analysis. The lupus mice exhibited a significant elevation in plasma levels of IL-4, IL-6, IL-7, IL-12, IL-17, IFN-α, IFN-γ, TGF-β, BAFF and APRIL and a marked elevation of IgG2a, IgG3 and ant-dsDNA autoantibodies compared with normal healthy mice. Infecting lupus mice with live but not gamma-irradiated malaria parasite partially and significantly restored the levels of the soluble mediators that contribute to the progression of lupus. Furthermore, the B cells of lupus mice exhibited an increased proliferative capacity; aberrant overexpression of the chemokine receptor CXCR4; and a marked elevation in responsiveness to their cognate ligand (CXCL12) via aberrant activation of the PI3K/AKT, NFκB and ERK signaling pathways. Interestingly, infecting lupus mice with live but not gamma-irradiated malaria parasite restored a normal proliferative capacity, surface expression of CXCR4 and B cell response to CXCL-12. Taken together, our data present interesting findings that clarify, for the first time, the molecular mechanisms of how infection of lupus mice with malaria parasite controls B cell autoreactivity and thus confers protection against lupus severity. PMID:25909640

Moringa olifeira Lam. Stimulates Activation of the Insulin-Dependent Akt Pathway. Antidiabetic Effect in a Diet-Induced Obesity (DIO) Mouse Model.

PubMed

Attakpa, E S; Sangaré, M M; Béhanzin, G J; Ategbo, J-M; Seri, B; Khan, N A

2017-01-01

We investigated the antidiabetic effect of Moringa olifeira Lam. in a diet-induced obesity (DIO) mouse model. Six mice were randomly selected as normal controls. Moringa olifeira Lam. leaf extract at a dose of 200, 400 or 600 mg/kg body weight, glibenclamide (Glib) at the dose of 10 mg/kg (positive control) and distilled water at 10 ml/kg (control group) were administered orally by gastric intubation, and each group consisted of six mice. Insulinsensitive tissues (liver, skeletal muscle) were collected to investigate antidiabetic effects and examine the plant's molecular mechanisms. Moringa olifeira Lam. leaf extract prevented weight gain. It also reduced blood glucose in DIO mice. Glib and Moringa olifeira Lam. leaf extract, 400 mg/kg, treatments restored insulin levels towards normal values (P < 0.05 versus diabetic control group). Western immunoblot analysis of different tissues, collected at the end of the study, demonstrated that Moringa olifeira Lam. stimulated activation of the insulin-dependent Akt pathway and increased the protein content of Glut 4 in skeletal muscle. The improvement of hepatic steatosis observed in DIO-treated mice was associated with a decrease in the hepatic content of SREBP-1, a transcription factor involved in de novo lipogenesis. The hepatic PPARα protein content in the plant extract- treated mice remained significantly higher than those of the control group (P < 0.05). In conclusion, this study provides the first evidence for direct action of Moringa olifeira Lam. on pancreatic β-cells, enhancing glucose-stimulated insulin secretion. This correlated with hypoglycaemic effects in diabetic mice associated with restored levels of plasma insulin.

Vitamin B5 and N-acetylcysteine in nonalcoholic steatohepatitis: a pre-clinical study in a dietary mouse model

PubMed Central

Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L.; Michelotti, Gregory Alexander; de Almeida Pereira, Thiago; Xie, Guanhua; Moylan, Cynthia A.; Diehl, Anna Mae

2015-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free Coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. Objectives We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. Methods CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD-diet fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Results Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity, and correlated with worse liver cell apoptosis, inflammation and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice. Conclusion In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH. PMID:26403427

SLEEPLESS is a bi-functional regulator of excitability and cholinergic synaptic transmission

PubMed Central

Wu, Meilin; Robinson, James E.; Joiner, William J.

2014-01-01

Summary Background Although sleep is conserved throughout evolution, the molecular basis of its control is still largely a mystery. We previously showed that the quiver/sleepless (qvr/sss) gene encodes a membrane-tethered protein that is required for normal sleep in Drosophila. SLEEPLESS (SSS) protein functions, at least in part, by upregulating the levels and open probability of Shaker (Sh) potassium channels to suppress neuronal excitability and enable sleep. Consistent with this proposed mechanism, loss-of-function mutations in Sh phenocopy qvr/sss null mutants. However, sleep is more genetically modifiable in Sh than in qvr/sss mutants, suggesting that sss may regulate additional molecules to influence sleep. Results Here we show that SSS also antagonizes nicotinic acetylcholine receptors (nAChRs) to reduce synaptic transmission and promote sleep. Mimicking this antagonism with the nAChR inhibitor mecamylamine or by RNAi knockdown of specific nAChR subunits is sufficient to restore sleep to qvr/sss mutants. Regulation of nAChR activity by SSS occurs post-transcriptionally since the levels of nAChR mRNAs are unchanged in qvr/sss mutants. Regulation of nAChR activity by SSS may in fact be direct, since SSS forms a stable complex with and antagonizes fly nAChR function in transfected cells. Intriguingly, lynx1, a mammalian homolog of SSS, can partially restore normal sleep to qvr/sss mutants, and lynx1 can form stable complexes with Shaker-type channels and nAChRs. Conclusions Together, our data point to an evolutionarily conserved, bi-functional role for SSS and its homologs in controlling excitability and synaptic transmission in fundamental processes of the nervous system such as sleep. PMID:24613312

Infection of Female BWF1 Lupus Mice with Malaria Parasite Attenuates B Cell Autoreactivity by Modulating the CXCL12/CXCR4 Axis and Its Downstream Signals PI3K/AKT, NFκB and ERK.

PubMed

Badr, Gamal; Sayed, Ayat; Abdel-Maksoud, Mostafa A; Mohamed, Amany O; El-Amir, Azza; Abdel-Ghaffar, Fathy A; Al-Quraishy, Saleh; Mahmoud, Mohamed H

2015-01-01

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormal autoreactivity in B cells. Lymphocytes and their soluble mediators contribute to the disease pathogenesis. We recently demonstrated that infecting lupus mice with malaria confers protection against lupus nephritis by attenuating oxidative stress in both liver and kidney tissues. In the current study, we further investigated B cell autoreactivity in female BWF1 lupus mice after infection with either live or gamma-irradiated malaria, using ELISA, flow cytometry and Western blot analysis. The lupus mice exhibited a significant elevation in plasma levels of IL-4, IL-6, IL-7, IL-12, IL-17, IFN-α, IFN-γ, TGF-β, BAFF and APRIL and a marked elevation of IgG2a, IgG3 and ant-dsDNA autoantibodies compared with normal healthy mice. Infecting lupus mice with live but not gamma-irradiated malaria parasite partially and significantly restored the levels of the soluble mediators that contribute to the progression of lupus. Furthermore, the B cells of lupus mice exhibited an increased proliferative capacity; aberrant overexpression of the chemokine receptor CXCR4; and a marked elevation in responsiveness to their cognate ligand (CXCL12) via aberrant activation of the PI3K/AKT, NFκB and ERK signaling pathways. Interestingly, infecting lupus mice with live but not gamma-irradiated malaria parasite restored a normal proliferative capacity, surface expression of CXCR4 and B cell response to CXCL-12. Taken together, our data present interesting findings that clarify, for the first time, the molecular mechanisms of how infection of lupus mice with malaria parasite controls B cell autoreactivity and thus confers protection against lupus severity.

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer's Disease.

PubMed

Del Cerro, Patricia; Alquézar, Carolina; Bartolomé, Fernando; González-Naranjo, Pedro; Pérez, Concepción; Carro, Eva; Páez, Juan A; Campillo, Nuria E; Martín-Requero, Ángeles

2018-05-07

Alzheimer's disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer's disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects. The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer's disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer's disease, contributing to the instigation of the disease. Lymphoblastoid cell lines from patients with Alzheimer's disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells. We report here that PGN33 normalized the increased proliferative activity of Alzheimer's disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells. Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer's disease.

A nanomedicine to treat ocular surface inflammation: performance on an experimental dry eye murine model.

PubMed

Contreras-Ruiz, L; Zorzi, G K; Hileeto, D; López-García, A; Calonge, M; Seijo, B; Sánchez, A; Diebold, Y

2013-05-01

MUC5AC is a glycoprotein with gel-forming properties, whose altered expression has been implicated in the pathogenesis of dry eye disease. The aim of our study was to achieve an efficient in vivo transfection of MUC5AC, restore its normal levels in an inflamed ocular surface and determine whether restored MUC5AC levels improve ocular surface inflammation. Cationized gelatin-based nanoparticles (NPs) loaded with a plasmid coding a modified MUC5AC protein (pMUC5AC) were instilled in healthy and experimental dry eye (EDE) mice. MUC5AC expression, clinical signs, corneal fluorescein staining and tear production were evaluated. Ocular specimens were processed for histopathologic evaluation, including goblet cell count and CD4 immunostaining. Neither ocular discomfort nor irritation was observed in vivo after NP treatment. Expression of modified MUC5AC was significantly higher in ocular surface tissue of pMUC5AC-NP-treated animals than that of controls. In healthy mice, pMUC5AC-NPs had no effect on fluorescein staining or tear production. In EDE mice, both parameters significantly improved after pMUC5AC-NP treatment. Anterior eye segment of treated mice showed normal architecture and morphology with lack of remarkable inflammatory changes, and a decrease in CD4+ T-cell infiltration. Thus, pMUC5AC-NPs were well tolerated and able to induce the expression of modified MUC5A in ocular surface tissue, leading to reduction of the inflammation and, consequently improving the associated clinical parameters, such as tear production and fluorescein staining. These results identify a potential application of pMUC5AC-NPs as a new therapeutic modality for the treatment of dry eye disease.

Combination Chemotherapy with Suboptimal Doses of Benznidazole and Pentoxifylline Sustains Partial Reversion of Experimental Chagas' Heart Disease

PubMed Central

Vilar-Pereira, Glaucia; Resende Pereira, Isabela; de Souza Ruivo, Leonardo Alexandre; Cruz Moreira, Otacilio; da Silva, Andrea Alice; Britto, Constança

2016-01-01

Chronic chagasic cardiomyopathy (CCC) progresses with parasite persistence, fibrosis, and electrical alterations associated with an unbalanced immune response such as high plasma levels of tumor necrosis factor (TNF) and nitric oxide (NO). Presently, the available treatments only mitigate the symptoms of CCC. To improve CCC prognosis, we interfered with the parasite load and unbalanced immune response using the trypanocidal drug benznidazole (Bz) and the immunoregulator pentoxifylline (PTX). C57BL/6 mice chronically infected with the Colombian strain of Trypanosoma cruzi and with signs of CCC were treated for 30 days with a suboptimal dose of Bz (25 mg/kg of body weight), PTX (20 mg/kg), or their combination (Bz plus PTX) and analyzed for electrocardiographic, histopathological, and immunological changes. Bz (76%) and Bz-plus-PTX (79%) therapies decreased parasite loads. Although the three therapies reduced myocarditis and fibrosis and ameliorated electrical alterations, only Bz plus PTX restored normal heart rate-corrected QT (QTc) intervals. Bz-plus-PTX-treated mice presented complementary effects of Bz and PTX, which reduced TNF expression (37%) in heart tissue and restored normal TNF receptor 1 expression on CD8+ T cells, respectively. Bz (85%) and PTX (70%) therapies reduced the expression of inducible nitric oxide synthase (iNOS/NOS2) in heart tissue, but only Bz (58%) reduced NO levels in serum. These effects were more pronounced after Bz-plus-PTX therapy. Moreover, 30 to 50 days after treatment cessation, reductions of the prolonged QTc and QRS intervals were sustained in Bz-plus-PTX-treated mice. Our findings support the importance of interfering with the etiological agent and immunological abnormalities to improve CCC prognosis, opening an opportunity for a better quality of life for Chagas' disease (CD) patients. PMID:27161638

Extinction Training Regulates Neuroadaptive Responses to Withdrawal from Chronic Cocaine Self-Administration

PubMed Central

Self, David W.; Choi, Kwang-Ho; Simmons, Diana; Walker, John R.; Smagula, Cynthia S.

2004-01-01

Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction. PMID:15466321

Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior.

PubMed

Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B; Singewald, Nicolas; Pollak, Daniela D

2016-01-01

Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.

[Energy corrective and antioxidative actions of cytoflavin during postischemic period of human dermal fibroblasts in vitro].

PubMed

Tiuriaeva, I I; Kuranova, M L; Gonchar, I V; Rozanov, Iu M

2012-01-01

The influence of metabolic drug Cytoflavin (CF) with antihypoxic and antioxidative properties on human dermal fibroblasts in a model of ischemia-reoxygenation in vitro was studied. It was revealed that the restoration of ATP synthesis in fibroblasts in the postischemic period was considerably accelerated (in 2.1 times) by the addition of CF to the culture medium. The drug had a cell protective effect of reducing cell mortality during the reoxygenation after ischemia by 2-2.7 times. CF effectively reduced the level of reactive oxygen species (ROS) in fibroblasts after H2O2 treatment which allowed maintaining their survival at the level of control cells. Pretreatment of the cells with CF for one day ensured the maintenance of normal levels of ROS during the investigated time period in the fibroblasts subjected to H2O2 treatment, and reduced H2O2-induced cell death by almost a third compared to control cells. The introduction of CF in culture medium after ischemia showed no influence on Hsp70 synthesis, but led to decrease in GRP78 synthesis, raised after ischemia, to the control level, indicating a resolve of the endoplasmic reticulum (ER) stress and functional normalization of ER.

Association between thyroid hormones and TRAIL.

PubMed

Bernardi, Stella; Bossi, Fleur; Toffoli, Barbara; Giudici, Fabiola; Bramante, Alessandra; Furlanis, Giulia; Stenner, Elisabetta; Secchiero, Paola; Zauli, Giorgio; Carretta, Renzo; Fabris, Bruno

2017-11-01

Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis-inducing ligand) might have a role in the regulation of body weight and metabolism. Interestingly, thyroid hormones seem to increase TRAIL tissue expression. This study aimed at evaluating whether overt thyroid disorders affected circulating TRAIL levels. TRAIL circulating levels were measured in euthyroid, hyperthyroid, and hypothyroid patients before and after thyroid function normalization. Univariate and multivariate analyses were performed to evaluate the correlation between thyroid hormones and TRAIL. Then, the stimulatory effect of both triiodothyronine (T3) and thyroxine (T4) on TRAIL was evaluated in vitro on peripheral blood mononuclear cells. Circulating levels of TRAIL significantly increased in hyperthyroid and decreased in hypothyroid patients as compared to controls. Once thyroid function was restored, TRAIL levels normalized. There was an independent association between TRAIL and both fT3 and fT4. Consistent with these findings, T3 and T4 stimulated TRAIL release in vitro. Here we show that thyroid hormones are associated with TRAIL expression in vivo and stimulate TRAIL expression in vitro. Given the overlap between the metabolic effects of thyroid hormones and TRAIL, this work sheds light on the possibility that TRAIL might be one of the molecules mediating thyroid hormones peripheral effects. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

77 FR 21584 - Notice of Meeting, Front Range Resource Advisory Council

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-10

... normal business hours. The FIRS is available 24 hours a day, 7 days a week, to leave a message or question with the above individual. You will receive a reply during normal business hours. SUPPLEMENTARY... of discussion items include: Trail work and native fish habitat restoration with the Orient Land...

Changes in Pore Water Quality After Peatland Restoration: Assessment of a Large-Scale, Replicated Before-After-Control-Impact Study in Finland

NASA Astrophysics Data System (ADS)

Menberu, Meseret Walle; Marttila, Hannu; Tahvanainen, Teemu; Kotiaho, Janne S.; Hokkanen, Reijo; Kløve, Bjørn; Ronkanen, Anna-Kaisa

2017-10-01

Drainage is known to affect peatland natural hydrology and water quality, but peatland restoration is considered to ameliorate peatland degradation. Using a replicated BACIPS (Before-After-Control-Impact Paired Series) design, we investigated 24 peatlands, all drained for forestry and subsequently restored, and 19 pristine control boreal peatlands with high temporal and spatial resolution data on hydroclimate and pore water quality. In drained conditions, total nitrogen (Ntot), total phosphorus (Ptot), and dissolved organic carbon (DOC) in pore water were several-fold higher than observed at pristine control sites, highlighting the impacts of long-term drainage on pore water quality. In general, pore water DOC and Ntot decreased after restoration measures but still remained significantly higher than at pristine control sites, indicating long time lags in restoration effects. Different peatland classes and trophic levels (vegetation gradient) responded differently to restoration, primarily due to altered hydrology and varying acidity levels. Sites that were hydrologically overrestored (inundated) showed higher Ptot, Ntot, and DOC than well-restored or insufficiently restored sites, indicating the need to optimize natural-like hydrological regimes when restoring peatlands drained for forestry. Rich fens (median pH 6.2-6.6) showed lower pore water Ptot, Ntot, and DOC than intermediate and poor peats (pH 4.0-4.6) both before and after restoration. Nutrients and DOC in pore water increased in the first year postrestoration but decreased thereafter. The most important variables related to pore water quality were trophic level, peatland class, water table level, and soil and air temperature.

Effect of aqueous extract of Tribulus terrestris on oxalate-induced oxidative stress in rats

PubMed Central

Kamboj, P.; Aggarwal, M.; Puri, S.; Singla, S. K.

2011-01-01

The present study was aimed at studying the effect of Tribulus terrestris on different parameters of oxidative stress and gene expression profiles of antioxidant enzymes in renal tissues of male wistar rats after induction of hyperoxaluria. The animals were divided into three groups. The animals in group I (control) were administered vehicle only. In group II, the animals were treated with ethylene glycol (hyperoxaluric agent) and those in group III were administered T. terrestris plant extract in addition to ethylene glycol. All treatments were continued for a period of seven weeks. Ethylene glycol feeding resulted in hyperoxaluria as well as increased excretion of calcium and phosphate. Serum creatinine, uric acid and blood urea nitrogen levels were also altered in hyperoxaluric animals. Various oxidative stress parameters viz. lipid peroxidation and activity of antioxidant enzymes were used to confirm the peroxidant state. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm whether steady-state transcription level of different antioxidant enzymes was altered. T. terrestris significantly reduced the excretion of oxalate, calcium, and phosphate along with decreased levels of blood urea nitrogen, uric acid and creatinine in serum. T. terrestris also reduced hyperoxaluria- caused oxidative stress, and restored antioxidant enzyme activity and their expression profile in kidney tissue. Histological analysis depicted that T. terrestris treatment decreased renal epithelial damage, inflammation, and restored normal glomerular morphology. PMID:21886973

Chlorella protects against hydrogen peroxide-induced pancreatic β-cell damage.

PubMed

Lin, Chia-Yu; Huang, Pei-Jane; Chao, Che-Yi

2014-12-01

Oxidative stress has been implicated in the etiology of pancreatic β-cell dysfunction and diabetes. Studies have shown that chlorella could be important in health promotion or disease prevention through its antioxidant capacity. However, whether chlorella has a cytoprotective effect in pancreatic β-cells remains to be elucidated. We investigated the protective effects of chlorella on H2O2-induced oxidative damage in INS-1 (832/13) cells. Chlorella partially restored cell viability after H2O2 toxicity. To further investigate the effects of chlorella on mitochondria function and cellular oxidative stress, we analyzed mitochondria membrane potential, ATP concentrations, and cellular levels of reactive oxygen species (ROS). Chlorella prevented mitochondria disruption and maintained cellular ATP levels after H2O2 toxicity. It also normalized intracellular levels of ROS to that of control in the presence of H2O2. Chlorella protected cells from apoptosis as indicated by less p-Histone and caspase 3 activation. In addition, chlorella not only enhanced glucose-stimulated insulin secretion (GSIS), but also partially restored the reduced GSIS after H2O2 toxicity. Our results suggest that chlorella is effective in amelioration of cellular oxidative stress and destruction, and therefore protects INS-1 (832/13) cells from H2O2-induced apoptosis and increases insulin secretion. Chlorella should be studied for use in the prevention or treatment of diabetes.

Evaluation of Four Different Restorative Materials for Restoration of the Periodontal Condition of Wedge-Shaped Defect: A Comparative Study.

PubMed

Ruan, Jian-Yong; Gong, Zheng-Lin; Zhang, Rui-Zhi; Zhang, Zhe; Xu, Ran; Li, Da-Xu; Ren, Le; Tao, Hong

2017-09-16

BACKGROUND This study aimed to conduct a clinical evaluation of four restorative materials for restoration of dental wedge-shaped defect (WSD) and their impacts on periodontal tissues. MATERIAL AND METHODS A total of 280 maxillary premolars with dental WSD were selected from 106 patients; the patient cases were divided into eight groups according to different combinations of restorative materials (flowable resin composites, Dyract compomers, glass ionomer cement (GIC), light-curing composite resin), and WSD positions (approaching gingival and subgingival positions). Gingival crevicular fluid (GCF) volume, levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and interleukin-1β (IL-1β) in GCF were analyzed, while probing depth (PD), plaque index (PLI), and sulcus bleeding index (SBI) were also measured. The periodontal conditions of all patients were followed prior to restoration, as well as six months and 12 months after restoration. RESULTS After six months of restoration, the overall clinical success rates of flowable resin composites, Dyract compomers, and light-curing composite resin were greater than those of GIC. GCF volume, GCF-AST, IL-1β levels, PD, PLI, and SBI of cases restored by GIC were higher than those restored by the other three materials. After 12 months of restoration, the overall clinical success rates of flowable resin composites and Dyract compomers were greater than those of light-curing composite resin and GIC. GCF volume, GCF-AST, GCF-ALP, IL-1β levels, PD, PLI, and SBI of cases restored by GIC were higher than those restored by the other three materials. CONCLUSIONS Our study provided evidence that the clinical efficacy of flowable resin composites, Dyract compomers, and light-curing composite resin was greater than that of GIC for restoration of dental WSD.

Evaluation of Four Different Restorative Materials for Restoration of the Periodontal Condition of Wedge-Shaped Defect: A Comparative Study

PubMed Central

Ruan, Jian-Yong; Gong, Zheng-Lin; Zhang, Rui-Zhi; Zhang, Zhe; Xu, Ran; Li, Da-Xu; Ren, Le; Tao, Hong

2017-01-01

Background This study aimed to conduct a clinical evaluation of four restorative materials for restoration of dental wedge-shaped defect (WSD) and their impacts on periodontal tissues. Material/Methods A total of 280 maxillary premolars with dental WSD were selected from 106 patients; the patient cases were divided into eight groups according to different combinations of restorative materials (flowable resin composites, Dyract compomers, glass ionomer cement (GIC), light-curing composite resin), and WSD positions (approaching gingival and subgingival positions). Gingival crevicular fluid (GCF) volume, levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and interleukin-1β (IL-1β) in GCF were analyzed, while probing depth (PD), plaque index (PLI), and sulcus bleeding index (SBI) were also measured. The periodontal conditions of all patients were followed prior to restoration, as well as six months and 12 months after restoration. Results After six months of restoration, the overall clinical success rates of flowable resin composites, Dyract compomers, and light-curing composite resin were greater than those of GIC. GCF volume, GCF-AST, IL-1β levels, PD, PLI, and SBI of cases restored by GIC were higher than those restored by the other three materials. After 12 months of restoration, the overall clinical success rates of flowable resin composites and Dyract compomers were greater than those of light-curing composite resin and GIC. GCF volume, GCF-AST, GCF-ALP, IL-1β levels, PD, PLI, and SBI of cases restored by GIC were higher than those restored by the other three materials. Conclusions Our study provided evidence that the clinical efficacy of flowable resin composites, Dyract compomers, and light-curing composite resin was greater than that of GIC for restoration of dental WSD. PMID:28917087

Involvement of brain ketone bodies and the noradrenergic pathway in diabetic hyperphagia in rats.

PubMed

Iwata, Kinuyo; Kinoshita, Mika; Yamada, Shunji; Imamura, Takuya; Uenoyama, Yoshihisa; Tsukamura, Hiroko; Maeda, Kei-Ichiro

2011-03-01

Uncontrolled type 1 diabetes leads to hyperphagia and severe ketosis. This study was conducted to test the hypothesis that ketone bodies act on the hindbrain as a starvation signal to induce diabetic hyperphagia. Injection of an inhibitor of monocarboxylate transporter 1, a ketone body transporter, into the fourth ventricle normalized the increase in food intake in streptozotocin (STZ)-induced diabetic rats. Blockade of catecholamine synthesis in the hypothalamic paraventricular nucleus (PVN) also restored food intake to normal levels in diabetic animals. On the other hand, hindbrain injection of the ketone body induced feeding, hyperglycemia, and fatty acid mobilization via increased sympathetic activity and also norepinephrine release in the PVN. This result provides evidence that hyperphagia in STZ-induced type 1 diabetes is signaled by a ketone body sensed in the hindbrain, and mediated by noradrenergic inputs to the PVN.

Diagnostic change and personality stability following functional restoration treatment in chronic low back pain patients.

PubMed

Vittengl, J R; Clark, L A; Owen-Salters, E; Gatchel, R J

1999-03-01

This study examined personality pathology in a group of patients with chronic low back pain (CLBP) using both diagnostic interviews and dimensional self-report instruments. A group of CLBP patients (N = 125) was assessed before functional restoration treatment and compared with a matched normal comparison group (N = 75). The CLBP group evidenced broad personality pathology in all assessment modes pretreatment relative to the normal comparison sample. In addition, two subsamples of CLBP patients (n = 49 and n = 56) were assessed after treatment. Reductions in personality pathology between pre- and posttreatment assessments were more pronounced for diagnostic interview than dimensional self-report assessments. These results are discussed in the context of personality assessment and CLBP.

Respiratory Syncytial Virus Inhibits Ciliagenesis in Differentiated Normal Human Bronchial Epithelial Cells: Effectiveness of N-Acetylcysteine

PubMed Central

Mata, Manuel; Sarrion, Irene; Armengot, Miguel; Carda, Carmen; Martinez, Isidoro; Melero, Jose A.; Cortijo, Julio

2012-01-01

Persistent respiratory syncytial virus (RSV) infections have been associated with the exacerbation of chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). This virus infects the respiratory epithelium, leading to chronic inflammation, and induces the release of mucins and the loss of cilia activity, two factors that determine mucus clearance and the increase in sputum volume. These alterations involve reactive oxygen species-dependent mechanisms. The antioxidant N-acetylcysteine (NAC) has proven useful in the management of COPD, reducing symptoms, exacerbations, and accelerated lung function decline. NAC inhibits RSV infection and mucin release in human A549 cells. The main objective of this study was to analyze the effects of NAC in modulating ciliary activity, ciliagenesis, and metaplasia in primary normal human bronchial epithelial cell (NHBEC) cultures infected with RSV. Our results indicated that RSV induced ultrastructural abnormalities in axonemal basal bodies and decreased the expression of β-tubulin as well as two genes involved in ciliagenesis, FOXJ1 and DNAI2. These alterations led to a decrease in ciliary activity. Furthermore, RSV induced metaplastic changes to the epithelium and increased the number of goblet cells and the expression of MUC5AC and GOB5. NAC restored the normal functions of the epithelium, inhibiting ICAM1 expression, subsequent RSV infection through mechanisms involving nuclear receptor factor 2, and the expression of heme oxygenase 1, which correlated with the restoration of the antioxidant capacity, the intracellular H2O2 levels and glutathione content of NHBECs. The results presented in this study support the therapeutic use of NAC for the management of chronic respiratory diseases, including COPD. PMID:23118923

Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.

PubMed

Byrne, Nikole J; Levasseur, Jody; Sung, Miranda M; Masson, Grant; Boisvenue, Jamie; Young, Martin E; Dyck, Jason R B

2016-05-15

Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Spallanzani's mouse: a model of restoration and regeneration.

PubMed

Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

2004-01-01

The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice.

PubMed

Suelves, Nuria; Miguez, Andrés; López-Benito, Saray; Barriga, Gerardo García-Díaz; Giralt, Albert; Alvarez-Periel, Elena; Arévalo, Juan Carlos; Alberch, Jordi; Ginés, Silvia; Brito, Verónica

2018-05-27

Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington's disease (HD). Furthermore, we and others have demonstrated that TrkB/p75 NTR imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75 NTR imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75 NTR expression. Genetic normalization of p75 NTR expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75 NTR imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75 NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75 NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75 NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75 NTR could be promising to prevent motor deficits in HD.

Ramipril restores PPARβ/δ and PPARγ expressions and reduces cardiac NADPH oxidase but fails to restore cardiac function and accompanied myosin heavy chain ratio shift in severe anthracycline-induced cardiomyopathy in rat.

PubMed

Cernecka, Hana; Doka, Gabriel; Srankova, Jasna; Pivackova, Lenka; Malikova, Eva; Galkova, Kristina; Kyselovic, Jan; Krenek, Peter; Klimas, Jan

2016-11-15

We hypothesized that peroxisome proliferator-activated receptors (PPARs) might be involved in a complex protective action of ACE inhibitors (ACEi) in anthracyclines-induced cardiomyopathy. For purpose of study, we compared effects of ramipril on cardiac dysfunction, cardiac failure markers and PPAR isoforms in moderate and severe chronic daunorubicin-induced cardiomyopathy. Male Wistar rats were administered with a single intravenous injection of daunorubicin: 5mg/kg (moderate cardiomyopathy), or 15mg/kg (severe cardiomyopathy) or co-administered with daunorubicin and ramipril (1mg/kg/d, orally) or vehicle for 8 weeks. Left ventricular function was measured invasively under anesthesia. Cardiac mRNA levels of heart failure markers (ANP, Myh6, Myh7, Myh7b) and PPARs (alpha, beta/delta and gama) were measured by qRT-PCR. Protein expression of NADPH subunit (gp91phox) was measured by Western blot. Moderate cardiomyopathy exhibited only minor cardiac dysfunction what was corrected by ramipril. In severe cardiomyopathy, hemodynamic dysfunction remained unaltered upon ramipril although it decreased the significantly up-regulated cardiac ANP mRNA expression. Simultaneously, while high-dose daunorubicin significantly decreased PPARbeta/delta and PPARgama mRNA, ramipril normalized these abnormalities. Similarly, ramipril reduced altered levels of oxidative stress-related gp91phox. On the other hand, ramipril was unable to correct both the significantly decreased relative abundance of Myh6 and increased Myh7 mRNA levels, respectively. In conclusion, ramipril had a protective effect on cardiac function exclusively in moderate chronic daunorubicin-induced cardiomyopathy. Although it normalized abnormal PPARs expression and exerted also additional protective effects also in severe cardiomyopathy, it was insufficient to influence impaired cardiac function probably because of a shift in myosin heavy chain isoform content. Copyright © 2016 Elsevier B.V. All rights reserved.

Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex.

PubMed

Chang, Weizhong; Barnes, Aileen M; Cabral, Wayne A; Bodurtha, Joann N; Marini, Joan C

2010-01-15

Null mutations in cartilage-associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) cause types VII and VIII OI, respectively, two novel recessive forms of osteogenesis imperfecta (OI) with severe to lethal bone dysplasia and overmodification of the type I collagen helical region. CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue of alpha1(I) and alpha1(II) collagen chains. We investigated the interaction of complex components in fibroblasts from types VII and VIII OI patients. Both CRTAP and P3H1 are absent or reduced on western blots and by immunofluorescence microscopy in cells containing null mutations in either gene. Levels of LEPRE1 or CRTAP transcripts, however, are normal in CRTAP- or LEPRE1-null cells, respectively. Stable transfection of a CRTAP or LEPRE1 expression construct into cells with null mutations for the transfected cDNA restored both CRTAP and P3H1 protein levels. Normalization of collagen helical modification in transfected CRTAP-null cells demonstrated that the restored proteins functioned effectively as a complex. These data indicate that CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex. CyPB levels were unaffected by mutations in either CRTAP or LEPRE1. Proteasomal inhibitors partially rescue P3H1 protein in CRTAP-null cells. In LEPRE1-null cells, secretion of CRTAP is increased compared with control cells and accounts for 15-20% of the decreased CRTAP detected in cells. Thus, mutual stabilization of P3H1 and CRTAP in the ER collagen modification complex is an underlying mechanism for the overlapping phenotype of types VII and VIII OI.

Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

PubMed Central

Barna, Maria; Pusic, Aya; Zollo, Ornella; Costa, Maria; Kondrashov, Nadya; Rego, Eduardo; Rao, Pulivarthi H; Ruggero, Davide

2008-01-01

The Myc oncogene regulates the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III, and rDNA1,2. An outstanding question is whether and how increasing the cellular protein synthesis capacity can affect the multi-step process leading to cancer. We utilized ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ–Myc/+ transgenic mice to normal levels and show that in this context Myc's oncogenic potential is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a novel paradigm that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation employed to regulate the expression of selective mRNAs. We show that an aberrant increase in cap-dependent translation downstream Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (p58-PITSLRE)3-5, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ–Myc/+ mice. When accurate translational control is re-established in Eμ–Myc/+ mice, genome instability is suppressed. Our findings reveal how perturbations in translational control provide a highly specific outcome on gene expression, genome stability, and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level. PMID:19011615

Extensional collapse along the Sevier Desert reflection, northern Sevier Desert basin, western United States

NASA Astrophysics Data System (ADS)

Coogan, James C.; Decelles, Peter G.

1996-10-01

Newly released and previously published seismic reflection data from the northern Sevier Desert basin provide a complete seismic transect between the tilted western margin of the basin and the eastern breakaway zone. When tied to well and surface age data, the transect delineates a continuum of extensional fault and basin fill geometries that developed between late Oligocene and Pleistocene time across the basin. A minimum of 18 km of top-to-the-west normal displacement is estimated across the Sevier Desert from only the most conspicuous growth geometries and offsets across listric normal faults that sole downward into the Sevier Desert reflection (SDR). The SDR clearly marks a normal fault zone beneath the entire basin, where stratal truncations are imaged for 50% of the 39 km length of the reflection east of the Cricket Mountains block. Restoration of extensional displacement along this entire 39 km fault length is necessary to reconstruct the pre-Oligocene configuration and erosion level of Sevier thrust sheets across the Sevier Desert area. The SDR normal fault zone underlies the former topographic crest of the Sevier orogenic belt, where it accommodated extensional collapse after cessation of regional contractile tectonism.

Contact with Nature and Children's Restorative Experiences: An Eye to the Future

PubMed Central

Collado, Silvia; Staats, Henk

2016-01-01

This article offers an overview of what has been done until now on restorative research with children and opens up new inquires for future research. Most of the work has studied children's exposure to nature and the restorative benefits this contact provides, focusing on the renewal of children's psychological resources. The paper begins with an introduction to children's current tendency toward an alienation from the natural world and sets out the objectives of the article. It is followed by four main sections. The first two sections report on what we already know in this research area, distinguishing between children with normal mental capabilities and those suffering from attention-deficit hyperactivity disorder (ADHD). The findings gathered in these sections suggest that children's contact with nature improves their mood and their cognitive functioning, increases their social interactions and reduces ADHD symptoms. The next section describes five suggestions for future research: (1) the need for considering the relational dynamics between the child and the environment in restoration research, and the concept of constrained restoration; (2) the possibility of restorative needs arising from understimulation; (3) the importance of considering children's social context for restoration; (4) the relationship between restoration and pro-social and pro-environmental behaviors; and (5) children's restorative environments other than nature. We close by making some final remarks about the importance of restoring daily depleted resources for children's healthy functioning. PMID:27965616

Insulin restores L-arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia.

PubMed

Salsoso, R; Guzmán-Gutiérrez, E; Sáez, T; Bugueño, K; Ramírez, M A; Farías, M; Pardo, F; Leiva, A; Sanhueza, C; Mate, A; Vázquez, C; Sobrevia, L

2015-03-01

Preeclampsia is associated with impaired placental vasodilation and reduced endothelial nitric oxide synthase (eNOS) activity in the foetoplacental circulation. Adenosine and insulin stimulate vasodilation in endothelial cells, and this activity is mediated by adenosine receptor activation in uncomplicated pregnancies; however, this activity has yet to be examined in preeclampsia. Early onset preeclampsia is associated with severe placental vasculature alterations that lead to altered foetus growth and development, but whether late-onset preeclampsia (LOPE) alters foetoplacental vascular function is unknown. Vascular reactivity to insulin (0.1-1000 nmol/L, 5 min) and adenosine (1 mmol/L, 5 min) was measured in KCl-preconstricted human umbilical vein rings from normal and LOPE pregnancies using a wire myograph. The protein levels of human cationic amino acid transporter 1 (hCAT-1), adenosine receptor subtypes, total and Ser¹¹⁷⁷- or Thr⁴⁹⁵-phosphorylated eNOS were detected via Western blot, and L-arginine transport (0-1000 μmol/L L-arginine, 3 μCi/mL L-[³H]arginine, 20 s, 37 °C) was measured in the presence or absence of insulin and adenosine receptor agonists or antagonists in human umbilical vein endothelial cells (HUVECs) from normal and LOPE pregnancies. LOPE increased the maximal L-arginine transport capacity and hCAT-1 and eNOS expression and activity compared with normal conditions. The A(2A) adenosine receptor (A(2A)AR) antagonist ZM-241385 blocked these effects of LOPE. Insulin-mediated umbilical vein ring relaxation was lower in LOPE pregnancies than in normal pregnancies and was restored using the A(2A)AR antagonist. The reduced foetoplacental vascular response to insulin may result from A(2A)AR activation in LOPE pregnancies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

PubMed Central

Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

2015-01-01

Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability. PMID:26269637

Discrimination of Urban Spaces with Different Level of Restorativeness Based on the Original and on a Shorter Version of Hartig et al.'s Perceived Restorativeness Scale.

PubMed

Negrín, Fátima; Hernández-Fernaud, Estefanía; Hess, Stephany; Hernández, Bernardo

2017-01-01

Restorativeness is defined as the potential of the environment to re-establish certain cognitive capacities related to human information processing. The most frequently used instrument for evaluating the restorativeness of places is the Perceived Restorativeness Scale, proposed by Hartig et al. (1991). Later on, shorter versions of the Perceived Restorativeness Scale were proposed. The aim of this work is to evaluate the discriminatory capacity of the original and of a shorter Spanish version of the PRS, considering urban settings previously selected for having different level of restorativeness, according to expert's criteria. The study involved 244 students and used a 3 × 2 mixed experimental design, with two independent variables: Restorativeness of a place (between-subjects), which was manipulated by showing pictures of settings selected with varying levels of restorativeness (high, medium, low), and length of the scale (within-subjects), which was manipulated by asking subjects to fill in both the original and a shorter version of the PRS. The order of presentation of the two scales was counterbalanced. Results show an appropriate reliability for both version of the scale. Items of being-away, fascination, and coherence of the shorter scale correlate more strongly with the corresponding factor of the original scale, compared to the others factors. Both scales produce similar values for the perceived restorativeness of the different places, except for places with low restorativeness.

Discrimination of Urban Spaces with Different Level of Restorativeness Based on the Original and on a Shorter Version of Hartig et al.’s Perceived Restorativeness Scale

PubMed Central

Negrín, Fátima; Hernández-Fernaud, Estefanía; Hess, Stephany; Hernández, Bernardo

2017-01-01

Restorativeness is defined as the potential of the environment to re-establish certain cognitive capacities related to human information processing. The most frequently used instrument for evaluating the restorativeness of places is the Perceived Restorativeness Scale, proposed by Hartig et al. (1991). Later on, shorter versions of the Perceived Restorativeness Scale were proposed. The aim of this work is to evaluate the discriminatory capacity of the original and of a shorter Spanish version of the PRS, considering urban settings previously selected for having different level of restorativeness, according to expert’s criteria. The study involved 244 students and used a 3 × 2 mixed experimental design, with two independent variables: Restorativeness of a place (between-subjects), which was manipulated by showing pictures of settings selected with varying levels of restorativeness (high, medium, low), and length of the scale (within-subjects), which was manipulated by asking subjects to fill in both the original and a shorter version of the PRS. The order of presentation of the two scales was counterbalanced. Results show an appropriate reliability for both version of the scale. Items of being-away, fascination, and coherence of the shorter scale correlate more strongly with the corresponding factor of the original scale, compared to the others factors. Both scales produce similar values for the perceived restorativeness of the different places, except for places with low restorativeness. PMID:29062293

Restoration of ovarian function and natural fertility following the cryopreservation and autotransplantation of whole adult sheep ovaries

PubMed Central

Campbell, B.K.; Hernandez-Medrano, J.; Onions, V.; Pincott-Allen, C.; Aljaser, F.; Fisher, J.; McNeilly, A.S.; Webb, R.; Picton, H.M.

2014-01-01

STUDY QUESTION Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)? SUMMARY ANSWER Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes. WHAT IS KNOWN ALREADY Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells. STUDY DESIGN, SIZE, DURATION Study 1 (2010–2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7–8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7–9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011–2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane®; n = 8) or eptifibatide (Integrilin®; n = 8) on ovarian function and fertility 11–23 months after WOCP&TP. PARTICIPANTS/MATERIALS, SETTING, METHODS Both studies utilized mature, parous, Greyface ewes aged 3–6 years and weighing 50–75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology. MAIN RESULTS AND THE ROLE OF CHANCE In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP. LIMITATIONS, REASONS FOR CAUTION Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure. WIDER IMPLICATIONS OF THE FINDINGS This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work. PMID:24939954

Restoration of ovarian function and natural fertility following the cryopreservation and autotransplantation of whole adult sheep ovaries.

PubMed

Campbell, B K; Hernandez-Medrano, J; Onions, V; Pincott-Allen, C; Aljaser, F; Fisher, J; McNeilly, A S; Webb, R; Picton, H M

2014-08-01

Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)? Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes. Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells. Study 1 (2010-2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7-8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7-9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011-2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane(®); n = 8) or eptifibatide (Integrilin(®); n = 8) on ovarian function and fertility 11-23 months after WOCP&TP. Both studies utilized mature, parous, Greyface ewes aged 3-6 years and weighing 50-75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology. In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP. Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure. This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue. Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Wetland Restoration Response Analysis using MODIS and Groundwater Data

PubMed Central

Melesse, Assefa M.; Nangia, Vijay; Wang, Xixi; McClain, Michael

2007-01-01

Vegetation cover and groundwater level changes over the period of restoration are the two most important indicators of the level of success in wetland ecohydrological restoration. As a result of the regular presence of water and dense vegetation, the highest evapotranspiration (latent heat) rates usually occur within wetlands. Vegetation cover and evapotranspiration of large areas of restoration like that of Kissimmee River basin, South Florida will be best estimated using remote sensing technique than point measurements. Kissimmee River basin has been the area of ecological restoration for some years. The current ecohydrological restoration activities were evaluated through fractional vegetation cover (FVC) changes and latent heat flux using Moderate Resolution Imaging Spectroradiometer (MODIS) data. Groundwater level data were also analyzed for selected eight groundwater monitoring wells in the basin. Results have shown that the average fractional vegetation cover and latent heat along 10 km buffer of Kissimmee River between Lake Kissimmee and Lake Okeechobee was higher in 2004 than in 2000. It is evident that over the 5-year period of time, vegetated and areas covered with wetlands have increased significantly especially along the restoration corridor. Analysis of groundwater level data (2000-2004) from eight monitoring wells showed that, the average monthly level of groundwater was increased by 20 cm and 34 cm between 2000 and 2004, and 2000 and 2003, respectively. This change was more evident for wells along the river. PMID:28903205

Restoration of C/EBPα in dedifferentiated liposarcoma induces G2/M cell cycle arrest and apoptosis

PubMed Central

Wu, Yuhsin V.; Okada, Tomoyo; DeCarolis, Penelope; Socci, Nicholas; O’Connor, Rachael; Geha, Rula C.; Somberg, C. Joy; Antonescu, Cristina; Singer, Samuel

2012-01-01

Well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) represent the most common biological group of liposarcoma, and there is a pressing need to develop targeted therapies for patients with advanced disease. To identify potential therapeutic targets, we sought to identify differences in the adipogenic pathways between DDLS, WDLS, and normal adipose tissue. In a microarray analysis of DDLS (n=84), WDLS (n=79), and normal fat (n=23), C/EBPα, a transcription factor involved in cell cycle regulation and differentiation, was underexpressed in DDLS compared to both WDLS and normal fat (15.2 fold and 27.8 fold, respectively). In normal adipose-derived stem cells, C/EBPα expression was strongly induced when cells were cultured in differentiation media, but in three DDLS cell lines, this induction was nearly absent. We restored C/EBPα expression in one of the cell lines (DDLS8817) by transfection of an inducible C/EBα expression vector. Inducing C/EBPα expression reduced proliferation and caused cells to accumulate in G2/M. Under differentiation conditions, the cell proliferation was reduced further, and 66% of the DDLS cells containing the inducible C/EBPα expression vector underwent apoptosis as demonstrated by annexin V staining. These cells in differentiation conditions expressed early adipocyte-specific mRNAs such as LPL and FABP4, but they failed to accumulate intracellular lipid droplets, a characteristic of mature adipocytes. These results demonstrate that loss of C/EBPα is an important factor in suppressing apoptosis and maintaining the dedifferentiated state in DDLS. Restoring C/EBPα may be a useful therapeutic approach for dedifferentiated liposarcomas. PMID:22170698

In-line Microwave Warmer for Blood and Intravenous Fluids. Phase 2.

DTIC Science & Technology

1988-02-15

occuring in the battlefield often requires restoring normothermia and infusion of fluids, such as saline or blood, into the patient. These two...elevation is required to restore normal body temperature in response to hypothermic cardioplegic arrest induced prior to the operation. 6 1.2 System... Microfiltration Devices," Acta Annaesth Scand, 23:40- 45, 1979. [20] K Linko, K Hynynen, "Erythrocyte Damage Caused by the Haemotherm Microwave Blood Warmer

Markets, Distribution, and Exchange after Societal Cataclysm

DTIC Science & Technology

1988-03-01

1457- Al ) Prepared by the Oak Ridge National Laboratory Oak Ridge, Tennessee 37831 operated by MARTIN MARIETTA ENERGY SYSTEMS, INC. for the U.S...to step in and restore order (Mileti et al 1975; Haas et al . 1977). Past experience with natural disasters suggests that there is not the opportunity...efficient start towards the restoration of normal routines" (Dynes et al . 1981). The problem is similar to natural disasters in that FEMA has very

23 CFR 777.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... substances into organic matter and recycled on a continuing basis. Compensatory mitigation means restoration... normal circumstances do support, a prevalence of vegetation typically adapted for life in saturated soil...

23 CFR 777.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... substances into organic matter and recycled on a continuing basis. Compensatory mitigation means restoration... normal circumstances do support, a prevalence of vegetation typically adapted for life in saturated soil...

23 CFR 777.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-04-01

... substances into organic matter and recycled on a continuing basis. Compensatory mitigation means restoration... normal circumstances do support, a prevalence of vegetation typically adapted for life in saturated soil...

23 CFR 777.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-04-01

... substances into organic matter and recycled on a continuing basis. Compensatory mitigation means restoration... normal circumstances do support, a prevalence of vegetation typically adapted for life in saturated soil...

23 CFR 777.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-04-01

... substances into organic matter and recycled on a continuing basis. Compensatory mitigation means restoration... normal circumstances do support, a prevalence of vegetation typically adapted for life in saturated soil...

Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis

PubMed Central

Lazennec, Gwendal

2006-01-01

Ovarian cancer is one of the leading cause of death from gynecological tumors in women. Several lines of evidence suggest that estrogens may play an important role in ovarian carcinogenesis, through their receptors, ERα and ERβ. Interestingly, malignant ovarian tumors originating from epithelial surface constitute about 90% of ovarian cancers and expressed low levels of ERβ, compared to normal tissues. In addition, restoration of ERβ in ovarian cancer cells, leads to strong inhibition of their proliferation and invasion, while apoptosis is enhanced. In this manuscript, recent data suggesting a possible tumor-suppressor role for ERβ in ovarian carcinogenesis are discussed. PMID:16399219

Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression

PubMed Central

Zhang, Kuo; Pan, Xing; Wang, Fang; Ma, Jie; Su, Guangyue; Dong, Yingxu; Yang, Jingyu; Wu, Chunfu

2016-01-01

Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT-induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX-positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation. PMID:27502757

Estrogen Deprivation in Primate Pregnancy Leads to Insulin Resistance in Offspring

PubMed Central

Maniu, Adina; Aberdeen, Graham W.; Lynch, Terrie J.; Nadler, Jerry L.; Kim, Soon OK; Quon, Michael J.; Pepe, Gerald J.; Albrecht, Eugene D.

2016-01-01

This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over 2-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1 min, average of the 1, 3 and 5 min, and area under the curve blood glucose and plasma insulin levels after an iv bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance and the capacity to metabolize glucose after birth. PMID:27207093

Development of a "Hydrologic Equivalent Wetland" Concept for Modeling Cumulative Effects of Wetlands on Watershed Hydrology

NASA Astrophysics Data System (ADS)

Wang, X.; Liu, T.; Li, R.; Yang, X.; Duan, L.; Luo, Y.

2012-12-01

Wetlands are one of the most important watershed microtopographic features that affect, in combination rather than individually, hydrologic processes (e.g., routing) and the fate and transport of constituents (e.g., sediment and nutrients). Efforts to conserve existing wetlands and/or to restore lost wetlands require that watershed-level effects of wetlands on water quantity and water quality be quantified. Because monitoring approaches are usually cost or logistics prohibitive at watershed scale, distributed watershed models, such as the Soil and Water Assessment Tool (SWAT), can be a best resort if wetlands can be appropriately represented in the models. However, the exact method that should be used to incorporate wetlands into hydrologic models is the subject of much disagreement in the literature. In addition, there is a serious lack of information about how to model wetland conservation-restoration effects using such kind of integrated modeling approach. The objectives of this study were to: 1) develop a "hydrologic equivalent wetland" (HEW) concept; and 2) demonstrate how to use the HEW concept in SWAT to assess effects of wetland restoration within the Broughton's Creek watershed located in southwestern Manitoba of Canada, and of wetland conservation within the upper portion of the Otter Tail River watershed located in northwestern Minnesota of the United States. The HEWs were defined in terms of six calibrated parameters: the fraction of the subbasin area that drains into wetlands (WET_FR), the volume of water stored in the wetlands when filled to their normal water level (WET_NVOL), the volume of water stored in the wetlands when filled to their maximum water level (WET_MXVOL), the longest tributary channel length in the subbasin (CH_L1), Manning's n value for the tributary channels (CH_N1), and Manning's n value for the main channel (CH_N2). The results indicated that the HEW concept allows the nonlinear functional relations between watershed processes and wetland characteristics (e.g., size and morphology) to be accurately represented in the models. The loss of the first 10 to 20% of the wetlands in the Minnesota study area would drastically increase the peak discharge and loadings of sediment, total phosphorus (TP), and total nitrogen (TN). On the other hand, the justifiable reductions of the peak discharge and loadings of sediment, TP, and TN in the Manitoba study area may require that 50 to 80% of the lost wetlands be restored. Further, the comparison between the predicted restoration and conservation effects revealed that wetland conservation seems to deserve a higher priority while both wetland conservation and restoration may be equally important. Moreover, although SWAT was used in this study, the HEW concept is generic and can also be applied with any other hydrologic models.

Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity.

PubMed

Wang, Hui; Megill, Andrea; He, Kaiwen; Kirkwood, Alfredo; Lee, Hey-Kyoung

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ) peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

Incidental Transient Cortical Blindness after Lung Resection.

PubMed

Oncel, Murat; Sunam, Guven Sadi; Varoglu, Asuman Orhan; Karabagli, Hakan; Yildiran, Huseyin

2016-03-01

Transient vision loss after major surgical procedures is a rare clinical complication. The most common etiologies are cardiac, spinal, head, and neck surgeries. There has been no report on vision loss after lung resection. A 65-year-old man was admitted to our clinic with lung cancer. Resection was performed using right upper lobectomy with no complications. Cortical blindness developed 12 hours later in the postoperative period. Results from magnetic resonance imaging and diffusion-weighted investigations were normal. The neurologic examination was normal. The blood glucose level was 92 mg/dL and blood gas analysis showed a PO 2 of 82 mm Hg. After 24 hours, the patient began to see and could count fingers, and his vision was fully restored within 72 hours after this point. Autonomic dysfunction due to impaired microvascular structures in diabetes mellitus may induce posterior circulation dysfunction, even when the hemodynamic state is normal in the perioperative period. The physician must keep in mind that vision loss may occur after lung resection due to autonomic dysfunction, especially in older patients with diabetes mellitus.

Tibial changes in experimental disuse osteoporosis in the monkey

NASA Technical Reports Server (NTRS)

Young, D. R.; Niklowitz, W. J.; Steele, C. R.

1983-01-01

The mechanical properties and structural changes in the monkey tibia with disuse osteoporosis and during subsequent recovery are investigated. Bone mending stiffness is evaluated in relation to microscopic changes in cortical bone and Norland bone mineral analysis. Restraint in the semireclined position is found to produce regional losses of bone most obviously in the anterior-proximal tibiae. After six months of restraint, the greatest losses of bone mineral in the proximal tibiae range from 23 percent to 31 percent; the largest changes in bone stiffness range from 36 percent to 40 percent. Approximately eight and one-half months of recovery are required to restore the normal bending properties. Even after 15 months of recovery, however, the bone mineral content does not necessarily return to normal levels. Histologically, resorption cavities in cortical bone are seen within one month of restraint; by two and one-half months of restraint there are large resorption cavities subperiosteally, endosteally, and intracortically. After 15 months of recovery, the cortex consists mainly of first-generation haversian systems. After 40 months, the cortex appears normal, with numerous secondary and tertiary generations of haversian systems.

Alternating Wolff-Parkinson-White syndrome associated with attack of angina

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

Mangiafico, R.A.; Petralito, A.; Grimaldi, D.R.

1990-07-01

In a patient with Wolff-Parkinson-White syndrome and an inferior-posterior bypass tract, transient restoration of normal conduction occurred during an attack of angina. The ECG pattern of inferior posterior ischemia was present when the conduction was normal. Thallium scintigraphy showed a reversible posterolateral perfusion defect. The possible mechanisms for production of intermittent preexcitation are discussed.

Recombinant IGF-I: Past, present and future.

PubMed

Bright, George M

2016-06-01

Normal linear growth in humans requires GH and IGF-I. Diminished GH action resulting in reduced availability of IGF-I and IGF-binding proteins is the hallmarks of GH Insensitivity Syndromes (GHIS). The deficiencies are the perceived mechanisms for the growth failure of affected patients and the therapeutic targets for the restoration of normal growth. Early treatment attempts with pituitary-derived GH had limited effects in GHIS patients. Recombinant human insulin-like growth factor-I (rhIGF-I) treatment initially provides accelerated growth to GHIS children and provides substantial benefit. But, in general, catch up growth is less substantial with rhIGF-I treatment of GHIS than with rhGH treatment of GH Deficiency. Few classic GHIS patients have reached heights in the normal range (height SD score between -2.0 SD and +2.0 SD) with rhIGF-I monotherapy. A potential explanation is that while rhIGF-I treatment increases circulating concentrations of IGF-1 and IGFBP-3, such treatment reduces endogenous GH levels by negative feedback inhibition of pituitary GH release. In as much as both GH and IGF-I are required for good catch up growth, the loss of any residual GH signaling during IGF-I monotherapy in GHIS patients may attenuate possible catch up growth. Consistent with this explanation is the finding that, as predicted by the preclinical studies by Ross Clark, combination of rhGH & rhIGF-1 provides better growth responses than rhIGF-1 monotherapy in prepubertal children with short stature and low IGF-I levels despite normal stimulated GH responses. In the future, rhGH and rhIGF-I combination therapy can potentially improve growth outcomes over that seen with rhIGF-I monotherapy in all GHIS patients except in those with a total lack of functional GH signaling. Future alternative treatments for GHIS subjects may also include the use of post-growth hormone receptor signaling agonists which restore both GH signaling and IGF-I exposures or the addition of long-acting rhGH species to rhIGF-I. Additional etiologic factors for the growth failure in GHIS should be considered if the growth deficits of GHIS do not resolve with treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fecal microbiota transplantation for gastrointestinal disorders.

PubMed

Malikowski, Thomas; Khanna, Sahil; Pardi, Darrell S

2017-01-01

The importance of the gut microbiome in human health is being increasingly recognized. The purpose of this review is to examine the existing literature pertaining to alterations in the gut microbiome and the utility of microbiome restoration therapies in gastrointestinal disorders. Imbalance and maladaptation of the microbiome, termed dysbiosis, has been associated with several disease states such as irritable bowel syndrome, Clostridium difficile infection, inflammatory bowel diseases, nonalcoholic fatty liver disease, and obesity among others. The possibility of restoration of normal microbiota has become an attractive concept for diseases in which the normal microbiome is perturbed. The rationale of using fecal microbiota transplantation to treat disease has been validated by its successful use in treating recurrent Clostridium difficile infection, which occurs as a result of decreased microbial diversity in the gut, most often in the setting of recent antibiotic treatment. Similar strategies may be applicable to other disorders. Alterations in the gut microbiome are associated with several disorders, and microbiome restoration based therapies such as fecal microbiota transplantation may be an adjunct to conventional treatments but more investigation is needed.

SET8 is involved in the regulation of hyperglycemic memory in human umbilical endothelial cells.

PubMed

Chen, Xiangyuan; Wu, Qichao; Jiang, Hui; Wang, Jiaqiang; Zhao, Yanjun; Xu, Yajun; Zhu, Minmin

2018-05-14

Hyperglycemic memory occurs in diabetic cardiovascular complications, but the underlying mechanism remains to be elucidated. Although the depletion of SET8 leads to increased mitochondrial oxidative stress via increasing cellular reactive oxygen species (ROS) production, the role of SET8 in hyperglycemic memory-induced mitochondrial dysfunction is not well understood. Here, we investigated the role of SET8 in this setting. Our results showed that high glucose-induced vascular inflammation, ROS production and apoptosis remained at high levels even when glucose returned to normal level. Elevated glucose reduced SET8 expression, which also remained at low level after returning to normoglycemia. SET8 overexpression protected cells from elevated glucose and hyperglycemic memory-induced endothelial injury by blocking ROS accumulation, attenuating vascular inflammation, and restoring nitric oxide production. Thus, our results suggest that SET8 may be a key mediator in hyperglycemic memory.

Perception of Binaural Cues Develops in Children Who Are Deaf through Bilateral Cochlear Implantation

PubMed Central

Gordon, Karen A.; Deighton, Michael R.; Abbasalipour, Parvaneh; Papsin, Blake C.

2014-01-01

There are significant challenges to restoring binaural hearing to children who have been deaf from an early age. The uncoordinated and poor temporal information available from cochlear implants distorts perception of interaural timing differences normally important for sound localization and listening in noise. Moreover, binaural development can be compromised by bilateral and unilateral auditory deprivation. Here, we studied perception of both interaural level and timing differences in 79 children/adolescents using bilateral cochlear implants and 16 peers with normal hearing. They were asked on which side of their head they heard unilaterally or bilaterally presented click- or electrical pulse- trains. Interaural level cues were identified by most participants including adolescents with long periods of unilateral cochlear implant use and little bilateral implant experience. Interaural timing cues were not detected by new bilateral adolescent users, consistent with previous evidence. Evidence of binaural timing detection was, for the first time, found in children who had much longer implant experience but it was marked by poorer than normal sensitivity and abnormally strong dependence on current level differences between implants. In addition, children with prior unilateral implant use showed a higher proportion of responses to their first implanted sides than children implanted simultaneously. These data indicate that there are functional repercussions of developing binaural hearing through bilateral cochlear implants, particularly when provided sequentially; nonetheless, children have an opportunity to use these devices to hear better in noise and gain spatial hearing. PMID:25531107

Ionic requirements of proximal tubular sodium transport. I. Bicarbonate and chloride.

PubMed

Green, R; Giebisch, G

1975-11-01

Simultaneous perfusion of peritubular capillaries and proximal convoluted tubules was used to study the effect of varying transepithelial ionic gradients on ionic fluxes. Results show that net sodium influx and volume flux was one-third of normal when bicarbonate was absent, no chloride gradient existed, and glucose and amino acids were absent. Addition of bicarbonate to the luminal fluid did not restore the flux to normal, but peritubular bicarbonate did restore it. A chloride gradient imposed when no bicarbonate was present could only increase the fluxes slightly, but his flux was significant even after cyanide had poisoned transport. Reversing the chloride concentration gradient decreased the net sodium and volume fluxes whether bicarbonate was present or not. Glucose had no effect on fluxes, but substitution of Na by choline abolished them entirely. It is concluded that sodium is actively transported, that a chloride concentration gradient from lumen to plasma could account for up to 20% of net transport, and that peritubular bicarbonate is necessary for normal rates of sodium and fluid absorption.

Transplantation Immunity in the Isologous Mouse Radiation Chimaera

PubMed Central

Bridges, J. B.; Loutit, J. F.; Micklem, H. S.

1960-01-01

The survival of skin homo- and heterografts on isologous CBA mouse chimaeras has been investigated. Homografts usually persist for considerably longer than on normal unirradiated mice. Immunization of the host against the appropriate foreign antigens before irradiation neither reduces nor increases the duration of this persistence. When an irradiated non-immune host is restored with bone marrow from an immunized donor, a measure of immunity is transferred. If adult spleen cells from normal or immunized donors are added to the restorative inoculum, strongly antigenic foreign skins are shed with something like normal rapidity, but weakly antigenic skins may be retained for 100 days or more, and even indefinitely. Heterografts do not enjoy a span of survival comparable with that of homografts. These findings are discussed, and it is concluded that two factors are of importance in the prolongation of graft survival: (1) A weakening of the mechanism by which antigens are recognized as foreign, (2) an overall central depression of the immune response. ImagesPLATE IPLATE IIPLATE III PMID:13804388

Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.

PubMed

Perry, Matthew D; Ng, Chai Ann; Phan, Kevin; David, Erikka; Steer, Kieran; Hunter, Mark J; Mann, Stefan A; Imtiaz, Mohammad; Hill, Adam P; Ke, Ying; Vandenberg, Jamie I

2016-07-15

Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression. Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored. Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics. Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels. For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. In the heart, Kv11.1 channels pass the rapid delayed rectifier current (IKr ) which plays critical roles in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Over 500 inherited mutations in Kv11.1 are known to cause long QT syndrome type 2 (LQTS2), a cardiac electrical disorder associated with an increased risk of life threatening arrhythmias. Most missense mutations in Kv11.1 reduce the amount of channel protein expressed at the membrane and, as a consequence, there has been considerable interest in developing pharmacological agents to rescue the expression of these channels. However, pharmacological chaperones will only have clinical utility if the mutant Kv11.1 channels function normally after membrane expression is restored. The aim of this study was to characterize the gating phenotype for a subset of LQTS2 mutations to assess what proportion of mutations may be suitable for rescue. As an initial screen we used reduced temperature to rescue expression defects of mutant channels expressed in Xenopus laevis oocytes. Over half (∼56%) of Kv11.1 mutants exhibited functional gating defects that either dramatically reduced the amount of current contributing to cardiac action potential repolarization and/or reduced the amount of protective current elicited in response to premature depolarizations. Our data demonstrate that if pharmacological rescue of protein expression defects is going to have clinical utility in the treatment of LQTS2 then it will be important to assess the gating phenotype of LQTS2 mutations before attempting rescue. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Evaluation of Hi-Tec Implant Restoration in Mandibular First Molar Region- A Prospective Clinical Study.

PubMed

Sreeram, Roopa Rani S; Prasad, L Krishna; Chakravarthi, P Srinivas; Devi, Naga Neelima; Kattimani, Vivekanand S; Sreeram, Sanjay Krishna

2015-08-01

Missing teeth lead to loss of structural balance, inefficient function, poor aesthetics and psychological effects on human beings, which needs restoration for normal contour, function and aesthetics. Several natural or synthetic substitutes are being used for replacement of missing tooth since centuries. Implants are the latest modality of replacement. So, the study was aimed to assess clinical success rate of Hi-Tec implant; which is economical and new in market. Results of the study will help clinician for appropriate implant selection. The study included 10 patients from 19 to 31 years and needed restoration of missing mandibular first molar. Restoration had done using Hi Tec Single-tooth implants with metal-ceramic single crown prosthesis after three months of osseointegration. The implants were evaluated clinically (bleeding on probing, probing depth, implant mobility- periotest) and radiographically (marginal bone loss and peri-implant radiolucency) for six years. The observers were blinded for the duration of the study to prevent bias. All the patients had uneventful post-surgical healing. No bleeding on probing, Implant mobility, peri-implant radiolucency with minimal marginal bone loss and constant probing depths were observed well within the normal range during follow-up periods. Two stage single-tooth Hi Tec implant restoration can be used as a successful treatment modality for replacing mandibular first molar in an economic way. However, these results were obtained after 6 years of follow up with a smaller sample size, so long term multi center studies with a larger sample size is recommended for the predictability of success rate conclusively.

Creep behaviour and creep mechanisms of normal and healing ligaments

NASA Astrophysics Data System (ADS)

Thornton, Gail Marilyn

Patients with knee ligament injuries often undergo ligament reconstructions to restore joint stability and, potentially, abate osteoarthritis. Careful literature review suggests that in 10% to 40% of these patients the graft tissue "stretches out". Some graft elongation is likely due to creep (increased elongation of tissue under repeated or sustained load). Quantifying creep behaviour and identifying creep mechanisms in both normal and healing ligaments is important for finding clinically relevant means to prevent creep. Ligament creep was accurately predicted using a novel yet simple structural model that incorporated both collagen fibre recruitment and fibre creep. Using the inverse stress relaxation function to model fibre creep in conjunction with fibre recruitment produced a superior prediction of ligament creep than that obtained from the inverse stress relaxation function alone. This implied mechanistic role of fibre recruitment during creep was supported using a new approach to quantify crimp patterns at stresses in the toe region (increasing stiffness) and linear region (constant stiffness) of the stress-strain curve. Ligament creep was relatively insensitive to increases in stress in the toe region; however, creep strain increased significantly when tested at the linear region stress. Concomitantly, fibre recruitment was evident at the toe region stresses; however, recruitment was limited at the linear region stress. Elevating the water content of normal ligament using phosphate buffered saline increased the creep response. Therefore, both water content and fibre recruitment are important mechanistic factors involved in creep of normal ligaments. Ligament scars had inferior creep behaviour compared to normal ligaments even after 14 weeks. In addition to inferior collagen properties affecting fibre recruitment and increased water content, increased glycosaminoglycan content and flaws in scar tissue were implicated as potential mechanisms of scar creep. Similarly, ligament autografts had persistently abnormal creep behaviour and creep recovery after 2 years likely due to infiltration by scar tissue. Short-term immobilization of autografts had long-term detrimental consequences perhaps due to re-injury of the graft at remobilization. Treatments that restore normal properties to these mechanistic factors in order to control creep would improve joint healing by restoring joint kinematics and maintaining normal joint loading.

THE RESPONSE OF X-IRRADIATED LIMBS OF ADULT URODELES TO NORMAL TISSUE GRAFTS. I. EFFECTS OF AUTOGRAFTS OF SIXTY-DAY FOREARM REGENERATES

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

Stinson, B.D.

1963-06-01

Results are reported of autoplastic transplantation of parts of nonirradiated, regenerated forelimb to the contralateral x-irradiated forelimb in adult Triturus viridescens. The right forelimbs were exposed to various doses of localized irradiation (1000 to 5000 r) followed by amputation of both left and right forelimbs through the mid forearm. Left limbs regenerated normally, but irradiated right limbs failed to exhibit any significant degree of regenerative activity over a 3-month period. Both forelimbs were reamputated through the distal humerus and observed for an additional two months. Left limbs produced normal regenerates, but irradiated right limbs gave no gross evidence of regenerationmore » at any of the radiation dose levels. Normal left regenerates were reamputated immediately distal to the elbow on the 60th day after the second amputation; the severed forearm was trimmed with scissors along anterior and posterior borders and denuded of skin over its proximal half, leaving an essentially complete forearm region as a normal autograft. This was implanted into the irradiated right upper arm stump, after ablation of the distal half of its humerus, with normal proximodistal polarity in all cases. The irradiated stump was reamputated through the distal portion of the implanted normal autograft two weeks after implantation, and was observed for four months. Periodic gross observations showed that over 90% of irradiated upper arms formed regenerates at a rate which paralleled that of nonirradiated controls. However, regenerates formed on irradiated upper arms exhibited a restriction of morphogenetic capacity, only 60% attaining 3- and 4-digit stages. Most of the morphologically more complex regenerates which developed on the irradiated upper arm stumps manifested left limb asymmetry despite their formation on right irradiated stumps, suggesting a relation between the asymmetry of the normal graft and that of the resulting regenerate. All regenerates which developed on irradiated upper arms showed marked deficiencies in the restoration of a complete proximodistal structural pattern appropriate to the level of amputation through the irradiated stump. However, the actual pattern produced was appropriate to the level of amputation through the implanted normal autograft. These findings support the hypothesis that normal grafts promote the formation of regenerates on irradiated limbs through the autonomous developmental activity of the transected graft. (BBB)« less

Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.

PubMed

Eirin, Alfonso; Zhu, Xiang-Yang; Ferguson, Christopher M; Riester, Scott M; van Wijnen, Andre J; Lerman, Amir; Lerman, Lilach O

2015-01-19

Percutaneous transluminal renal angioplasty (PTRA) fails to fully improve cardiac injury and dysfunction in patients with renovascular hypertension (RVH). Mesenchymal stem cells (MSCs) restore renal function, but their potential for attenuating cardiac injury after reversal of RVH has not been explored. We hypothesized that replenishment of MSCs during PTRA would improve cardiac function and oxygenation, and decrease myocardial injury in porcine RVH. Pigs were studied after 16 weeks of RVH, RVH treated 4 weeks earlier with PTRA with or without adjunct intra-renal delivery of MSC (10^6 cells), and controls. Cardiac structure, function (fast-computed tomography (CT)), and myocardial oxygenation (Blood-Oxygen-Level-Dependent- magnetic resonance imaging) were assessed in-vivo. Myocardial microvascular density (micro-CT) and myocardial injury were evaluated ex-vivo. Kidney venous and systemic blood levels of inflammatory markers were measured and their renal release calculated. PTRA normalized blood pressure, yet stenotic-kidney glomerular filtration rate, similarly blunted in RVH and RVH + PTRA, normalized only in PTRA + MSC-treated pigs. PTRA attenuated left ventricular remodeling, whereas myocardial oxygenation, subendocardial microvascular density, and diastolic function remained decreased in RVH + PTRA, but normalized in RVH + PTRA-MSC. Circulating isoprostane levels and renal release of inflammatory cytokines increased in RVH and RVH + PTRA, but normalized in RVH + PTRA-MSC, as did myocardial oxidative stress, inflammation, collagen deposition, and fibrosis. Intra-renal MSC delivery during PTRA preserved stenotic-kidney function, reduced systemic oxidative stress and inflammation, and thereby improved cardiac function, oxygenation, and myocardial injury four weeks after revascularization, suggesting a therapeutic potential for adjunctive MSC delivery to preserve cardiac function and structure after reversal of experimental RVH.

Photovoltaic restoration of sight with high visual acuity

PubMed Central

Lorach, Henri; Goetz, Georges; Smith, Richard; Lei, Xin; Mandel, Yossi; Kamins, Theodore; Mathieson, Keith; Huie, Philip; Harris, James; Sher, Alexander; Palanker, Daniel

2015-01-01

Patients with retinal degeneration lose sight due to gradual demise of photoreceptors. Electrical stimulation of the surviving retinal neurons provides an alternative route for delivery of visual information. We demonstrate that subretinal arrays with 70 μm photovoltaic pixels provide highly localized stimulation, with electrical and visual receptive fields of comparable sizes in rat retinal ganglion cells. Similarly to normal vision, retinal response to prosthetic stimulation exhibits flicker fusion at high frequencies, adaptation to static images and non-linear spatial summation. In rats with retinal degeneration, these photovoltaic arrays provide spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in pigmented rats. Ease of implantation of these wireless and modular arrays, combined with their high resolution opens the door to functional restoration of sight. PMID:25915832

Effect of fluorocarbons on acetylcholinesterase activity and some counter measures

NASA Technical Reports Server (NTRS)

Young, W.; Parker, J. A.

1975-01-01

An isolated vagal sympathetic heart system has been successfully used for the study of the effect of fluorocarbons (FCs) on cardiac performance and in situ enzyme activity. Dichlorodifluoromethane sensitizes this preparation to sympathetic stimulation and to exogenous epinephrine challenge. Partial and complete A-V block and even cardiac arrest have been induced by epinephrine challenge in the FC sensitized heart. Potassium chloride alone restores the rhythmicity but not the normal contractility of the heart in such a situation. Addition of glucose will, however, completely restore the normal function of the heart which is sensitized by dichlorodifluoromethane. The ED 50 values of acetylcholinesterase activity which are used as a measure of relative effectiveness of fluorocarbons are compared with the maximum permissible concentration. Kinetic studies indicate that all the fluorocarbons tested so far are noncompetitive.

Ghost suppression in image restoration filtering

NASA Technical Reports Server (NTRS)

Riemer, T. E.; Mcgillem, C. D.

1975-01-01

An optimum image restoration filter is described in which provision is made to constrain the spatial extent of the restoration function, the noise level of the filter output and the rate of falloff of the composite system point-spread away from the origin. Experimental results show that sidelobes on the composite system point-spread function produce ghosts in the restored image near discontinuities in intensity level. By redetermining the filter using a penalty function that is zero over the main lobe of the composite point-spread function of the optimum filter and nonzero where the point-spread function departs from a smoothly decaying function in the sidelobe region, a great reduction in sidelobe level is obtained. Almost no loss in resolving power of the composite system results from this procedure. By iteratively carrying out the same procedure even further reductions in sidelobe level are obtained. Examples of original and iterated restoration functions are shown along with their effects on a test image.

Icaritin opposes the development of social aversion after defeat stress via increases of GR mRNA and BDNF mRNA in mice.

PubMed

Wu, Xiao; Wu, Jinfeng; Xia, Shijin; Li, Bei; Dong, Jingcheng

2013-11-01

Icariin is a major constituent of flavonoids isolated from Herba Epimedii. Several previous studies have demonstrated the antidepressant-like effects of icariin. After oral administration of icariin, 19 metabolites of icariin were detected in rat plasma. Icaritin is one such of metabolite of icariin. In this study, a chronic social defeat protocol is used as a mouse model for depression, and the effects of icaritin administration on social avoidance are investigated. The data indicates that icaritin (5mg/kg and 10mg/kg) oral administration opposes the development of social aversion after defeat stress. In vitro corticosterone sensitivity assay demonstrated that icaritin partially restored social defeat-induced impairment of glucocorticoid sensitivity. The expressions of GR mRNA and BDNFmRNA in the hippocampus were increased after icaritin treatment. Meanwhile, the social defeat-induced increases in CRH mRNA in hypothalamus were restored by icaritin administration. Our data also suggests that icaritin administration remarkably attenuated the increases in serum IL-6 and TNF-α level that occur following exposure to social defeat. In conclusion, icaritin is a novel antidepressant. It partially restored social defeat-induced impairment of glucocorticoid sensitivity, HPA axis hyperactivity. These effects are at least partially attributed to normalization of the GR function and increases in BDNF expression. Copyright © 2013 Elsevier B.V. All rights reserved.

Restoration handbook for sagebrush steppe ecosystems with emphasis on greater sage-grouse habitat—Part 3. Site level restoration decisions

USGS Publications Warehouse

Pyke, David A.; Chambers, Jeanne C.; Pellant, Mike; Miller, Richard F.; Beck, Jeffrey L.; Doescher, Paul S.; Roundy, Bruce A.; Schupp, Eugene W.; Knick, Steven T.; Brunson, Mark; McIver, James D.

2017-02-14

Sagebrush steppe ecosystems in the United States currently (2016) occur on only about one-half of their historical land area because of changes in land use, urban growth, and degradation of land, including invasions of non-native plants. The existence of many animal species depends on the existence of sagebrush steppe habitat. The greater sage-grouse (Centrocercus urophasianus) depends on large landscapes of intact habitat of sagebrush and perennial grasses for their existence. In addition, other sagebrush-obligate animals have similar requirements and restoration of landscapes for greater sage-grouse also will benefit these animals. Once sagebrush lands are degraded, they may require restoration actions to make those lands viable habitat for supporting sagebrush-obligate animals, livestock, and wild horses, and to provide ecosystem services for humans now and for future generations.When a decision is made on where restoration treatments should be applied, there are a number of site-specific decisions managers face before selecting the appropriate type of restoration. This site-level decision tool for restoration of sagebrush steppe ecosystems is organized in nine steps.Step 1 describes the process of defining site-level restoration objectives.Step 2 describes the ecological site characteristics of the restoration site. This covers soil chemistry and texture, soil moisture and temperature regimes, and the vegetation communities the site is capable of supporting.Step 3 compares the current vegetation to the plant communities associated with the site State and Transition models.Step 4 takes the manager through the process of current land uses and past disturbances that may influence restoration success.Step 5 is a brief discussion of how weather before and after treatments may impact restoration success.Step 6 addresses restoration treatment types and their potential positive and negative impacts on the ecosystem and on habitats, especially for greater sage-grouse. We discuss when passive restoration options may be sufficient and when active restoration may be necessary to achieve restoration objectives.Step 7 addresses decisions regarding post-restoration livestock grazing management.Step 8 addresses monitoring of the restoration; we discuss important aspects associated with implementation monitoring as well as effectiveness monitoring.Step 9 takes the information learned from monitoring to determine how restoration actions in the future might be adapted to improve restoration success.

The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

PubMed

Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M; Malik, Mazhar; Brown, W Ted; Li, Xiaohong

2012-01-01

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models

PubMed Central

Verma, Neeraj; Singh, Anil P.; Amresh, G.; Sahu, P. K.; Rao, Ch. V.

2011-01-01

Objective: To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl4)-induced liver damage in preventive and curative models. Materials and Methods: Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl4-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), γ-glutamyltransferase (γ -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content. Result and Discussion: The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, γ-GT, and bilirubin due to CCl4 treatment were restored toward normal in a dose-dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl4-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl4-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl4-induced hepatic damage in rats. PMID:21713093

Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes

PubMed Central

Delépine, Chloé; Meziane, Hamid; Nectoux, Juliette; Opitz, Matthieu; Smith, Amos B.; Ballatore, Carlo; Saillour, Yoann; Bennaceur-Griscelli, Annelise; Chang, Qiang; Williams, Emily Cunningham; Dahan, Maxime; Duboin, Aurélien; Billuart, Pierre; Herault, Yann; Bienvenu, Thierry

2016-01-01

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2308/y male mice. These findings represent a first step toward the validation of an innovative treatment for RTT. PMID:26604147

Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models.

PubMed

Verma, Neeraj; Singh, Anil P; Amresh, G; Sahu, P K; Rao, Ch V

2011-05-01

To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl(4))-induced liver damage in preventive and curative models. Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl(4)-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), γ-glutamyltransferase (γ -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content. The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, γ-GT, and bilirubin due to CCl(4) treatment were restored toward normal in a dose-dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl(4)-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl(4)-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl(4)-induced hepatic damage in rats.

Involvement of Infralimbic Prefrontal Cortex but not Lateral Habenula in Dopamine Attenuation After Chronic Mild Stress.

PubMed

Moreines, Jared L; Owrutsky, Zoe L; Grace, Anthony A

2017-03-01

Emerging evidence supports a role for dopamine in major depressive disorder (MDD). We recently reported fewer spontaneously active ventral tegmental area (VTA) dopamine neurons (ie, reduced dopamine neuron population activity) in the chronic mild stress (CMS) rodent model of MDD. In this study, we examined the role of two brain regions that have been implicated in MDD in humans, the infralimbic prefrontal cortex (ILPFC)-that is, rodent homolog of Brodmann area 25 (BA25), and the lateral habenula (LHb) in the CMS-induced attenuation of dopamine neuron activity. The impact of activating the ILPFC or LHb was evaluated using single-unit extracellular recordings of identified VTA dopamine neurons. The involvement of each region in dopamine neuron attenuation following 5-7 weeks of CMS was then evaluated by selective inactivation. Activation of either ILPFC or LHb in normal rats potently suppressed dopamine neuron population activity, but in unique patterns. ILPFC activation selectively inhibited dopamine neurons in medial VTA, which were most impacted by CMS. Conversely, LHb activation selectively inhibited dopamine neurons in lateral VTA, which were unaffected by CMS. Moreover, only ILPFC inactivation restored dopamine neuron population activity to normal levels following CMS; LHb inactivation had no restorative effect. These data suggest that, in the CMS model of MDD, the ILPFC is the primary driver of diminished dopamine neuron responses. These findings support a neural substrate for ILPFC/BA25 linking affective and motivational circuitry dysfunction in MDD.

Lycopene ameliorates neuropathic pain by upregulating spinal astrocytic connexin 43 expression.

PubMed

Zhang, Fang Fang; Morioka, Norimitsu; Kitamura, Tomoya; Fujii, Shiori; Miyauchi, Kazuki; Nakamura, Yoki; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

2016-06-15

Peripheral nerve injury upregulates tumor necrosis factor (TNF) expression. In turn, connexin 43 (Cx43) expression in spinal astrocytes is downregulated by TNF. Therefore, restoration of spinal astrocyte Cx43 expression to normal level could lead to the reduction of nerve injury-induced pain. While the non-provitaminic carotenoid lycopene reverses thermal hyperalgesia in mice with painful diabetic neuropathy, the antinociceptive mechanism is not entirely clear. The current study evaluated whether the antinociceptive effect of lycopene is mediated through the modulation of Cx43 expression in spinal astrocytes. The effect of lycopene on Cx43 expression was examined in cultured rat spinal astrocytes. The effect of intrathecal lycopene on Cx43 expression and neuropathic pain were evaluated in mice with partial sciatic nerve ligation (PSNL). Treatment of cultured rat spinal astrocytes with lycopene reversed TNF-induced downregulation of Cx43 protein expression through a transcription-independent mechanism. By contrast, treatment of cultured spinal astrocytes with either pro-vitamin A carotenoid β-carotene or antioxidant N-acetyl cysteine had no effect on TNF-induced downregulation of Cx43 protein expression. In addition, repeated, but not single, intrathecal treatment with lycopene of mice with a partial sciatic nerve ligation significantly prevented not only the downregulation of Cx43 expression in spinal dorsal horn but mechanical hypersensitivity as well. The current findings suggest a significant spinal mechanism that mediates the analgesic effect of lycopene, through the restoration of normal spinal Cx43 expression. Copyright © 2016 Elsevier Inc. All rights reserved.

The Therapeutic effect of Memantine through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome

PubMed Central

Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M.; Malik, Mazhar; Brown, W. Ted; Li, Xiaohong

2012-01-01

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs. PMID:22615862

K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport

PubMed Central

2010-01-01

Background Lung epithelial Na+ channels (ENaC) are regulated by cell Ca2+ signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K+ channel modulators regulate ENaC activity in normal lungs, the therapeutical relevance and the underlying mechanisms have not been completely explored. We hypothesized that K+ channel openers may restore calcium channel blocker-inhibited alveolar fluid clearance (AFC) by up-regulating both apical and basolateral ion transport. Methods Verapamil-induced depression of heterologously expressed human αβγ ENaC in Xenopus oocytes, apical and basolateral ion transport in monolayers of human lung epithelial cells (H441), and in vivo alveolar fluid clearance were measured, respectively, using the two-electrode voltage clamp, Ussing chamber, and BSA protein assays. Ca2+ signal in H441 cells was analyzed using Fluo 4AM. Results The rate of in vivo AFC was reduced significantly (40.6 ± 6.3% of control, P < 0.05, n = 12) in mice intratracheally administrated verapamil. KCa3.1 (1-EBIO) and KATP (minoxidil) channel openers significantly recovered AFC. In addition to short-circuit current (Isc) in intact H441 monolayers, both apical and basolateral Isc levels were reduced by verapamil in permeabilized monolayers. Moreover, verapamil significantly altered Ca2+ signal evoked by ionomycin in H441 cells. Depletion of cytosolic Ca2+ in αβγ ENaC-expressing oocytes completely abolished verapamil-induced inhibition. Intriguingly, KV (pyrithione-Na), K Ca3.1 (1-EBIO), and KATP (minoxidil) channel openers almost completely restored the verapamil-induced decrease in Isc levels by diversely up-regulating apical and basolateral Na+ and K+ transport pathways. Conclusions Our observations demonstrate that K+ channel openers are capable of rescuing reduced vectorial Na+ transport across lung epithelial cells with impaired Ca2+ signal. PMID:20507598

A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia.

PubMed

Lemper, Marie; De Groef, Sofie; Stangé, Geert; Baeyens, Luc; Heimberg, Harry

2016-09-01

When the beta cell mass or function declines beyond a critical point, hyperglycaemia arises. Little is known about the potential pathways involved in beta cell rescue. As two cytokines, epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF), restored a functional beta cell mass in mice with long-term hyperglycaemia by reprogramming acinar cells that transiently expressed neurogenin 3 (NGN3), the current study assesses the effect of these cytokines on the functional beta cell mass after an acute chemical toxic insult. Glycaemia and insulin levels, pro-endocrine gene expression and beta cell origin, as well as the role of signal transducer and activator of transcription 3 (STAT3) signalling, were assessed in EGF+CNTF-treated mice following acute hyperglycaemia. The mice were hyperglycaemic 1 day following i.v. injection of the beta cell toxin alloxan, when the two cytokines were applied. One week later, 68.6 ± 4.6% of the mice had responded to the cytokine treatment and increased their insulin(+) cell number to 30% that of normoglycaemic control mice, resulting in restoration of euglycaemia. Although insulin(-) NGN3(+) cells appeared following acute EGF+CNTF treatment, genetic lineage tracing showed that the majority of the insulin(+) cells originated from pre-existing beta cells. Beta cell rescue by EGF+CNTF depends on glycaemia rather than on STAT3-induced NGN3 expression in acinar cells. In adult mice, EGF+CNTF allows the rescue of beta cells in distress when treatment is given shortly after the diabetogenic insult. The rescued beta cells restore a functional beta cell mass able to control normal blood glucose levels. These findings may provide new insights into compensatory pathways activated early after beta cell loss.

Ghrelin restoration of function in vitro in somatotropes from male mice lacking the Janus kinase (JAK)-binding site of the leptin receptor.

PubMed

Syed, Mohsin; Cozart, Michael; Haney, Anessa C; Akhter, Noor; Odle, Angela K; Allensworth-James, Melody; Crane, Christopher; Syed, Farhan M; Childs, Gwen V

2013-04-01

Deletion of the signaling domain of leptin receptors selectively in somatotropes, with Cre-loxP technology, reduced the percentage of immunolabeled GH cells and serum GH. We hypothesized that the deficit occurred when leptin's postnatal surge failed to stimulate an expansion in the cell population. To learn more about the deficiency in GH cells, we tested their expression of GHRH receptors and GH mRNA and the restorative potential of secretagogue stimulation in vitro. In freshly plated dissociated pituitary cells from control male mice, GHRH alone (0.3 nM) increased the percentage of immunolabeled GH cells from 27 ± 0.05% (vehicle) to 42 ± 1.8% (P < .002) and the secretion of GH 1.8-3×. Deletion mutant pituitary cells showed a 40% reduction in percentages of immunolabeled GH cells (16.7 ± 0.4%), which correlated with a 47% reduction in basal GH levels (50 ng/mL control; 26.7 ng/mL mutants P = .01). A 50% reduction in the percentage of mutant cells expressing GHRH receptors (to 12%) correlated with no or reduced responses to GHRH. Ghrelin alone (10 nM) stimulated more GH cells in mutants (from 16.7-23%). When added with 1-3 nM GHRH, ghrelin restored GH cell percentages and GH secretion to levels similar to those of stimulated controls. Counts of somatotropes labeled for GH mRNA confirmed normal percentages of somatotropes in the population. These discoveries suggest that leptin may optimize somatotrope function by facilitating expression of membrane GHRH receptors and the production or maintenance of GH stores.

Triiodothyronine Activates Lactate Oxidation Without Impairing Fatty Acid Oxidation and Improves Weaning From Extracorporeal Membrane Oxygenation

PubMed Central

Kajimoto, Masaki; Ledee, Dolena R.; Xu, Chun; Kajimoto, Hidemi; Isern, Nancy G.; Portman, Michael A.

2017-01-01

Background Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. It has previously been shown that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. Methods and Results Nineteen immature piglets (9.1–15.3 kg) were separated into 3 groups with ECMO (6.5 h) and wean: normal circulation (Group-C); transient coronary occlusion (10 min) for ischemia-reperfusion (IR) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon (13C)-labeled lactate, medium-chain and long-chain FAs, was infused as oxidative substrates. Substrate fractional contribution (FC) to the citric acid cycle was analyzed by 13C-nuclear magnetic resonance. ECMO depressed circulating T3 levels to 40% of the baseline at 4 h and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [adenosine triphosphate]/[adenosine diphosphate] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. Conclusions T3 releases inhibition of lactate oxidation following IR injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning. PMID:25421230

Ulcerative Colitis Impairs the Acylethanolamide-Based Anti-Inflammatory System Reversal by 5-Aminosalicylic Acid and Glucocorticoids

PubMed Central

Suárez, Juan; Romero-Zerbo, Yanina; Márquez, Lucia; Rivera, Patricia; Iglesias, Mar; Bermúdez-Silva, Francisco J.; Andreu, Montserrat; de Fonseca, Fernando Rodríguez

2012-01-01

Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages. PMID:22662201

Cell painting with an engineered EPCR to augment the protein C system

PubMed Central

Bouwens, Eveline A. M.; Stavenuiter, Fabian; Mosnier, Laurent O.

2016-01-01

The protein C (PC) system conveys beneficial anticoagulant and cytoprotective effects in numerous in vivo disease models. The endothelial protein C receptor (EPCR) plays a central role in these pathways as cofactor for PC activation and by enhancing activated protein C (APC)-mediated protease-activated receptor (PAR) activation. During inflammatory disease, expression of EPCR on cell membranes is often diminished thereby limiting PC activation and APC’s effects on cells. Here a caveolae-targeting glycosylphosphatidylinositol (GPI)-anchored EPCR (EPCR-GPI) was engineered to restore EPCR’s bioavailability via “cell painting.” The painting efficiency of EPCR-GPI on EPCR-depleted endothelial cells was time- and dose-dependent. The EPCR-GPI bioavailability after painting was long lasting since EPCR surface levels reached 400% of wild-type cells after 2 hours and remained >200% for 24 hours. EPCR-GPI painting conveyed APC binding to EPCR-depleted endothelial cells where EPCR was lost due to shedding or shRNA. EPCR painting normalized PC activation on EPCR-depleted cells indicating that EPCR-GPI is functional active on painted cells. Caveolin-1 lipid rafts were enriched in EPCR after painting due to the GPI-anchor targeting caveolae. Accordingly, EPCR painting supported PAR1 and PAR3 cleavage by APC and augmented PAR1-dependent Akt phosphorylation by APC. Thus, EPCR-GPI painting achieved physiological relevant surface levels on endothelial cells, restored APC binding to EPCR-depleted cells, supported PC activation, and enhanced APC-mediated PAR cleavage and cytoprotective signaling. Therefore, EPCR-GPI provides a novel tool to restore the bioavailability and functionality of EPCR on EPCR-depleted and deficient cells. PMID:26272345

Anesthetic management of comprehensive dental restoration in a child with glutaric aciduria type 1 using volatile sevoflurane.

PubMed

Teng, Wei-Nung; Lin, Su-Man; Niu, Dau-Ming; Kuo, Yi-Min; Chan, Kwok-Hon; Sung, Chun-Sung

2014-10-01

Glutaric aciduria type 1 (GA1) is a rare, inherited mitochondrial disorder that results from deficiency of mitochondrial glutaryl-CoA dehydrogenase. Most patients develop neurological dysfunction early in life, which leads to severe disabilities. We present a 37-month-old girl with GA1 manifested as macrocephaly and hypotonia who received comprehensive dental restoration surgery under general anesthesia with sevoflurane. She was placed on specialized fluid management during a preoperative fasting period and anesthesia was administered without complications. All the physiological parameters, including glucose and lactate blood levels and arterial blood gas were carefully monitored and maintained within normal range perioperatively. Strategies for anesthetic management should include prevention of pulmonary aspiration, dehydration, hyperthermia and catabolic state, adequate analgesia to minimize surgical stress, and avoidance of prolonged neuromuscular blockade. We administered general anesthesia with sevoflurane uneventfully, which was well tolerated by our patient with GA1. Additionally, communication with a pediatric geneticist and surgeons should be undertaken to formulate a comprehensive anesthetic strategy in these patients. Copyright © 2014. Published by Elsevier B.V.

Molecular Dynamic Simulation Insights into the Normal State and Restoration of p53 Function

PubMed Central

Fu, Ting; Min, Hanyi; Xu, Yong; Chen, Jianzhong; Li, Guohui

2012-01-01

As a tumor suppressor protein, p53 plays a crucial role in the cell cycle and in cancer prevention. Almost 50 percent of all human malignant tumors are closely related to a deletion or mutation in p53. The activity of p53 is inhibited by over-active celluar antagonists, especially by the over-expression of the negative regulators MDM2 and MDMX. Protein-protein interactions, or post-translational modifications of the C-terminal negative regulatory domain of p53, also regulate its tumor suppressor activity. Restoration of p53 function through peptide and small molecular inhibitors has become a promising strategy for novel anti-cancer drug design and development. Molecular dynamics simulations have been extensively applied to investigate the conformation changes of p53 induced by protein-protein interactions and protein-ligand interactions, including peptide and small molecular inhibitors. This review focuses on the latest MD simulation research, to provide an overview of the current understanding of interactions between p53 and its partners at an atomic level. PMID:22949826

Effect of conditions of three dimensional clinostating on testicular cell machinery

NASA Astrophysics Data System (ADS)

Uva, Bianca Maria; Strollo, Felice; Ricci, Franco; Pastorino, Martina; Mason, Ian J.; Angela Masini, Maria

2007-02-01

Our scope was to study the effects of on ground random positioning machine rotation on swine testicular cells in culture. Cells of the 2n karyotype line, from trypsinized swine testes, were submitted to modeled microgravity (μG) using a 3D RPM from 15 min to 24 h. The cultured cells were then fixed and submitted to immunohistochemistry using antibodies to steroid dehydrogenases, heat shock proteins and the sodium pump (Na+/K+ ATPase). The results revealed that, after 15 min at modeled μG, all the cells showed damages at cytoskeletal level. The immunoreactions for 3βHSD, 17βHSD and Na+/K+ ATPase were almost abolished. After 24 h of treatment, the presence of the enzymes was restored, and small heat shock proteins were strongly immunostainable. On the other hand, in the 1×G cultures, the expression of HSPs was very weak. We conclude that modeled μG by random positioning of cells affects testicular cells in culture for a short time, while the normal activity of the cells is restored after 24 h.

Exercise as a countermeasure for physiological adaptation to prolonged spaceflight

NASA Technical Reports Server (NTRS)

Convertino, V. A.

1996-01-01

Exercise represents the primary countermeasure used during spaceflight to maintain or restore maximal aerobic capacity (VO2max), musculoskeletal structure, and orthostatic function. However, no single exercise or combination of prescriptions has proven entirely effective in restoring cardiovascular and musculoskeletal functions to preflight levels following prolonged spaceflight. As human spaceflight exposures increase in duration, assessment and development of various effective exercise-based protective procedures become paramount. This must involve improvement in specific countermeasure prescription as well as development of additional approaches that will allow space travelers greater flexibility and medical safety during long flights. Effective exercise prescription will be based on identification of basic physiological stimuli that maintain normal function in terrestrial gravity and understanding of how specific combinations of exercise characteristics e.g., duration, frequency, intensity, mode) can mimic these stimuli and affect the overall process of adaptation to microgravity. This can be accomplished only with greater emphasis of research on ground-based experiments. Future attention must be directed to improving exercise compliance while minimizing both crew time and the impact of the exercise on life-support resources.

Restoration of Full Shoulder Range of Motion After Application of the Fascial Distortion Model.

PubMed

Boucher, Joshua D; Figueroa, Jose

2018-05-01

Decreased active and passive range of motion (ROM) accompanied by pain in the shoulder is a common presentation for patients with frozen shoulder, and it can be difficult to restore normal function. Through the fascial distortion model, physicians can apply a manual technique to rapidly and effectively increase ROM and decrease pain. A 28-year-old man presented 18 months after sustaining a shoulder hyperextension injury. On active and passive ROM examination, he had approximately 90° of shoulder abduction and moderately reduced internal rotation associated with 8/10 pain. After 2 applications of the fascial distortion model, his shoulder restored to full abduction and internal rotation with no pain.

Elevated plasma TGF-beta1 in renal diseases: cause or consequence?

PubMed

Junker, U; Haufe, C C; Nuske, K; Rebstock, K; Steiner, T; Wunderlich, H; Junker, K; Reinhold, D

2000-07-01

We previously reported elevated levels of TGF-beta1 in patients with renal carcinoma. Certain aspects led us to ask whether they might be caused by chronic damage to the kidney(s). Here we report on an extended set of patients with various renal diseases, lung cancer, humoral immunodeficiency and controls. For latent TGF-beta1 in plasma, we find that the control, immunodeficiency, lung cancer and kidney transplant groups do not differ significantly (means, 7.0-8.8 ng/ml). Also, acute short-term renal stress (extracorporal lithotrypsy) does not lead to an increase of TGF-beta1. However, the pyelonephritis patients present with levels of 19.0 ng/ml, chronic extracorporal dialysis patients with 15.5 ng/ml, and renal cell carcinoma patients with 22.8 ng/ml. For active TGF-beta1 these findings are exactly recovered. For serum levels, only the renal carcinoma group presents with significantly elevated levels of TGF-beta1. Kidney transplantation seems to normalize TGF-beta1 levels, while in the kidney cancer patients surgery has an effect only in part of the group. We conclude that elevated plasma TGF-beta1 levels are common in at least two chronic renal disease conditions, and that it normalizes with restoration of renal function. It is tempting to speculate that chronic elevation of TGF-beta1 in these patients may be critically involved in these conditions predisposing to renal cancer. Copyright 2000 Academic Press.

Restoring coastal wetlands that were ditched for mosquito control: a preliminary assessment of hydro-leveling as a restoration technique

USGS Publications Warehouse

Smith, Thomas J.; Tiling, Ginger; Leasure, Pamela S.

2007-01-01

The wetlands surrounding Tampa Bay, Florida were extensively ditched for mosquito control in the 1950s. Spoil from ditch construction was placed adjacent to the wetlands ditches creating mound-like features (spoil-mounds). These mounds represent a loss of 14% of the wetland area in Tampa Bay. Spoil mounds interfere with tidal flow and are locations for non-native plants to colonize (e.g., Schinus terebinthifolius). Removal of the spoil mounds to eliminate exotic plants, restore native vegetation, and re-establish natural hydrology is a restoration priority for environmental managers. Hydro-leveling, a new technique, was tested in a mangrove forest restoration project in 2004. Hydro-leveling uses a high pressure stream of water to wash sediment from the spoil mound into the adjacent wetland and ditch. To assess the effectiveness of this technique, we conducted vegetation surveys in areas that were hydro-leveled and in non-hydro-leveled areas 3 years post-project. Adult Schinus were reduced but not eliminated from hydro-leveled mounds. Schinus seedlings however were absent from hydro-leveled sites. Colonization by native species was sparse. Mangrove seedlings were essentially absent (≈2 m−2) from the centers of hydro-leveled mounds and were in low density on their edges (17 m−2) in comparison to surrounding mangrove forests (105 m−2). Hydro-leveling resulted in mortality of mangroves adjacent to the mounds being leveled. This was probably caused by burial of pneumatophores during the hydro-leveling process. For hydro-leveling to be a useful and successful restoration technique several requirements must be met. Spoil mounds must be lowered to the level of the surrounding wetlands. Spoil must be distributed further into the adjacent wetland to prevent burial of nearby native vegetation. Finally, native species may need to be planted on hydro-leveled areas to speed up the re-vegetation process.

Angiogenic and Restorative Abilities of Human Mesenchymal Stem Cells Were Reduced Following Treatment With Serum From Diabetes Mellitus Type 2 Patients.

PubMed

Rezaie, Jafar; Mehranjani, Malek S; Rahbarghazi, Reza; Shariatzadeh, Mohammad A

2018-01-01

This experiment investigated the impact of serum from patients with type 2 diabetes mellitus on the angiogenic behavior of human mesenchymal stem cells in vitro. Changes in the level of Ang-1, Ang-2, cell migration, and trans-differentiation into pericytes and endothelial lineage were monitored after 7 days. The interaction of mesenchymal stem cells with endothelial cells were evaluated using surface plasmon resonance technique. Paracrine restorative effect of diabetic stem cells was tested on pancreatic β cells. Compared to data from FBS and normal serum, diabetic serum reduced the stem cell survival and chemotaxis toward VEGF and SDF-1α (P < 0.05). Diabetic condition were found to decline cell migration rate and the activity of MMP-2 and -9 (P < 0.05). The down-regulation of VEGFR-2 and CXCR-4 was observed with an increase in the level of miR-1-3p and miR-15b-5p at the same time. The paracrine angiogenic potential of diabetic stem cells was disturbed via the changes in the dynamic of Ang-1, Ang-2, and VEGF. Surface plasmon resonance analysis showed that diabetes could induce an aberrant increase in the interaction of stem cells with endothelial cells. After treatment with diabetic serum, the expression of VE-cadherin and NG2 and ability for uptake of Dil-Ac-LDL were reduced (P < 0.01). Conditioned media prepared from diabetic stem cells were unable to decrease fatty acid accumulation in β-cells (P < 0.05). The level of insulin secreted by β-cells was not affected after exposure to supernatant from diabetic or non-diabetic mesenchymal stem cells. Data suggest diabetes could decrease angiogenic and restorative effect of stem cells in vitro. J. Cell. Biochem. 119: 524-535, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production.

PubMed

Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C; Tsokos, George C

2016-06-15

T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity. In SLE T cells, SAP protein is also subject to increased degradation by caspase-3. Forced expression of SAP in SLE T cells normalized IL-2 production, calcium (Ca(2+)) responses, and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR Abs, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP, probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. Copyright © 2016 by The American Association of Immunologists, Inc.

21 CFR 870.5310 - Automated external defibrillator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... shock of a maximum of 360 joules of energy used for defibrillating (restoring normal heart rhythm) the atria or ventricles of the heart. An AED analyzes the patient's electrocardiogram, interprets the...

21 CFR 870.5310 - Automated external defibrillator.

Code of Federal Regulations, 2014 CFR

2014-04-01

... shock of a maximum of 360 joules of energy used for defibrillating (restoring normal heart rhythm) the atria or ventricles of the heart. An AED analyzes the patient's electrocardiogram, interprets the...

21 CFR 870.5310 - Automated external defibrillator.

Code of Federal Regulations, 2012 CFR

2012-04-01

... shock of a maximum of 360 joules of energy used for defibrillating (restoring normal heart rhythm) the atria or ventricles of the heart. An AED analyzes the patient's electrocardiogram, interprets the...

21 CFR 870.5310 - Automated external defibrillator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... shock of a maximum of 360 joules of energy used for defibrillating (restoring normal heart rhythm) the atria or ventricles of the heart. An AED analyzes the patient's electrocardiogram, interprets the...

21 CFR 870.5310 - Automated external defibrillator.

Code of Federal Regulations, 2013 CFR

2013-04-01

... shock of a maximum of 360 joules of energy used for defibrillating (restoring normal heart rhythm) the atria or ventricles of the heart. An AED analyzes the patient's electrocardiogram, interprets the...

Is saltmarsh restoration success constrained by matching natural environments or altered succession? A test using niche models.

PubMed

Sullivan, Martin J P; Davy, Anthony J; Grant, Alastair; Mossman, Hannah L

2018-05-01

Restored habitats, such as saltmarsh created through managed realignment, sometimes fail to meet targets for biological equivalence with natural reference sites. Understanding why this happens is important in order to improve restoration outcomes.Elevation in the tidal frame and sediment redox potential are major controls on the distribution of saltmarsh plants. We use niche models to characterize 10 species' responses to these, and test whether differences in species occurrence between restored and natural saltmarshes in the UK result from failure to recreate adequate environmental conditions.Six species occurred less frequently in recently restored marshes than natural marshes. Failure of restored marshes to achieve the elevation and redox conditions of natural marshes partially explained the underrepresentation of five of these species, but did not explain patterns of occurrence on older (>50 years) restored marshes.For all species, an effect of marsh age remained after controlling for differences in environmental conditions. This could be due to differences in successional mechanism between restored and natural marshes. In recently restored marshes, high-marsh species occurred lower in the tidal frame and low-marsh species occurred higher in the tidal frame than in natural marshes. This supports the hypothesis that competition is initially weaker in restored marshes, because of the availability of bare sediment across the whole tidal frame. Species that establish outside their normal realized niche, such as Atriplex portulacoides , may inhibit subsequent colonization of other species that occurred less frequently than expected on older restored marshes. Synthesis and applications . Niche models can be used to test whether abiotic differences between restored sites and their natural counterparts are responsible for discrepancies in species occurrence. In saltmarshes, simply replicating environmental conditions will not result in equivalent species occurrence.

Restoration of C/EBPα in dedifferentiated liposarcoma induces G2/M cell cycle arrest and apoptosis.

PubMed

Wu, Yuhsin V; Okada, Tomoyo; DeCarolis, Penelope; Socci, Nicholas; O'Connor, Rachael; Geha, Rula C; Joy Somberg, C; Antonescu, Cristina; Singer, Samuel

2012-04-01

Well-differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) represent the most common biological group of liposarcoma, and there is a pressing need to develop targeted therapies for patients with advanced disease. To identify potential therapeutic targets, we sought to identify differences in the adipogenic pathways between DDLS, WDLS, and normal adipose tissue. In a microarray analysis of DDLS (n = 84), WDLS (n = 79), and normal fat (n = 23), C/EBPα, a transcription factor involved in cell cycle regulation and differentiation, was underexpressed in DDLS when compared to both WDLS and normal fat (15.2- and 27.8-fold, respectively). In normal adipose-derived stem cells, C/EBPα expression was strongly induced when cells were cultured in differentiation media, but in three DDLS cell lines, this induction was nearly absent. We restored C/EBPα expression in one of the cell lines (DDLS8817) by transfection of an inducible C/EBPα expression vector. Inducing C/EBPα expression reduced proliferation and caused cells to accumulate in G2/M. Under differentiation conditions, the cell proliferation was reduced further, and 66% of the DDLS cells containing the inducible C/EBPα expression vector underwent apoptosis as demonstrated by annexin V staining. These cells in differentiation conditions expressed early adipocyte-specific mRNAs such as LPL and FABP4, but they failed to accumulate intracellular lipid droplets, a characteristic of mature adipocytes. These results demonstrate that loss of C/EBPα is an important factor in suppressing apoptosis and maintaining the dedifferentiated state in DDLS. Restoring C/EBPα may be a useful therapeutic approach for DDLS. Copyright © 2011 Wiley Periodicals, Inc.

Hepatic gene expression profiling of 5′-AMP-induced hypometabolism in mice

PubMed Central

Miki, Takao; Van Oort-Jansen, Anita; Matsumoto, Tomoko; Loose, David S.; Lee, Cheng Chi

2011-01-01

There is currently much interest in clinical applications of therapeutic hypothermia. Hypothermia can be a consequence of hypometabolism. We have recently established a procedure for the induction of a reversible deep hypometabolic state in mice using 5′-adenosine monophosphate (5′-AMP) in conjunction with moderate ambient temperature. The current study aims at investigating the impact of this technology at the gene expression level in a major metabolic organ, the liver. Our findings reveal that expression levels of the majority of genes in liver are not significantly altered by deep hypometabolism. However, among those affected by hypometabolism, more genes are differentially upregulated than downregulated both in a deep hypometabolic state and in the early arousal state. These altered gene expression levels during 5′-AMP induced hypometabolism are largely restored to normal levels within 2 days of the treatment. Our data also suggest that temporal control of circadian genes is largely stalled during deep hypometabolism. PMID:21224422

Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain.

PubMed

Mantzoros, C; Flier, J S; Lesem, M D; Brewerton, T D; Jimerson, D C

1997-06-01

Studies in rodents have shown that leptin acts in the central nervous system to modulate food intake and energy metabolism. To evaluate the possible role of leptin in the weight loss of anorexia nervosa, this study compared cerebrospinal fluid (CSF) and plasma leptin concentrations in anorexic patients and controls. Subjects included 11 female patients with anorexia nervosa studied at low weight and after treatment, and 15 healthy female controls. Concentrations of leptin in blood and CSF were measured by RIA. Patients with anorexia nervosa, compared to controls, had decreased concentrations of leptin in CSF (98 +/- 26 vs. 160 +/- 58 pg/mL; P < 0.0005) and plasma (1.75 +/- 0.46 vs. 7.01 +/- 3.92 ng/mL; P < 0.005). The CSF to plasma leptin ratio, however, was higher for patients (0.060 +/- 0.023) than for controls (0.025 +/- 0.007; P < 0.0001). At posttreatment testing, although patients had not yet reached normal body weight, CSF and plasma leptin concentrations had increased to normal levels. These results demonstrate the dynamic changes in plasma and CSF leptin during positive energy balance in anorexia nervosa. The results further suggest that normalization of CSF leptin levels before full weight restoration during treatment of anorexic patients could contribute to resistance to weight gain and/or incomplete weight recovery.

Loss of Gq/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice

PubMed Central

Wettschureck, N.; Moers, A.; Wallenwein, B.; Parlow, A. F.; Maser-Gluth, C.; Offermanns, S.

2005-01-01

Heterotrimeric G proteins of the Gq/11 family transduce signals from a variety of neurotransmitter and hormone receptors and have therefore been implicated in various functions of the nervous system. Using the Cre/loxP system, we generated mice which lack the genes coding for the α subunits of the two main members of the Gq/11 family, gnaq and gna11, selectively in neuronal and glial precursor cells. Mice with defective gnaq and gna11 genes were morphologically normal, but they died shortly after birth. Mice carrying a single gna11 allele survived the early postnatal period but died within 3 to 6 weeks as anorectic dwarfs. In these mice, postnatal proliferation of pituitary somatotroph cells was strongly impaired, and plasma growth hormone (GH) levels were reduced to 15%. Hypothalamic levels of GH-releasing hormone (GHRH), an important stimulator of somatotroph proliferation, were strongly decreased, and exogenous administration of GHRH restored normal proliferation. The hypothalamic effects of ghrelin, a regulator of GHRH production and food intake, were reduced in these mice, suggesting that an impairment of ghrelin receptor signaling might contribute to GHRH deficiency and abnormal eating behavior. Taken together, our findings show that Gq/11 signaling is required for normal hypothalamic function and that impairment of this signaling pathway causes somatotroph hypoplasia, dwarfism, and anorexia. PMID:15713647

Effects of a Tripeptide Iron on Iron-Deficiency Anemia in Rats.

PubMed

Xiao, Chen; Lei, Xingen; Wang, Qingyu; Du, Zhongyao; Jiang, Lu; Chen, Silu; Zhang, Mingjie; Zhang, Hao; Ren, Fazheng

2016-02-01

This study aims to investigate the effects of a tripeptide iron (REE-Fe) on iron-deficiency anemia rats. Sprague-Dawley rats were randomly divided into seven groups: a normal control group, an iron-deficiency control group, and iron-deficiency groups treated with ferrous sulfate (FeSO4), ferrous glycinate (Fe-Gly), or REE-Fe at low-, medium-, or high-dose groups. The rats in the iron-deficiency groups were fed on an iron-deficient diet to establish iron-deficiency anemia (IDA) model. After the model established, different iron supplements were given to the rats once a day by intragastric administration for 21 days. The results showed that REE-Fe had effective restorative action returning body weight, organ coefficients, and hematological parameters in IDA rats to normal level. In addition, comparing with FeSO4 or Fe-Gly, high-dose REE-Fe was more effective on improving the levels of renal coefficient, total iron-binding capacity, and transferrin. Furthermore, the liver hepcidin messenger RNA (mRNA) expression in the high-dose group was significantly higher (p < 0.05) than that in the FeSO4 or Fe-Gly group and showed no significant difference (p > 0.05) with the normal control group. The findings suggest that REE-Fe is an effective source of iron supplement for IDA rats and might be exploited as a new iron fortifier.

River restoration and biocoenoses improvement in two streams renaturated using bioengeneering.

NASA Astrophysics Data System (ADS)

Leoni, B.; Forasacco, E.; Dobner, R.; Cotta Ramusino, M.

2003-04-01

The Bioengineering is a constructive discipline having its own technical, ecological and environmental friendly scopes, by using living materials. The aim of this study is to assess the river restoration efficiency of Bioengineering. The basic goals of many management-concepts are the integrity of the river habitat, self-regulation and self-regeneration, the preservation of intact resources, to recreate the uniqueness, diversity and beauty of natural river landscape. From an ecological point of view the richness, diversity and age composition of the populations developing after restoration as a result of habitat improvement reveal the degree to which comprehensive concepts were applied (Jungwirth et al., 1995). The following results summarised an investigation on streams Boesio and Rancina in Valcuvia, (Varese, Northern Italy). These streams are characterised by human impacts like water pollution, river engineering and river bioengineering (palificata doppia viva). The samples of macrobenthic fauna were collected between August 2000 and July 2001 in 4 stations for each stream, where the 3rd station of Boesio and Rancina streams is characterised by bioengeneering measure, using a Surber sampler (0.125 m2, mesh size 0.45 mm). The zoobenthic communities of these pre-alpine streams are characterised by low richness and diversity and few families and genera were predominant. In Rancina stream, Ephemeroptera (genus Baetis), Trichoptera (families Hydropsychidae, Limnephilidae and Rhyacophilidae) and Diptera (families Chironomidae and Simuliidae) are present throughout the year with significant densities. The faunal composition of Boesio stream is similar. It differs, only, from stream Rancina to costant presence of Plecoptera with genus Leuctra. To evaluate the restoration of environmental quality two indices were applied: Indice Biotico Esteso (I.B.E.- Ghetti, 1995); Indice di Funzionalità Fluviale (I.F.F.- Siligardi, 2000). The E.B.I. scores of Boesio stream indicate that stations 1 and 2 are in good condition (Ecological status classification: II): therefore the level of diversity and abundance of macrobenthic taxa is slightly outside the range associated with the normal conditions and the most of the sensitive taxa of the type specific communities are present. The stations 3 and 4 are in moderate condition (Ecological status classification: III): the level of diversity and abundance of invertebrate taxa is moderately outside the normal condition range, the taxa indicative of pollution are present and many of the sensitive taxa of the type specific communities are absent. In the Rancina stream in all of the 4 stations the ecological status is indicated like moderate (Ecological status classification: III): there is a predominance of taxa more resistant at pollution and at changes in other biological components of the stream. The I.F.F. show that in Boesio stream the right shore score is moderate-good and the left shore score is moderate-poor. Differently, the Rancina stream presents the right shore with a value poor and the left shore with a wide gradient between good and poor-bad. In conclusion, we can affirm the low efficiency of Bioengineering to restore the Boesio and Rancina streams, because we cannot observe the habitat and aquatic biocoenoses improvement. An explication could be that the conversions are restricted to morphological measures, which are carried out on a small way of banks. Whereas, the restoration using the Bioengineering requires taking the entire catchment area into consideration.

miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2.

PubMed

Wei, Guangxia; Xu, Yahuan; Peng, Tao; Yan, Jie

2018-03-01

Dysregulated microRNAs (miRNAs) reported to involve into the oncogenesis and progression in various human cancers. However, the roles and mechanism of miR-133 in lung adenocarcinoma remain largely unclear. In this study, qPCR assay and western blot were used to detect the expression levels of miR-133, Akt and FLOT2. Luciferase reporter assay was used to identify the target role of miR-133 on FLOT2. The cell invasion and the migration capability were performed using the transwell invasion assay and wound healing assay. We found that miR-133 expression levels were downregulated in human lung adenocarcinoma specimens and cell lines compared with the adjacent normal tissues and normal human bronchial epithelial cell. miR-133 significantly suppressed metastasis of lung adenocarcinoma cells in vitro. Furthermore, FLOT2 (flotillin-2) identified as a direct target of miR-133, and FLOT2 expression levels were inversely correlated with miR-133 expression levels in human lung adenocarcinoma specimens. And the restoration studies suggested FGF2 as a downstream effector of miR-133 which acted through Akt signalling pathway. Our study revealed the mechanism that miR-133 suppresses lung adenocarcinoma metastasis by targeting FLOT2 via Akt signalling pathway, implicating a potential prognostic biomarker and therapeutic target for lung adenocarcinoma treatment.

Exogenous ghrelin regulates proliferation and apoptosis in the hypotrophic gut mucosa of the rat.

PubMed

de Segura, Ignacio A Gómez; Vallejo-Cremades, María Teresa; Lomas, Jesús; Sánchez, Miriam F; Caballero, María Isabel; Largo, Carlota; De Miguel, Enrique

2010-04-01

Ghrelin is the natural endogenous ligand for growth hormone secretagogue receptors. This peptide regulates energy homeostasis and expenditure and is a potential link between gut absorptive function and growth. We hypothesized that ghrelin may induce a proliferative and antiapoptotic action promoting the recovery of the hypotrophic gut mucosa. Therefore, the aim of the study was to determine the action of exogenous ghrelin following gut mucosal hypotrophia in rats fed an elemental diet. An elemental diet provides readily absorbable simple nutrients and is usually given to patients with absorptive dysfunction. Male Wistar rats (n = 48) were fed the elemental diet for one week to induce mucosal hypotrophy and then treated for another week with systemic ghrelin and pair-fed with either a normoproteic or hyperproteic isocaloric liquid diet. Another group received a standard diet instead of the elemental diet and served as control (normotrophy). The elemental diet induced intestinal hypotrophia characterized by decreased proliferation in the ileum and increased apoptosis in jejunum and ileum. Ghrelin administration restored normal levels of proliferation in the ileum and apoptosis in the jejunum, with partial apoptosis restoration in the ileum. Ghrelin levels in plasma and fundus were increased in all groups, although the highest levels were found in rats treated with exogenous ghrelin. Ghrelin administration has a positive effect in the hypotrophic gut, regulating both proliferation and apoptosis towards a physiological balance counteracting the negative changes induced by an elemental diet in the intestines.

Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia

PubMed Central

Button, Brian; Picher, Maryse; Boucher, Richard C

2007-01-01

In the lungs, the first line of defence against bacterial infection is the thin layer of airway surface liquid (ASL) lining the airway surface. The superficial airway epithelium exhibits complex regulatory pathways that blend ion transport to adjust ASL volume to maintain proper mucociliary clearance (MCC). We hypothesized that stresses generated by airflow and transmural pressures during breathing govern ASL volume by regulating the rate of epithelial ATP release. Luminal ATP, via interactions with apical membrane P2-purinoceptors, regulates the balance of active ion secretion versus absorption to maintain ASL volume at optimal levels for MCC. In this study we tested the hypothesis that cyclic compressive stress (CCS), mimicking normal tidal breathing, regulates ASL volume in airway epithelia. Polarized tracheobronchial epithelial cultures from normal and cystic fibrosis (CF) subjects responded to a range of CCS by increasing the rate of ATP release. In normal airway epithelia, the CCS-induced increase in ASL ATP concentration was sufficient to induce purinoceptor-mediated increases in ASL height and MCC, via inhibition of epithelial Na+-channel-mediated Na+ absorption and stimulation of Cl− secretion through CFTR and the Ca2+-activated chloride channels. In contrast, static, non-oscillatory stress did not stimulate ATP release, ion transport or MCC, emphasizing the importance of rhythmic mechanical stress for airway defence. In CF airway cultures, which exhibit basal ASL depletion, CCS was partially effective, producing less ASL volume secretion than in normal cultures, but a level sufficient to restore MCC. The present data suggest that CCS may (1) regulate ASL volume in the normal lung and (2) improve clearance in the lungs of CF patients, potentially explaining the beneficial role of exercise in lung defence. PMID:17317749

Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells.

PubMed

Kim, Boyun; Kim, Hee Seung; Jung, Eun-Ji; Lee, Jung Yun; K Tsang, Benjamin; Lim, Jeong Mook; Song, Yong Sang

2016-05-01

Prolonged accumulation of misfolded or unfolded proteins caused by cellular stress, including oxidative stress, induces endoplasmic reticulum stress, which then activates an unfolded protein response (UPR). ER stress is usually maintained at higher levels in cancer cells as compared to normal cells due to altered metabolism in cancer. Here, we investigated whether curcumin is ER stress-mediated apoptosis in cervical cancer cells, and ROS increased by curcumin are involved in the process as an upstream contributor. Curcumin inhibited proliferation of cervical cancer cells (C33A, CaSki, HeLa, and ME180) and induced apoptotic cell death. Curcumin activated ER-resident UPR sensors, such as PERK, IRE-1α, and ATF6, and their downstream-signaling proteins in cervical cancer cells, but not in normal epithelial cells and peripheral blood mononuclear cells (PBMCs). CHOP, a key factor involved in ER stress-mediated apoptosis, was also activated by curcumin. CHOP decreased the ratio of anti-apoptotic protein Bcl-2 to pro-apoptotic protein Bax expression, and subsequently increased the apoptotic population of cervical cancer cells. Furthermore, curcumin elevated levels of intracellular reactive oxygen species (ROS) in cervical cancer cells, but not in normal epithelial cells. Scavenging ROS resulted in inhibition of ER stress and partially restored cell viability in curcumin-treated cancer cells. Collectively, these observations show that curcumin promotes ER stress-mediated apoptosis in cervical cancer cells through increase of cell type-specific ROS generation. Therefore, modulation of these differential responses to curcumin between normal and cervical cancer cells could be an effective therapeutic strategy without adverse effects on normal cells. © 2015 Wiley Periodicals, Inc.

Regeneration of defective epithelial basement membrane and restoration of corneal transparency

PubMed Central

Marino, Gustavo K.; Santhiago, Marcony R.; Santhanam, Abirami; Torricelli, Andre A. M.; Wilson, Steven E.

2018-01-01

PURPOSE To study regeneration of the normal ultrastructure of the epithelial basement membrane (EBM) in rabbit corneas that had -9D photorefractive keratectomy (PRK) and developed late haze (fibrosis) with restoration of transparency over one to four months after surgery and in corneas that had incisional wounds. METHODS Twenty-four rabbits had one of their eyes included into one of the two procedure groups (-9D PRK or nearly full-thickness incisional wounds), while the opposite eye serving as unwounded controls. All corneas were evaluated with slit lamp photos, transmission electron microscopy and immunohistochemistry for the myofibroblast marker alpha-smooth muscle actin and collagen type III. RESULTS In the ‘-9D PRK group’, corneas at one month after surgery had dense corneal haze and no evidence of regenerated EBM ultrastructure. By two months after surgery, however, small areas of stromal clearing began to appear within the confluent opacity (lacunae), and these corresponded to small islands of normally-regenerated EBM detected within larger area of the excimer laser-ablated zone with no evidence of normal EBM. By four months after surgery, the EBM was fully-regenerated and the corneal transparency was completely restored to the ablated zone. In the ‘Incisional wound group’, the two dense, linear corneal opacities were observed at one month after surgery and progressively faded by two and three months after surgery. The EBM ultrastructure was fully regenerated at the site of the incisions, including around epithelial plugs that extended into the stroma, by one month after surgery in all eyes. CONCLUSIONS In the rabbit model, spontaneous resolution of corneal fibrosis (haze) after high correction PRK is triggered by regeneration of EBM with normal ultrastructure in the excimer laser- ablated zone. Conversely, incisional wounds heal in rabbit corneas without the development of myofibroblasts because the EBM regenerates normally by one month after surgery. PMID:28486725

Structure and function of conjugative pili: monoclonal antibodies as probes for structural variants of F pili.

PubMed Central

Grossman, T H; Frost, L S; Silverman, P M

1990-01-01

The lac-tra operon fusion plasmid pTG801 contains the known F plasmid DNA transfer (tra) genes required by Escherichia coli to elaborate functional F pili (T. Grossman and P. M. Silverman, J. Bacteriol. 171:650-656, 1989). Here, we show that these pili are actually structural variants of normal F pili and that the F plasmid must contain additional genes that affect pilus structure and function. We confirmed a previous report that two monoclonal antibodies that recognize epitopes at and near the amino terminus of F pilin do not decorate the sides of normal F pili, as determined by immunogold electron microscopy. However, both antibodies laterally decorated pTG801 pili. The epitope for one of the antibodies has been shown to include the amino-terminal acetyl group of F pilin, which must therefore also be present on pTG801 pilin. Normal antibody staining was restored to pTG801 pili when cells contained, in addition to pTG801, the compatible plasmid pRS31, which must therefore include at least one gene affecting F-pilus structure. One candidate, traD, was excluded as the sole such gene, since traD+ derivatives of a pTG801 strain still elaborated pili that could be laterally decorated with antibody. Moreover, although traD alone restored RNA bacteriophage R17 infectivity to pTG801 cells, as expected, it did not mimic pRS31 in restoring to pTG801 pili other characteristics of normal F pili. We conclude that pRS31 contains as yet uncharacterized genes required for elaboration of structurally normal F pili. Finally, we identified vesicular material, especially abundant in cultures of pTG801 transformants, that stained heavily with the anti-F-pilin monoclonal antibodies. This material may reflect the inner membrane pool of F pilin. Images FIG. 3 FIG. 4 FIG. 5 PMID:1689713

Rehabilitation of the elbow following sports injury.

PubMed

Ellenbecker, Todd S; Pieczynski, Tad E; Davies, George J

2010-01-01

Evaluation of the athlete with an elbow injury involves a complete upper extremity approach and a corresponding treatment approach that addresses the identified deficiencies to restore normal function. A significant focus should be placed on the proximal aspect of the upper extremity in addition to the obvious distal injury. A detailed review of the available treatment modalities fails to identify any clear definitive choice to address pain levels; however, a combination of modalities and appropriate exercise can be used in the early rehabilitation phases. The use of a total arm strengthening program along with evaluation of the athlete's sport mechanics is required to successfully return the patient back to their preinjury level of function. A supervised interval sport return program is also a necessary component of the complete rehabilitation program for the athlete with an elbow injury.

Maintaining physiological testosterone levels by adding dehydroepiandrosterone to combined oral contraceptives: I. Endocrine effects.

PubMed

Coelingh Bennink, Herjan J T; Zimmerman, Yvette; Laan, Ellen; Termeer, Hanneke M M; Appels, Nicole; Albert, Adelin; Fauser, Bart C J M; Thijssen, Jos H H; van Lunsen, Rik H W

2017-11-01

To determine whether adding dehydroepiandrosterone to combined oral contraceptives (COCs) maintains physiological levels of free testosterone. A randomized, double-blind, placebo-controlled, two-way crossover study conducted in 81 healthy women (age range: 20-35 years; Body mass index (BMI) range: 18-35 kg/m 2 ) using oral contraceptives. Androgens, sex hormone-binding globulin (SHBG), estradiol (E2) and estrone (E1) were measured, and free testosterone and the free testosterone index were calculated. Subjects discontinued oral contraceptive use for at least one menstrual cycle before being randomized to receive five cycles of ethinyl estradiol (EE) combined with either levonorgestrel (EE/LNG group) or drospirenone (EE/DRSP group) together with either dehydroepiandrosterone (DHEA) (50 mg/day orally) or placebo. Subsequently, all subjects crossed over to the other treatment arm for an additional five cycles. Both COCs decreased the levels of all androgens measured. Significant decreases (p<.05) were found with EE/LNG and EE/DRSP for total testosterone (54.5% and 11.3%, respectively) and for free testosterone (66.8% and 75.6%, respectively). Adding DHEA to the COCs significantly increased all androgens compared to placebo. Moreover, including DHEA restored free testosterone levels to baseline values in both COC groups and total testosterone levels to baseline in the EE/LNG group and above baseline in the EE/DRSP group. SHBG concentrations were significantly higher with EE/DRSP compared to EE/LNG (p<.0001). The addition of DHEA did not affect the levels of SHBG. Taking COCs reduces total and free testosterone levels and increases SHBG concentrations. By coadministration with DHEA, physiological levels of total and free testosterone are restored while using EE/LNG. With EE/DRSP, only the free testosterone level is normalized by DHEA coadministration. A daily oral dose of 50-mg DHEA maintains physiological free and total testosterone levels in women who are using an EE/LNG-containing COC. Copyright © 2016 Pantarhei Bioscience. Published by Elsevier Inc. All rights reserved.

Quantitative analysis of protein and gene expression in salivary glands of Sjogren's-like disease NOD mice treated by bone marrow soup.

PubMed

Misuno, Kaori; Tran, Simon D; Khalili, Saeed; Huang, Junwei; Liu, Younan; Hu, Shen

2014-01-01

Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Whole BM cells were lysed and soluble intracellular contents ("BM Soup") were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment.

Quantitative Analysis of Protein and Gene Expression in Salivary Glands of Sjogren’s-Like Disease NOD Mice Treated by Bone Marrow Soup

PubMed Central

Misuno, Kaori; Khalili, Saeed; Huang, Junwei; Liu, Younan

2014-01-01

Background Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Methods Whole BM cells were lysed and soluble intracellular contents (“BM Soup”) were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. Results BM Soup restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. Conclusion BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment. PMID:24489858

[Correction of the combined vitamin deficiency in growing rats fed fiber enriched diets with different doses of vitamins].

PubMed

Beketova, N A; Kodentsova, V M; Vrzhesinskaia, O A; Kosheleva, O V; Pereverzeva, O G; Sokol'nikov, A A; Aksenov, I V

2014-01-01

The effect of 5% dietary wheat bran (WB) on the correction of combined vitamin deficiency by two doses of vitamins (physiological and enhanced) has been analyzed using a rat model (8 groups, n = 8/group). Vitamin deficiency in male weanling Wistar rats (58.1 ± 0.5 g) was induced by 5-fold reduction of vitamin mixture amount in the feed and complete vitamin E, B1 and B2 exclusion from the mixture for 30 days, then deficit was corrected within 5 days. Rats from control group were fed a complete semisynthetic diet containing microcrystalline cellulose 2%. Vitamin deficient diet for 35 days resulted in reduced (p < 0.05) levels of vitamin A in the liver by 25 fold, vitamin E and B1--2.0-2.3 fold, vitamin B2--by 40%, 25(OH)D blood plasma concentration--by 21% compared with the control. Feed consumption of the animals treated with vitamin deficient diet and WB was higher by 43% than in rats with vitamin deficit. Their rate of weight occupied the intermediate position between the rates of weight in deficit and in control animals, and they could not serve a full control to evaluate the WB impact on vitamin sufficiency. After filling the vitamin diet content to an adequate level vitamin E liver content was fully restored. To restore vitamins B1 and B2 liver level higher doses of vitamins (120-160% of adequate content) were required, and to restore the reduced levels of vitamin A in rat liver even 2-fold increased dose of vitamin A was insufficient. The diet enrichment with WB had no effect on vitamin B1 and B2 liver content, regardless of the amount of vitamins in the diet. Adding fiber to the diet of animals adequately provided with vitamins resulted in significantly 1,3-fold increase of 25(OH)D blood plasma concentration and a slight but significant decrease of α-tocopherol liver level by 16% as compared to rats not receiving WB. The enrichment of rat diet with dietary fibers worsened restoration of the reduced vitamin E status not only by filling vitamin content in the diet to an adequate level, but also by using 2-fold enhanced dose of vitamin. Within 5 days deficiency of vitamins A, B1, B2 was not eliminated with increasing vitamin diet content to an adequate level. Higher doses of vitamins are needed for the complete correction of vitamin status. The addition of vitamins to an adequate level was sufficient to normalize the elevated liver levels of MDA in rats with combined vitamin deficiency that may be associated with vitamin E status improvement. The diet enrichment with fiber did not affect on the intensity of lipid peroxidation in rat liver regardless of their provision with vitamins.

A bill to amend the Health Forests Restoration Act of 2003 to promote timely emergency rehabilitation and restoration of Federal forest land impacted by catastrophic events, to redirect for a 5-year-period funding normally made available for land acquisition to mechanical forest treatment and salvage operations due to catastrophic events, and for other purposes.

THOMAS, 113th Congress

Sen. Thune, John [R-SD

2013-03-22

Senate - 03/22/2013 Read twice and referred to the Committee on Agriculture, Nutrition, and Forestry. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

Effect of dental restorative materials on total antioxidant capacity and calcium concentration of unstimulated saliva.

PubMed

Ramezani, Gholam H; Moghadam, Mona-Momeni; Saghiri, Mohammad-Ali; Garcia-Godoy, Franklin; Asatourian, Armen; Aminsobhani, Mohsen; Scarbecz, Mark; Sheibani, Nader

2017-01-01

To evaluate the effect of dental amalgam and composite restorations on total antioxidant capacity (TAC) and calcium (Ca) ion concentration of unstimulated saliva. Forty-eight children aged 6-10 years selected and divided into three groups of sixteen (8 males, 8 females). In group A and B, samples consisted of two class II dental composite or amalgam restorations, while in group C samples were caries-free (control group). Unstimulated saliva from all samples was collected and TAC was measured by spectrophotometry using an adaptation of 2, 2'-azino-di-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) assay. The Ca ion level was estimated by an auto- analyzer. Data were analyzed with one- and two-way ANOVA test, at a p <.05 level of significance. Composite samples showed significantly higher TAC and lower Ca ion levels compared to amalgam and caries-free samples ( p <.05). The TAC values showed only significant difference between groups ( p <.05), while the Ca ion results showed significant differences within and between groups ( p <.05). Dental composite restorations increased TAC and decreased Ca ion levels more than amalgam restorations in saliva. Gender is an effective factor in changes induced in oral cavity as females showed more emphatic reaction to dental filling materials than males. Patients who have dental restorations, especially dental composites, should pay more attention to their dental hygiene, because dental restorations can increase oxidative stress and decrease Ca ion level in saliva, which might jeopardize remineralization process of tooth structures after demineralization. Key words: Amalgam, caries, composite, saliva, total antioxidant capacity.

Afforestation or intense pasturing improve the ecological and economic value of abandoned tropical farmlands.

PubMed

Knoke, Thomas; Bendix, Jörg; Pohle, Perdita; Hamer, Ute; Hildebrandt, Patrick; Roos, Kristin; Gerique, Andrés; Sandoval, María L; Breuer, Lutz; Tischer, Alexander; Silva, Brenner; Calvas, Baltazar; Aguirre, Nikolay; Castro, Luz M; Windhorst, David; Weber, Michael; Stimm, Bernd; Günter, Sven; Palomeque, Ximena; Mora, Julio; Mosandl, Reinhard; Beck, Erwin

2014-11-26

Increasing demands for livelihood resources in tropical rural areas have led to progressive clearing of biodiverse natural forests. Restoration of abandoned farmlands could counter this process. However, as aims and modes of restoration differ in their ecological and socio-economic value, the assessment of achievable ecosystem functions and benefits requires holistic investigation. Here we combine the results from multidisciplinary research for a unique assessment based on a normalization of 23 ecological, economic and social indicators for four restoration options in the tropical Andes of Ecuador. A comparison of the outcomes among afforestation with native alder or exotic pine, pasture restoration with either low-input or intense management and the abandoned status quo shows that both variants of afforestation and intense pasture use improve the ecological value, but low-input pasture does not. Economic indicators favour either afforestation or intense pasturing. Both Mestizo and indigenous Saraguro settlers are more inclined to opt for afforestation.

Ecological Restoration of Antibiotic-Disturbed Gastrointestinal Microbiota in Foregut and Hindgut of Cows

PubMed Central

Ji, Shoukun; Jiang, Tao; Yan, Hui; Guo, Chunyan; Liu, Jingjing; Su, Huawei; Alugongo, Gibson M.; Shi, Haitao; Wang, Yajing; Cao, Zhijun; Li, Shengli

2018-01-01

Antibiotically disturbed gastrointestinal microbiota needs a long period time to be restored to normal, which may cause a series of problems to the host. The understanding of restoration of the biased microbiota by antibiotics remains largely unknown. Here, we investigated the microbiota shift in foregut (rumen) and hindgut (rectum) of lactating cows after antibiotics exposure as well as after antibiotics withdrawal with (Microbiota transplantation, MT group) or without (Control, CON group) microbiota transplantation. We were able to demonstrate that microbiota in both foregut and hindgut significantly changed after 3 or 14 days of antibiotics exposure, and the changes persisted over long period of time (>18 days) after withdrawing the antibiotics. We further observed a faster restoration of microbiota in both foregut and hindgut of MT group than CON group, microbiota in foregut was mainly benefited from microbiota transplantation by restoring the alpha-diversity as well as within-group similarity, while microbiota in hindgut was primarily benefited from microbiota transplantation by reestablishing the co-occurrence network (nodes number, edges number, density, modularity as well as closeness centrality). These results together expanded our understanding of restoration of the biased microbiota by antibiotics, and may also be instructive to deal with the delayed microbiota restoration at least in cows. PMID:29594071

Adrenomedullin and angiopoietin-1 additively restore erectile function in diabetic rats: comparison with the combination therapy of vascular endothelial growth factor and angiopoietin-1.

PubMed

Nishimatsu, Hiroaki; Suzuki, Etsu; Nomiya, Akira; Niimi, Aya; Suzuki, Motofumi; Fujimura, Tetsuya; Fukuhara, Hiroshi; Homma, Yukio

2013-07-01

Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A). Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α-smooth muscle actin (SMA), VE-cadherin and type I collagen was assessed by Western blot analysis. Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body. © 2013 International Society for Sexual Medicine.

Vision restoration after brain and retina damage: the "residual vision activation theory".

PubMed

Sabel, Bernhard A; Henrich-Noack, Petra; Fedorov, Anton; Gall, Carolin

2011-01-01

Vision loss after retinal or cerebral visual injury (CVI) was long considered to be irreversible. However, there is considerable potential for vision restoration and recovery even in adulthood. Here, we propose the "residual vision activation theory" of how visual functions can be reactivated and restored. CVI is usually not complete, but some structures are typically spared by the damage. They include (i) areas of partial damage at the visual field border, (ii) "islands" of surviving tissue inside the blind field, (iii) extrastriate pathways unaffected by the damage, and (iv) downstream, higher-level neuronal networks. However, residual structures have a triple handicap to be fully functional: (i) fewer neurons, (ii) lack of sufficient attentional resources because of the dominant intact hemisphere caused by excitation/inhibition dysbalance, and (iii) disturbance in their temporal processing. Because of this resulting activation loss, residual structures are unable to contribute much to everyday vision, and their "non-use" further impairs synaptic strength. However, residual structures can be reactivated by engaging them in repetitive stimulation by different means: (i) visual experience, (ii) visual training, or (iii) noninvasive electrical brain current stimulation. These methods lead to strengthening of synaptic transmission and synchronization of partially damaged structures (within-systems plasticity) and downstream neuronal networks (network plasticity). Just as in normal perceptual learning, synaptic plasticity can improve vision and lead to vision restoration. This can be induced at any time after the lesion, at all ages and in all types of visual field impairments after retinal or brain damage (stroke, neurotrauma, glaucoma, amblyopia, age-related macular degeneration). If and to what extent vision restoration can be achieved is a function of the amount of residual tissue and its activation state. However, sustained improvements require repetitive stimulation which, depending on the method, may take days (noninvasive brain stimulation) or months (behavioral training). By becoming again engaged in everyday vision, (re)activation of areas of residual vision outlasts the stimulation period, thus contributing to lasting vision restoration and improvements in quality of life. Copyright © 2011 Elsevier B.V. All rights reserved.

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function.

PubMed

Kandasamy, Ram; Calsbeek, Jonas J; Morgan, Michael M

2017-01-15

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund's Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED 50 dose of morphine (3.2mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function

PubMed Central

Kandasamy, Ram; Calsbeek, Jonas J.; Morgan, Michael M.

2016-01-01

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED50 dose of morphine (3.2 mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0 mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. PMID:27746208

β-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice.

PubMed

Iskandar, Anita R; Liu, Chun; Smith, Donald E; Hu, Kang-Quan; Choi, Sang-Woon; Ausman, Lynne M; Wang, Xiang-Dong

2013-04-01

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-β to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments.

Effectiveness of benzocaine in reducing deep cavity restoration and post-extraction stress in dental patients.

PubMed

Al-Samadani, Khalid H; Gazal, Giath

2015-11-01

To investigate the effectiveness of topical anesthetic, 20% benzocaine in relieving pain and stress in patients following deep cavity restoration and extraction of teeth under local anesthesia (LA). A prospective clinical trial was conducted from October 2014 until April 2015 at Taibah University, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. Forty-five patients were included in the 20% benzocaine group, and 46 in the normal saline group. Evaluation of the dental stress was made pre-operatively and immediately post-operative treatment using the visual analogue scale (VAS). Furthermore, discomfort of the injections were recorded by the patients after each treatment on standard 100 mm VAS, tagged at the endpoints with "no pain" (0 mm) and "unbearable pain" (100 mm). There were statistically significant differences between the mean stress scores for patients in the benzocaine and normal saline groups post-operatively (p=0.002). There were significant differences between the mean pain scores for patients in the post buccal injection (p=0.001), post palatal injection (p=0.01), and the post inferior alveolar nerve block groups (p=0.02). Buccal, palatal, and inferior alveolar nerve block injections were more painful for patients in the normal saline group than the benzocaine group. This investigation has demonstrated that post-operative stress associated with deep cavity restoration and dental extractions under LA can be reduced by the application of topical anesthetic (20% benzocaine) at the operative site for intra-oral injections.

Effectiveness of benzocaine in reducing deep cavity restoration and post-extraction stress in dental patients

PubMed Central

Al-Samadani, Khalid H.; Gazal, Giath

2015-01-01

Objectives: To investigate the effectiveness of topical anesthetic, 20% benzocaine in relieving pain and stress in patients following deep cavity restoration and extraction of teeth under local anesthesia (LA). Methods: A prospective clinical trial was conducted from October 2014 until April 2015 at Taibah University, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. Forty-five patients were included in the 20% benzocaine group, and 46 in the normal saline group. Evaluation of the dental stress was made pre-operatively and immediately post-operative treatment using the visual analogue scale (VAS). Furthermore, discomfort of the injections were recorded by the patients after each treatment on standard 100 mm VAS, tagged at the endpoints with “no pain” (0 mm) and “unbearable pain” (100 mm). Results: There were statistically significant differences between the mean stress scores for patients in the benzocaine and normal saline groups post-operatively (p=0.002). There were significant differences between the mean pain scores for patients in the post buccal injection (p=0.001), post palatal injection (p=0.01), and the post inferior alveolar nerve block groups (p=0.02). Buccal, palatal, and inferior alveolar nerve block injections were more painful for patients in the normal saline group than the benzocaine group. Conclusion: This investigation has demonstrated that post-operative stress associated with deep cavity restoration and dental extractions under LA can be reduced by the application of topical anesthetic (20% benzocaine) at the operative site for intra-oral injections. PMID:26593169

Insomnia, metabolic rate and sleep restoration.

PubMed

Bonnet, M H; Arand, D L

2003-07-01

Studies have shown occasional evidence of increased physiological activity in patients with primary insomnia. We hypothesized that metabolic rate, as measured by overall oxygen use (VO2), might be a more general index of increased physiological activity. An initial experiment found elevated VO2 both at night and during the day in patients with primary insomnia as compared with matched normal sleepers. A second experiment found significant but more modest increases in VO2 in patients with Sleep State Misperception Insomnia [who complain of poor sleep but who had normal sleep by electroencephalographic (EEG) criteria]. In a third experiment, normal young adults were given caffeine 400 mg three times per day (TID) for 1 week as a means of increasing VO2 and possibly producing other symptoms of insomnia. Participants developed many symptoms consistent with those seen in patients with primary insomnia (poor sleep, increased latency on the Multiple Sleep Latency Test, increasing fatigue despite physiological activation, and increased anxiety on the Minnesota Multiphasic Personality Inventory (MMPI)). In a final experiment, physiological arousal was again produced by caffeine to determine if sleep with elevated arousal would be less restorative. All subjects (Ss) slept for 3.5 h after being given 400 mg of caffeine. During 41 h of sleep deprivation that followed, there was no significant condition difference for the Multiple Sleep Latency Test or mood measures. The results provided only weak support for the idea that sleep is less restorative after physiological arousal.

A Simple Laparoscopic Procedure to Restore a Normal Vaginal Length After Colpohysterectomy With Large Upper Colpectomy for Cervical and/or Vaginal Neoplasia.

PubMed

Leblanc, Eric; Bresson, Lucie; Merlot, Benjamin; Puga, Marco; Kridelka, Frederic; Tsunoda, Audrey; Narducci, Fabrice

2016-01-01

Colpohysterectomy is sometimes associated with a large upper colpectomy resulting in a shortened vagina, potentially impacting sexual function. We report on a preliminary experience of a laparoscopic colpoplasty to restore a normal vaginal length. Patients with shortened vaginas after a laparoscopic colpohysterectomy were considered for a laparoscopic modified Davydov's procedure to create a new vaginal vault using the peritoneum of the rectum and bladder. From 2010 to 2014, 8 patients were offered this procedure, after informed preoperative consent. Indications were 2 extensive recurrent vaginal intraepithelial neoplasias grade 3 and 6 radical hysterectomies for cervical cancer. Mean vaginal length before surgery was 3.8 cm (standard deviation, 1.6). Median operative time was 50 minutes (range, 45-90). Blood loss was minimal (50-100 mL). No perioperative complications occurred. Median vaginal length at discharge was 11.3 cm (range, 9-13). Sexual intercourse could be resumed around 10 weeks after surgery. At a median follow-up of 33.8 months (range, 2.4-51.3), 6 patients remained sexually active but 2 had stopped. Although this experience is small, this laparoscopic modified Davydov's procedure seems to be an effective procedure, adaptable to each patient's anatomy. If the initial postoperative regular self-dilatation is carefully observed, vaginal patency is durably restored and enables normal sexual function. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

Destruction of newly released red blood cells in space flight

NASA Technical Reports Server (NTRS)

Alfrey, C. P.; Udden, M. M.; Huntoon, C. L.; Driscoll, T.

1996-01-01

Space flight results in a rapid change in total blood volume, plasma volume, and red blood cell mass because the space to contain blood is decreased. The plasma volume and total blood volume decreases during the first hours in space and remain at a decreased level for the remainder of the flight. During the first several hours following return to earth, plasma volume and total blood volume increase to preflight levels. During the first few days in space recently produced red blood cells disappear from the blood resulting in a decrease in red blood cell mass of 10-15%. Red cells 12 d old or older survive normally and production of new cells continues at near preflight levels. After the first few days in space, the red cell mass is stable at the decreased level. Following return to earth the hemoglobin and red blood cell mass concentrations decrease reflecting the increase in plasma volume. The erythropoietin levels increase responding to "postflight anemia"; red cell production increases, and the red cell mass is restored to preflight levels after several weeks.

Structural optimization of dental restorations using the principle of adaptive growth.

PubMed

Couegnat, Guillaume; Fok, Siu L; Cooper, Jonathan E; Qualtrough, Alison J E

2006-01-01

In a restored tooth, the stresses that occur at the tooth-restoration interface during loading could become large enough to fracture the tooth and/or restoration and it has been estimated that 92% of fractured teeth have been previously restored. The tooth preparation process for a dental restoration is a classical optimization problem: tooth reduction must be minimized to preserve tooth tissue whilst stress levels must be kept low to avoid fracture of the restored unit. The objective of the present study was to derive alternative optimized designs for a second upper premolar cavity preparation by means of structural shape optimization based on the finite element method and biological adaptive growth. Three models of cavity preparations were investigated: an inlay design for preparation of a premolar tooth, an undercut cavity design and an onlay preparation. Three restorative materials and several tooth/restoration contact conditions were utilized to replicate the in vitro situation as closely as possible. The optimization process was run for each cavity geometry. Mathematical shape optimization based on biological adaptive growth process was successfully applied to tooth preparations for dental restorations. Significant reduction in stress levels at the tooth-restoration interface where bonding is imperfect was achieved using optimized cavity or restoration shapes. In the best case, the maximum stress value was reduced by more than 50%. Shape optimization techniques can provide an efficient and effective means of reducing the stresses in restored teeth and hence has the potential of prolonging their service lives. The technique can easily be adopted for optimizing other dental restorations.

Methoxistasis: Integrating the Roles of Homocysteine and Folic Acid in Cardiovascular Pathobiology

PubMed Central

Joseph, Jacob; Loscalzo, Joseph

2013-01-01

Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or “methoxistasis”, exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure. PMID:23955381

Modulation of B16-BL6 murine melanoma metastatic phenotype by tyrosine and phenylalanine restriction in the absence of host selection pressures.

PubMed

Elstad, C A; Meadows, G G

1993-01-01

We previously showed that restriction of tyrosine (Tyr) and phenylalanine (Phe) in vivo dramatically suppresses the metastatic phenotype of B16-BL6 (BL6) murine melanoma. Present results indicate a direct effect of Tyr and Phe restriction on the tumor in the absence of host selection pressures. Lung colonizing ability of BL6 is dramatically suppressed after one passage in vitro in media containing low levels of Tyr and Phe. This antimetastatic effect is immediate, stable for at least 5 in vitro passages in Tyr and Phe restricted media, and evident event after levels of Tyr and Phe are restored to normal. Heterogeneity for lung colonizing ability is suppressed, as evidence by fewer tumor colonies formed by clones following i.v. inoculation into mice fed normal diet. This suppression of BL6 metastatic phenotype is not due to differential clearance and retention in the lung or to decreased growth, but is specific for these two amino acids. As the mechanism(s) for the antitumor effects of Tyr and Phe restriction are detailed, the relevance of Tyr and Phe restriction as an early adjuvant to effective cancer treatment can be explored.

Hyperfunctioning thyroid nodules in children and adolescents.

PubMed

de Luca, F; Chaussain, J L; Job, J C

1986-01-01

Eight children and adolescents, seven female and one male, aged 7.1 to 15.0 years, referred over a 12-year period for a solitary mass in an otherwise normal thyroid gland, exhibited a hyperfunctioning nodule on thyroid scintiscan. Tracer uptake in the surrounding thyroid tissue was reduced or completely suppressed, but could be restored after TSH stimulation. Only one patient had mild clinical hyperthyroidism with normal T4 but increased T3 serum levels and blunted TSH responsiveness to TRH. A similar hormonal pattern suggestive of subclinical hyperthyroidism was found in three other subjects who were clinically euthyroid. One patient initially euthyroid progressed to subclinical hyperthyroidism two years later. In the whole group a significant negative relationship was found between serum T3 level and TRH-stimulated TSH peak (r = -0.829, p less than 0.02). All the patients underwent selective surgery after a 3-month to 2-year period of follow-up. Microscopic examination was consistent with adenoma in seven patients, while in one case a well-encapsulated papillary adenocarcinoma was found. Though hyperfunctioning nodules are seldom malignant, their surgical removal must be recommended when they become thyrotoxic, exceed 3 cm or show progressive enlargement.

The Development of an Accelerometer System for Measuring Pelvic Motion During Walking.

DTIC Science & Technology

1979-01-01

9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT, PROJECT, T ASK AFIT STUDENT AT: University of Oxford CONTROLLING OFFICE NAME AND...bones, joints or muscles and physiotherapy to improve the functioning of impaired lower limbs. When irreparable damage occurs, the normal locomotor system...restoring near normal functioning of the locomotor system. Any improvement in surgical procedures, physiotherapy techniques, orthoses or prostheses

Sub-Network Access Control Technology Demonstrator: Software Design of the Network Management System

DTIC Science & Technology

2002-08-01

Canadian Operational Fleet. Requirements The proposed network management solution must provide the normal monitoring and configuration mechanisms generally...Joint Warrior Inter- operability Demonstrations (JWID) m and the Communication System Network Inter- Operability (CSNI) Navy Network Trials. In short...management functional area normally includes two main functions: fault isolation and diagnosis, and restoration of the system . In short, an operator

Antihyperglycemic and antilipidperoxidative effects of dry matter of culture broth of Inonotus obliquus in submerged culture on normal and alloxan-diabetes mice.

PubMed

Sun, Jun-En; Ao, Zong-Hua; Lu, Zhen-Ming; Xu, Hong-Yu; Zhang, Xiao-Mei; Dou, Wen-Fang; Xu, Zheng-Hong

2008-06-19

The antihyperglycemic and antilipidperoxidative effects of the dry matter of culture broth (DMCB) of Inonotus obliquus were investigated. The normal, glucose-induced hyperglycemic and alloxan-induced diabetic mice were used to evaluate the antihyperglycemic and antilipidperoxidative effects of the DMCB of Inonotus obliquus. Treatment with the DMCB (500 and 1000 mg/kg body weight) exhibited a mild hypoglycemic effect in normal mice, and failed to reduce the peak glucose levels after glucose administration. However, euglycemia was achieved in the DMCB of Inonotus obliquus (1000 mg/kg) and glibenclamide-treated mice after 120 min of glucose loading. In alloxan-induced diabetic mice, the DMCB (500 and 1000 mg/kg body weight for 21 days) showed a significant decrease in blood glucose level, the percentages reduction on the 7th day were 11.90 and 15.79%, respectively. However, feeding of this drug for 3 weeks produced reduction was 30.07 and 31.30%. Furthermore, the DMCB treatment significantly decreased serum contents of free fatty acid (FFA), total cholesterol (TC), triglyceride (TG) and low density lipoprotein-cholesterol (LDL-C), whereas effectively increased high density lipoprotein-cholesterol (HDL-C), insulin level and hepatic glycogen contents in liver on diabetic mice. Besides, the DMCB treatment significantly increased catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities except for decreasing maleic dialdehyde (MDA) level in diabetic mice. Histological morphology examination showed that the DMCB restored the damage of pancreas tissues in mice with diabetes mellitus. The results showed that the DMCB of Inonotus obliquus possesses significant antihyperglycemic, antilipidperoxidative and antioxidant effects in alloxan-induced diabetic mice.

The role of nickel in urea assimilation by algae.

PubMed

Rees, T A; Bekheet, I A

1982-12-01

Nickel is required for urease synthesis by Phaeodactylum tricornutum and Tetraselmis subcordiformis and for growth on urea by Phaeodactylum. There is no requirement for nickel for urea amidolyase synthesis by Chlorella fusca var. vacuolata. Neither copper nor palladium can substitute for nickel but cobalt partially restored urease activity in Phaeodactylum. The addition of nickel to nickel-deficient cultures of Phaeodactylum or Tetraselmis resulted in a rapid increase of urease activity to 7-30 times the normal level; this increase was not inhibited by cycloheximide. It is concluded that nickel-deficient cells over-produce a non-functional urease protein and that either nickel or the functional urease enzyme participates in the regulation of the production of urease protein.

Effect of tibial plateau leveling osteotomy on femorotibial contact mechanics and stifle kinematics.

PubMed

Kim, Stanley E; Pozzi, Antonio; Banks, Scott A; Conrad, Bryan P; Lewis, Daniel D

2009-01-01

To evaluate the effects of tibial plateau leveling osteotomy (TPLO) on femorotibial contact mechanics and 3-dimensional (3D) kinematics in cranial cruciate ligament (CrCL)-deficient stifles of dogs. In vitro biomechanical study. Unpaired pelvic limbs from 8 dogs, weighing 28-35 kg. Digital pressure sensors placed subjacent to the menisci were used to measure femorotibial contact force, contact area, peak and mean contact pressure, and peak pressure location with the limb under an axial load of 30% body weight and a stifle angle of 135 degrees. Three-dimensional static poses of the stifle were obtained using a Microscribe digitizing arm. Each specimen was tested under normal, CrCL-deficient, and TPLO-treated conditions. Repeated measures analysis of variance with a Tukey post hoc test (P<.05) was used for statistical comparison. Significant disturbances to all measured contact mechanical variables were evident after CrCL transection, which corresponded to marked cranial tibial subluxation and increased internal tibial rotation in the CrCL-deficient stifle. No significant differences in 3D femorotibial alignment were observed between normal and TPLO-treated stifles; however, femorotibial contact area remained significantly smaller and peak contact pressures in both medial and lateral stifle compartments were positioned more caudally on the tibial plateau, when compared with normal. Whereas TPLO eliminates craniocaudal stifle instability during simulated weight bearing, the procedure fails to concurrently restore femorotibial contact mechanics to normal. Progression of stifle osteoarthritis in dogs treated with TPLO may be partly the result of abnormal stifle contact mechanics induced by altering the orientation of the proximal tibial articulating surface.

Initiating change locally in bullying and aggression through the school environment (INCLUSIVE): study protocol for a cluster randomised controlled trial.

PubMed

Bonell, Chris; Allen, Elizabeth; Christie, Deborah; Elbourne, Diana; Fletcher, Adam; Grieve, Richard; LeGood, Rosa; Mathiot, Anne; Scott, Stephen; Wiggins, Meg; Viner, Russell M

2014-09-30

Systematic reviews suggest that interventions that address school organisation are effective in reducing victimisation and bullying. We successfully piloted a school environment intervention modified from international studies to incorporate 'restorative justice' approaches. This trial aims to establish the effectiveness and cost-effectiveness of the INCLUSIVE intervention in reducing aggression and bullying in English secondary schools. cluster randomised trial. 40 state-supported secondary schools. OUTCOMES assessed among the cohort of students in year 8 (n = approximately 6,000) in intervention year 1. INCLUSIVE is a school-led intervention which combines changes to the school environment with the promotion of social and emotional skills and restorative practices through: the formation of a school action group involving students and staff supported by an external facilitator to review local data on needs, determine priorities, and develop and implement an action plan for revising relevant school policies/rules and other actions to improve relationships at school and reduce aggression; staff training in restorative practices; and a new social and emotional skills curriculum. The intervention will be delivered by schools supported in the first two years by educational facilitators independent of the research team, with a third locally facilitated intervention year.Comparator: normal practice. primary: 2 primary outcomes at student level assessed at baseline and at 36 months:1. Aggressive behaviours in school: Edinburgh Study of Youth Transitions and Crime school misbehaviour subscale (ESYTC)2. Bullying and victimisation: Gatehouse Bullying Scale (GBS)Secondary outcomes assessed at baseline, 24 and 36 months will include measures relating to the economic evaluation, psychosocial outcomes in students and staff and school-level truancy and exclusion rates. 20 schools per arm will provide 90% power to identify an effect size of 0.25 SD with a 5% significance level.Randomisation: eligible consenting schools will be randomised stratified for single sex versus mixed sex schools, school-level deprivation and measures of school attainment. The trial will be run by independent research and intervention teams and supervised by a Trial Steering Committee and a Data Monitoring Committee (DMC). Current Controlled Trials ISRCTN10751359 (Registered 11 March 2014).

Urinary levels of nickel and chromium associated with dental restoration by nickel–chromium based alloys

PubMed Central

Chen, Bo; Xia, Gang; Cao, Xin-Ming; Wang, Jue; Xu, Bi-Yao; Huang, Pu; Chen, Yue; Jiang, Qing-Wu

2013-01-01

This paper aims to investigate if the dental restoration of nickel–chromium based alloy (Ni–Cr) leads to the enhanced excretions of Ni and Cr in urine. Seven hundred and ninety-five patients in a dental hospital had single or multiple Ni–Cr alloy restoration recently and 198 controls were recruited to collect information on dental restoration by questionnaire and clinical examination. Urinary concentrations of Ni and Cr from each subject were measure by graphite furnace atomic absorption spectrometry. Compared to the control group, the urinary level of Ni was significantly higher in the patient group of <1 month of the restoration duration, among which higher Ni excretions were found in those with either a higher number of teeth replaced by dental alloys or a higher index of metal crown not covered with the porcelain. Urinary levels of Cr were significantly higher in the three patient groups of <1, 1 to <3 and 3 to <6 months, especially in those with a higher metal crown exposure index. Linear curve estimations showed better relationships between urinary Ni and Cr in patients within 6-month groups. Our data suggested significant increased excretions of urinary Ni and Cr after dental restoration. Potential short- and long-term effects of Ni–Cr alloy restoration need to be investigated. PMID:23579466

Physiological and biochemical effects of 17β estradiol in aging female rat brain.

PubMed

Kumar, Pardeep; Taha, Asia; Kale, R K; Cowsik, S M; Baquer, Najma Zaheer

2011-07-01

Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's disease. These changes increase during menopausal condition in females when the level of estradiol is decreased. The objective of this study was to observe the changes in activities of monoamine oxidase, glucose transporter-4 levels, membrane fluidity, lipid peroxidation levels and lipofuscin accumulation occurring in brains of female rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of estradiol (0.1 μg/g body weight for 1 month). The results obtained in the present work revealed that normal aging was associated with significant increases in the activity of monoamine oxidase, lipid peroxidation levels and lipofuscin accumulation in the brains of aging female rats, and a decrease in glucose transporter-4 level and membrane fluidity. Our data showed that estradiol treatment significantly decreased monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in brain regions of aging rats, and a reversal of glucose transporter-4 levels and membrane fluidity was achieved, therefore it can be concluded from the present findings that estradiol's beneficial effects seemed to arise from its antilipofuscin, antioxidant and antilipidperoxidative effects, implying an overall anti-aging action. The results of this study will be useful for pharmacological modification of the aging process and applying new strategies for control of age related disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells.

PubMed

Sorokina, Tamara; Shipounova, Irina; Bigildeev, Alexey; Petinati, Nataliya; Drize, Nina; Turkina, Anna; Chelysheva, Ekaterina; Shukhov, Oleg; Kuzmina, Larisa; Parovichnikova, Elena; Savchenko, Valery

2016-09-01

The development of leukemia impairs normal hematopoiesis and marrow stromal microenvironment. The aim of the investigation was to study the ability of multipotent mesenchymal stromal cells (MSCs) derived from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. MSCs were obtained from the bone marrow of 14 patients with acute lymphoblastic (ALL), 25 with myeloid (AML), and 15 with chronic myeloid (CML) leukemia. As a control, MSCs from 22 healthy donors were used. The incidence of cobblestone area forming cells (CAFC 7-8 d) in the bone marrow of healthy donor cultivated on the supportive layer of patients MSCs was measured. The ability of MSCs from AML and ALL patients at the moment of diagnosis to maintain normal CAFC was significantly decreased when compared to donors. After chemotherapy, the restoration of ALL patients' MSCs functions was slower than that of AML. CML MSCs maintained CAFC better than donors' at the moment of diagnosis and this ability increased with treatment. The ability of patients' MSCs to maintain normal hematopoietic progenitor cells was shown to change in comparison with MSCs from healthy donors and depended on nosology. During treatment, the functional capacity of patients' MSCs had been partially restored. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of petroleum on adrenocortical activity and on hepatic naphthalene-metabolizing activity in mallard ducks

USGS Publications Warehouse

Gorsline, J.; Holmes, W.N.

1981-01-01

Unstressed mallard ducks (Anas platyrhychos), given uncontaminated food and maintained on a short photoperiod, show two daily maxima in plasma corticosterone concentration ([B]); one occurring early in the light phase and a second just before the onset of darkness. After one week of exposure to food containing 3% (v/w) South Louisiana crude oil, plasma [B] were significantly lowered throughout the day. Similar abrupt declines in plasma [B] also occurred during the first 10 days of exposure to food containing 1% and 0.5% crude oil. Although the plasma [B] in birds consuming food contaminated with 0.5% crude oil increased between 10 and 50 days of exposure, the concentration after 50 days was still lower than normal. During the same interval, normal plasma [B] were restored in birds consuming food containing 1% and 3% crude oil. Significant increases occurred in the naphthalene-metabolizing properties of hepatic microsomes prepared from birds acutely exposed to all levels of petroleum-contaminated food and elevated levels were sustained throughout the first 50 days of exposure. Birds given food containing 3% crude oil for more than 50 days, however, showed steady declines in hepatic naphthalene-metabolizing activity. After 500 days, the activity was similar to that found in contemporaneous controls. During the same interval, the plasma [B] increased until the levels were higher than normal after 500 days of exposure; at this time, an inverse relationship, similar to that seen during the first week of exposure to contaminated food, was once more established between plasma [B] and the concomitant hepatic naphthalene-metabolizing activity.

Vitamin E mitigates cisplatin-induced nephrotoxicity due to reversal of oxidative/nitrosative stress, suppression of inflammation and reduction of total renal platinum accumulation.

PubMed

Darwish, Mostafa A; Abo-Youssef, Amira M; Khalaf, Marwa M; Abo-Saif, Ali A; Saleh, Ibrahim G; Abdelghany, Tamer M

2017-01-01

Cisplatin (CP) is one of the most effective chemotherapeutic agents. Unfortunately, CP-induced nephrotoxicity hampered its use. This study aims to investigate the effect of vitamin E (Vit E) on CP-induced nephrotoxicity. Male white albino rats were divided to four group's six rats each and received either, 1% tween 80 in normal saline or Vit E (75 mg/kg) per day for 14 consecutive days or a single injection of CP (6 mg/kg) alone or CP (6 mg/kg) together with Vit E (75 mg/kg per day for 14 consecutive days). Five days after the CP injection, rats were euthanized; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly increased serum levels of creatinine and urea. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CP treatment. Vit E successfully lowered serum levels of urea and creatinine, enhanced creatinine clearance and diuresis, and normalized relative kidney/body weight. Furthermore, Vit E successfully normalized renal MDA and nitrite concentrations, elevated GSH level, and restored CAT and SOD activities in renal tissues. Histopathological examination of rat kidney revealed that Vit E significantly mitigated CP-induced renal damage. Importantly, administration of Vit E reduced kidney total platinum concentration indicating a role of platinum renal accumulation on the ability of Vit E to protect against CP nephrotoxicity. © 2016 Wiley Periodicals, Inc.

Lung autophagic response following exposure of mice to whole body irradiation, with and without amifostine

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

Zois, Christos E.; Giatromanolaki, Alexandra; Kainulainen, Heikki

2011-01-07

Research highlights: {yields} We investigated the effect 6 Gy of WBI on the autophagic machinery of normal mouse lung. {yields} Irradiation induces dysfunction of the autophagic machinery in normal lung, characterized by decreased transcription of the LC3A/Beclin-1 mRNA and accumulation of the LC3A, and p62 proteins. {yields} The membrane bound LC3A-II protein levels increased in the cytosolic fraction (not in the pellet), contrasting the patterns noted after starvation-induced autophagy. {yields} Administration of amifostine, reversed all the LC3A and p62 findings, suggesting protection of the normal autophagic function. -- Abstract: Purpose: The effect of ionizing irradiation on the autophagic response ofmore » normal tissues is largely unexplored. Abnormal autophagic function may interfere the protein quality control leading to cell degeneration and dysfunction. This study investigates its effect on the autophagic machinery of normal mouse lung. Methods and materials: Mice were exposed to 6 Gy of whole body {gamma}-radiation and sacrificed at various time points. The expression of MAP1LC3A/LC3A/Atg8, beclin-1, p62/sequestosome-1 and of the Bnip3 proteins was analyzed. Results: Following irradiation, the LC3A-I and LC3A-II protein levels increased significantly at 72 h and 7 days. Strikingly, LC3A-II protein was increased (5.6-fold at 7 days; p < 0.001) only in the cytosolic fraction, but remained unchanged in the membrane fraction. The p62 protein, was significantly increased in both supernatant and pellet fraction (p < 0.001), suggesting an autophagosome turnover deregulation. These findings contrast the patterns of starvation-induced autophagy up-regulation. Beclin-1 levels remained unchanged. The Bnip3 protein was significantly increased at 8 h, but it sharply decreased at 72 h (p < 0.05). Administration of amifostine (200 mg/kg), 30 min before irradiation, reversed all the LC3A and p62 findings on blots, suggesting restoration of the normal autophagic function. The LC3A and Beclin1 mRNA levels significantly declined following irradiation (p < 0.01), whereas Bnip3 levels increased. Conclusions: It is suggested that irradiation induces dysfunction of the autophagic machinery in normal lung, characterized by decreased transcription of the LC3A/Beclin-1 mRNA and accumulation of the LC3A, and p62 proteins. Whether this is due to defective maturation or to aberrant degradation of the autophagosomes requires further investigation.« less

Lower extremity thrust and non-thrust joint mobilization for patellofemoral pain syndrome: a case report.

PubMed

Simpson, Brad G; Simon, Corey B

2014-05-01

A 40-year old female presented to physical therapy with a one-year history of insidious right anteromedial and anterolateral knee pain. Additionally, the patient had a history of multiple lateral ankle sprains bilaterally, the last sprain occurring on the right ankle 1 year prior to the onset of knee pain. The patient was evaluated and given a physical therapy diagnosis of patellofemoral pain syndrome (PFPS), with associated talocrural and tibiofemoral joint hypomobility limiting ankle dorsiflexion and knee extension, respectively. Treatment included a high-velocity low amplitude thrust manipulation to the talocrural joint, which helped restore normal ankle dorsiflexion range of motion. The patient also received tibiofemoral joint non-thrust manual therapy to regain normal knee extension mobility prior to implementing further functional progression exercises to her home program (HEP). This case report highlights the importance of a detailed evaluation of knee and ankle joint mobility in patients presenting with anterior knee pain. Further, manual physical therapy to the lower extremity was found to be successful in restoring normal movement patterns and pain-free function in a patient with chronic anterior knee pain.

The usage of image trigonometry in bone measurements.

PubMed

Dymond, Ian W; Ashforth, James A; Dymond, Graeme F; Spirakis, Thanos; Learmonth, Ian D

2013-01-01

The entire musculo-skeletal system responds dynamically to stresses and strains applied to it. Restoring normal biomechanics contributes to the normal function that ensures that physiological stresses and strains are preserved. Appropriate preoperative planning is mandatory to restore normal biomechanics at reconstructive surgery. Effective preoperative planning depends on the ability to reproducibly make accurate measurements of lengths and angles from plain radiographs. Measurement has become an integral part of orthopaedics to define morphological abnormality, to plan for reconstruction and for comparative research. The most prevalent method of measurement is usually based on lines drawn on radiographs with no accurate reference to the actual geometry of the structures. This two-dimensional projection of an asymmetrical three-dimensional structure leads to inaccuracy and consequently to a compromise in the overall precision of many procedures. In addition it is also difficult to monitor the progression of disease as the exact relationship of the bones and joints to each other, and to prosthetics, cannot be accurately recorded. This paper presents a method of digitally measuring relevant bone parameters in a geometric manner in order to achieve accurate, repeatable measurements.

Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol.

PubMed

Rahman, Khalidur; Desai, Chirayu; Iyer, Smita S; Thorn, Natalie E; Kumar, Pradeep; Liu, Yunshan; Smith, Tekla; Neish, Andrew S; Li, Hongliang; Tan, Shiyun; Wu, Pengbo; Liu, Xiaoxiong; Yu, Yuanjie; Farris, Alton B; Nusrat, Asma; Parkos, Charles A; Anania, Frank A

2016-10-01

There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH. Male C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy. F11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation. Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Knockdown of prothrombin in zebrafish.

PubMed

Day, Kenneth; Krishnegowda, Naveen; Jagadeeswaran, Pudur

2004-01-01

Thrombin is a serine protease generated from its zymogen, prothrombin, and plays a central role in the coagulation cascade. It is also important for mammalian development. The zebrafish has now been established as an excellent genetic model for studies on mammalian hemostasis and development. In this report, we used prothrombin-specific antisense morpholinos to knock down the levels of prothrombin to characterize the effects of prothrombin deficiency in the zebrafish embryo. Prothrombin morpholino-injected zebrafish embryos yielded an early phenotype exhibiting severe abnormalities that later showed occasional bleeding. In a second late phenotype, the embryos had no observable morphological abnormalities in early stages, but showed occasional bleeding at later stages. These phenotypes resembled characteristics shown by prothrombin knockout mice. Laser-induced vascular injury on some of the normal appearing phenotypic larvae showed a prolonged time to occlusion, and recombinant zebrafish prothrombin injected into these larvae restored a normal time to occlusion thus showing the specificity of the morpholino effect. The system developed here should be useful for investigation of the role of thrombin in vertebrate development.

Antidiabetic Evaluation of Momordica charantia L Fruit Extracts

PubMed Central

Tahira, S; Hussain, F

2014-01-01

To investigate hypoglycaemic, hypolipidaemic and pancreatic beta cell regeneration activities of Momordica charantia L fruits (MC). Alloxan-induced diabetic rabbits were treated with methanolic and ethanolic MC extract. Effects of plant extracts and the drug glibenclamide on serum glucose, lipid profile and pancreatic beta cell were determined after two weeks of treatment. Serum glucose and lipid profiles were assayed by kit methods. Pancreatic tissue histopathology was performed to study pancreatic beta cell regeneration. Momordica charantia extracts produced significant hypoglycaemic effects (p < 0.05). Hypolipidaemic activity of MC was negligible. Momordica charantia supplementations were unable to normalize glucose and lipid profiles. Glibenclamide, a standard drug, not only lowered hyperglycaemia and hyperlipidaemia but also restored the normal levels. Regeneration of pancreatic beta cells by MC extracts was minimal, with fractional improvement produced by glibenclamide. The most significant finding of the present study was a 28% reduction in hyperglycaemia by MC ethanol extracts. To determine reliable antidiabetic potentials of MC, identification of the relevant antidiabetic components and underlying mechanisms is warranted. PMID:25429471

[The ultrastructure and activities of free radical scavenger in discolored gingiva adjacent to porcelain fused to metal crowns].

PubMed

Zhang, Zhong-ti; Yan, Lu; Zhong, Ming; Yang, Xiao-dong; Ai, Hong-jun

2007-04-01

This study was designed to study the discolored gingiva adjacent to porcelain fused to metal (PFM) crowns in terms of ultrastructure , SOD and GSH activities in 40 cases. The discolored gingival ultrastructures were observed and metal X-ray energy level was analyzed;The activities of SOD and GSH were measured and compared with normal control by student's t test and one-way ANOVA with SPSS10.0 software package. The discolored gingival ultrastructure had changes compared with the normal gingiva. Nickel and chromium were not found in the particles through X-ray energy machine within the discolored gingiva adjacent to PFM crown. The activities of SOD and GSH in discolored gingiva were significantly different from control(P<0.05) and the values at 6 to 18 months were significantly different from those at other times. The ultrastructure underwent changes in discolored gingiva after PFM restoration; the activity of SOD and GSH in discolored gingiva changed to result in apoptosis, and discoloration.

Neither Hematocrit Normalization nor Exercise Training Restores Oxygen Consumption to Normal Levels in Hemodialysis Patients

PubMed Central

Stray-Gundersen, James; Parsons, Dora Beth; Thompson, Jeffrey R.

2016-01-01

Patients treated with hemodialysis develop severely reduced functional capacity, which can be partially ameliorated by correcting anemia and through exercise training. In this study, we determined perturbations of an erythroid-stimulating agent and exercise training to examine if and where limitation to oxygen transport exists in patients on hemodialysis. Twenty-seven patients on hemodialysis completed a crossover study consisting of two exercise training phases at two hematocrit (Hct) values: 30% (anemic) and 42% (physiologic; normalized by treatment with erythroid-stimulating agent). To determine primary outcome measures of peak power and oxygen consumption (VO2) and secondary measures related to components of oxygen transport and utilization, all patients underwent numerous tests at five time points: baseline, untrained at Hct of 30%, after training at Hct of 30%, untrained at Hct of 42%, and after training at Hct of 42%. Hct normalization, exercise training, or the combination thereof significantly improved peak power and VO2 relative to values in the untrained anemic phase. Hct normalization increased peak arterial oxygen and arteriovenous oxygen difference, whereas exercise training improved cardiac output, citrate synthase activity, and peak tissue diffusing capacity. However, although the increase in arterial oxygen observed in the combination phase reached a value similar to that in healthy sedentary controls, the increase in peak arteriovenous oxygen difference did not. Muscle biopsy specimens showed markedly thickened endothelium and electron–dense interstitial deposits. In conclusion, exercise and Hct normalization had positive effects but failed to normalize exercise capacity in patients on hemodialysis. This effect may be caused by abnormalities identified within skeletal muscle. PMID:27153927

Effect of apolipoprotein A-I deficiency on lecithin:cholesterol acyltransferase activation in mouse plasma.

PubMed

Parks, J S; Li, H; Gebre, A K; Smith, T L; Maeda, N

1995-02-01

Plasma cholesteryl ester (CE) synthesis by lecithin cholesterol acyltransferase (LCAT) is activated by apolipoprotein (apo)A-I. We studied the effect of plasma apoA-I concentration on LCAT activation, using normal, heterozygous or homozygous apoA-I-deficient mice made by gene targeting. Plasma esterified cholesterol concentrations of mice fed chow diets were ordered (mean +/- SEM): 105 +/- 7 (normal) > 70 +/- 5 (heterozygotes) > 26 +/- 2 (homozygotes) mg/dl. Plasma free cholesterol concentrations were similar among the three genotypes. Endogenous LCAT activity, measured as the decrease in plasma free cholesterol after a 1 h incubation at 37 degrees C, was ordered: 44 +/- 3 (normal) > 21 +/- 2 (heterozygotes) > 5 +/- 1 (homozygotes) nmol CE formed/h per ml plasma. Using a recombinant exogenous substrate consisting of egg yolk phospholipid, [14C]cholesterol, and apoA-I, CE formation of normals and heterozygotes was similar (27.4 +/- 0.6 and 28.8 +/- 1.3 nmol/h per ml plasma, respectively), but was significantly less for homozygotes (19.2 +/- 1.7 nmol/h per ml plasma). However, using a small unilamellar vesicle substrate particle containing phospholipid and [14C]cholesterol, CE formation was ordered: 1.6 +/- 0.1 (normal) = 1.6 +/- 0.1 (heterozygotes) > 0.6 +/- 0.1 (homozygotes) nmol/h per ml plasma; addition of apoA-I to the plasma of homozygous animals restored CE formation to normal levels (1.6 +/- 0.1). CE fatty acid analysis demonstrated that plasma from homozygous mice contained significantly more saturated and monounsaturated and fewer polyunsaturated fatty acids compared to normal and heterozygous mice.(ABSTRACT TRUNCATED AT 250 WORDS)

School league tables: a new population based predictor of dental restorative treatment need.

PubMed

Crowley, Evelyn; O'Brien, Graham; Marcenes, Wagner

2003-06-01

To test whether dental restorative treatment need was related to the school league tables and level of social deprivation of the school ward. An ecological study using clinical data aggregated at school level, collected in the school dental screening examinations (1996-97), National Census (1991) and the results of the UK school league tables--Key Stage 2 SATs (1996-97). State primary schools in the Greenwich District of SE London, UK (1996-97). 12,854 pupils (6-11 years of age) in 62 schools. The percentage of 6 to 11 year old pupils per school requiring dental restorative treatment. Deprivation as measured by the overall Jarman Under Privileged Area Index (UPA) of the school ward was not associated with dental restorative treatment need (p > 0.05). Only two components of the Jarman Index, level of unemployment and the number of lone parent families in the school ward were found to be significantly associated with dental restorative treatment need (p < 0.05). Results of stepwise multiple linear regression analysis showed that the association with the school league table results in all three subjects, English, Mathematics and Science remained statistically significant after adjusting for levels of unemployment and single parents. Results of multiple linear regression analysis showed that a high level of dental restorative treatment need was significantly associated with poor school league table results in English, Mathematics and Science (p < 0.05) after adjusting for the overall Jarman score of the school ward. A separate analysis for the 11-year-old pupils aggregated by school (n = 46 schools) gave similar results. Aggregate measures of academic achievement may be a potential indicator of dental restorative treatment need.

[The effect of N-stearoylethanolamine on liver phospholipid composition of rats with insulin resistance caused by alimentary obesity].

PubMed

Onopchenko, O V; Kosiakova, H V; Horid'ko, T M; Klimashevskyĭ, V M; Hula, N M

2014-01-01

We used alimentary obesity-induced insulin resistance (IR) model in rats to investigate the influence of N-stearoylethanolamine on the content of phospholipids and their fatty acid composition. Our results show that prolonged high-fat diet triggers considerable aberrations in the composition of main phospholipids in the liver and can be one of the causes of IR in rats. In particular, the increase of phosphatidylcholine, phosphatidylethanolamine and significant decrease of other phospholipids: lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, phosphatidylinositol, phosphatidylserine and diphosphaglicerol were observed. The levels of monounsaturated (erucic, nervonic, oleic) and polyunsaturated (eicosatrienoic, docosatrienoic, arachidonic) fatty acids were increased; meanwhile the content of diunsaturated acids was decreased. The NSE administration (50 mg/kg of body weight) caused restoration of the phospholipids content in the liver of rats with diet-induced IR that highly correlated with the decrease in plasma insulin level and the improvement of insulin sensitivity. Moreover, the effect of NSE was accompanied by the normalization of fatty acids composition of phospholipids that could be related to modulating influence of NSE on the activity of the main fatty acid desaturases. It is known that the imbalance in phospholipid composition of the rat liver causes substantial metabolic alterations that are associated with the development of IR. Accordingly, the compensations of the imbalance by NSE can help to restore insulin sensitivity, inhibit the development of obesity, IR and type 2 diabetes.

Virgin coconut oil reverses hepatic steatosis by restoring redox homeostasis and lipid metabolism in male Wistar rats.

PubMed

Narayanankutty, Arunaksharan; Palliyil, Devika Mukundan; Kuruvilla, Kezia; Raghavamenon, Achuthan C

2018-03-01

Hepatosteatosis, a form of nonalcoholic fatty liver disease (NAFLD), is being increasingly recognized as a major health burden worldwide. Insulin resistance, dyslipidemia and imbalances in adipokine/cytokine interplay are reported to be involved in the onset and progression of this disease. Use of dietary nutraceuticals in prevention and treatment of NAFLD is emerging. Virgin coconut oil (VCO), a fermented product of fresh coconut kernel, has been shown to impede the development of hepatosteatosis in rats. This study analyzes the potential of VCO to reverse the already developed hepatosteatosis condition. Hyperglycemia, reduced glucose tolerance, dyslipidemia, and hepatic macrovesicles in high-fructose-diet-fed rats (4 weeks) confirmed the development of hepatosteatosis. Natural reversion in these parameters was observed upon shifting to normal diet in untreated control animals. Administration of VCO, however, increased this natural reversion by improving high-density lipoprotein cholesterol level (53.5%) and reducing hepatic and serum triacylglycerols (78.0 and 51.7%). Increased hepatic glutathione level (P < 0.01), antioxidant enzyme activities (P < 0.05) and reduced lipid peroxidation were also noticed in these animals. These observations were in concordance with reduced liver enzyme activities (P < 0.01) and restoration of altered hepatic architecture. The study indicates that VCO can be used as a nutraceutical against hepatosteatosis. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Cadmium induced pathophysiology: prophylactic role of edible jute (Corchorus olitorius) leaves with special emphasis on oxidative stress and mitochondrial involvement.

PubMed

Dewanjee, Saikat; Gangopadhyay, Moumita; Sahu, Ranabir; Karmakar, Sarmila

2013-10-01

The present study was undertaken to evaluate the protective effect of aqueous extract of Corchorus olitorius leaves (AECO) against CdCl₂ intoxication. In vitro bioassay on isolated mice hepatocytes confirmed dose dependent cytoprotective effect of AECO. The CdCl₂ (30 μM) exhibited a significantly increased levels of lipid peroxidation, protein carbonylation along with the reduction of antioxidant enzymes and reduced glutathione levels in hepatocytes. AECO (200 and 400 μg/ml) + CdCl₂ (30 μM) could significantly restore the aforementioned oxidation parameters in hepatocytes. Beside this, AECO could significantly reduce Cd-induced increase in Bad/Bcl-2 ratio and the over-expression of NF-κB, caspase 3 and caspase 9. In in vivo assay, CdCl₂ (4 mg/kg body weight, for 6 days) treated rats exhibited a significantly increased intracellular Cd accumulation, oxidative stress and DNA fragmentation in the organs. In addition, the haematological parameters were significantly altered in the CdCl₂ treated rats. Simultaneous administration of AECO (50 and 100 mg/kg body weight), could significantly restore the biochemical, antioxidant and haematological parameters near to the normal status. Histological studies of the organs supported the protective role of jute leaves. Presence of substantial quantity of phenolic compounds and flavonoids in extract may be responsible for overall protective effect. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Pathomechanism and therapeutic strategy of Fukuyama congenital muscular dystrophy and related disorders].

PubMed

Toda, Tatsushi

2009-11-01

Hypoglycosylation and reduced laminin-binding activity of alpha-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. We previously identified the genes for Fukuyama congenital muscular dystrophy (FCMD) and muscle-eye-brain disease (MEB). FCMD, caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. Knock-in mice carrying the founder retrotransposal insertion exhibited hypoglycosylated alpha-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact alpha-dystroglycan, and solid-phase assays determined laminin binding levels to be approximately 50% of normal. In contrast, intact alpha-dystroglycan is undetectable in the dystrophic Large mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact alpha-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. Transfer of fukutin into knock-in mice restored glycosylation of alpha-dystroglycan. Transfer of LARGE produced laminin-binding forms of alpha-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse. These data suggest that even partial restoration of alpha-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.

Modeling joint restoration strategies for interdependent infrastructure systems.

PubMed

Zhang, Chao; Kong, Jingjing; Simonovic, Slobodan P

2018-01-01

Life in the modern world depends on multiple critical services provided by infrastructure systems which are interdependent at multiple levels. To effectively respond to infrastructure failures, this paper proposes a model for developing optimal joint restoration strategy for interdependent infrastructure systems following a disruptive event. First, models for (i) describing structure of interdependent infrastructure system and (ii) their interaction process, are presented. Both models are considering the failure types, infrastructure operating rules and interdependencies among systems. Second, an optimization model for determining an optimal joint restoration strategy at infrastructure component level by minimizing the economic loss from the infrastructure failures, is proposed. The utility of the model is illustrated using a case study of electric-water systems. Results show that a small number of failed infrastructure components can trigger high level failures in interdependent systems; the optimal joint restoration strategy varies with failure occurrence time. The proposed models can help decision makers to understand the mechanisms of infrastructure interactions and search for optimal joint restoration strategy, which can significantly enhance safety of infrastructure systems.

Characterizing fish responses to a river restoration over 21 years based on species' traits.

PubMed

Höckendorff, Stefanie; Tonkin, Jonathan D; Haase, Peter; Bunzel-Drüke, Margret; Zimball, Olaf; Scharf, Matthias; Stoll, Stefan

2017-10-01

Understanding restoration effectiveness is often impaired by a lack of high-quality, long-term monitoring data and, to date, few researchers have used species' trait information to gain insight into the processes that drive the reaction of fish communities to restoration. We examined fish-community responses with a highly resolved data set from 21 consecutive years of electrofishing (4 years prerestoration and 17 years postrestoration) at multiple restored and unrestored reaches from a river restoration project on the Lippe River, Germany. Fish abundance peaked in the third year after the restoration; abundance was 6 times higher than before the restoration. After 5-7 years, species richness and abundance stabilized at 2 and 3.5 times higher levels relative to the prerestoration level, respectively. However, interannual variability of species richness and abundance remained considerable, illustrating the challenge of reliably assessing restoration outcomes based on data from individual samplings, especially in the first years following restoration. Life-history and reproduction-related traits best explained differences in species' responses to restoration. Opportunistic short-lived species with early female maturity and multiple spawning runs per year exhibited the strongest increase in abundance, which reflected their ability to rapidly colonize new habitats. These often small-bodied and fusiform fishes typically live in dynamic and ephemeral instream and floodplain areas that river-habitat restorations often aim to create, and in this case their increases in abundance indicated successful restoration. Our results suggest that a greater consideration of species' traits may enhance the causal understanding of community processes and the coupling of restoration to functional ecology. Trait-based assessments of restoration outcomes would furthermore allow for easier transfer of knowledge across biogeographic borders than studies based on taxonomy. © 2017 Society for Conservation Biology.

Therapeutic effect of low molecular weight chitosan containing sepia ink on ethanol-induced gastric ulcer in rats.

PubMed

Zhang, Wei; Liu, Kang; Li, Lei; Li, Yingxin; Sui, Xianxian; Rao, Yinzhu; Wu, Jiahao; Wu, Qiuping

2016-12-01

To evaluate the role of low molecular chitosan containing sepia ink (LMCS) in ethanol-induced (5 ml/kg) gastric ulcer in rats. Animals were divided into four groups (n = 12): normal group (Normal), negative control group (Con), experiment group (LMCS) and positive control Omeprazole group (OMZ). Gastric empty rate was detected in the first 7 days. Rats were sacrificed at 7, 14 and 21 day for histology and ELISA detections. Gastric empty was no significant differences among the groups (P > 0.05). Histological observation showed gastric mucosal LMCS treated had better healing effect. Hydroxyproline (Hyp) was significantly increased from 7 day (P < 0.05). LMCS significantly inhibited malondialdehyde (MDA) generation for lipid peroxidation from 7 day (P < 0.05). LMCS significantly promoted the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) at the earlier stage (P < 0.05). OMZ had the similar effects above. As for myeloperoxidase (MPO), LMCS significantly decreased and restored it to normal levels from 7 day (P < 0.05), it is earlier than OMZ which is from 14 day. LMCS can improve gastric mucosa tissue repair, exert significant influences on oxidative and antioxidant enzyme activities and neutrophil infiltration.

Determining factors for implant referral rates.

PubMed

Levin, Roger P

2002-01-01

The research findings indicate that the field of implant dentistry will only grow at a moderately low level unless certain changes are made. Findings indicated that the effort by the implant companies has been nothing short of dramatic, and yet almost 60% of restorative doctors do not participate annually in any implant case. There was no clear indication that younger restorative doctors will significantly increase the number of implant referrals, as their overall implant education has not dramatically differed from those dentists who graduated in earlier years. Once the research was completed, it became obvious to Levin Group that the driving force behind implant referral growth will be implant surgeons, because of their one-to-one relationship with restorative doctors. The Levin Group Implant Management and Marketing Consulting Program is based on approaching restorative doctors in several different levels, starting with awareness all the way through to case facilitation and long-term tracking and communication. Finally, a continuing marketing/education effort needs to be consistently in place with effective materials, not only to create a high level of awareness, but also to motivate restorative doctors to refer cases and then work through the case with the implant surgeon to a satisfactory completion for the restorative doctor, implant surgeon, and patient. While the surgical insertion of implants may seem to carry a high-profit margin relative to the restoration of implants, the truth is that the restoration of implants usually provides a 40% higher profit margin for the restorative doctor than traditional dental services. One of the key issues is that referring doctors have not necessarily learned how to set fees and present cases with regard to implant dentistry. The key factor here is to ensure that the patient understands that implant services involve higher fees than traditional services, because of the necessarily higher levels of experience, education, and cost associated with implant dentistry. It is also important to emphasize to patients that the quality of life far outweighs the differential in fees.

MASH TL-4 crash testing and evaluation of the RESTORE barrier.

DOT National Transportation Integrated Search

2015-11-01

Three full-scale vehicle crash tests were conducted according to the MASH Test Level 4 (TL-4) safety performance criteria on a : restorable and reusable energy-absorbing roadside/median barrier, designated the RESTORE barrier. The system utilized for...

Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo.

PubMed

Gundala, Naveen K V; Naidu, Vegi G M; Das, Undurti N

2017-03-01

We studied whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5F) cells against alloxan-induced apoptosis in vitro and type 1 diabetes mellitus (type 1 DM) in vivo and if so, mechanism of this beneficial action. In vitro study was conducted using RIN5F cells while in vivo study was performed in Wistar rats. The effect of PUFAs, cyclo-oxygenase and lipoxygenase inhibitors, various eicosanoids and PUFAs metabolites: lipoxin A4 (LXA4), resolvin D2 and protectin against alloxan-induced cytotoxicity to RIN5F cells and type 1 DM was studied. Expression of PDX1, P65 NF-kB and IKB in RIN5F cells and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue and plasma glucose, insulin and tumor necrosis factor-α and antioxidants, lipid peroxides and nitric oxide were measured. Of all, arachidonic acid (AA) was found to be the most effective against alloxan-induced cytotoxicity to RIN5F cells and preventing type 1 DM. Both cyclo-oxygenase and lipoxygenase inhibitors did not block the beneficial actions of AA in vitro and in vivo. Alloxan inhibited LXA4 production by RIN5F cells and in alloxan-induced type 1 DM Wistar rats. AA-treatment restored LXA4 levels to normal both in vitro and in vivo. LXA4 protected RIN5F cells against alloxan-induced cytotoxicity and prevented type 1 DM and restored expression of Nrf2, Glut2, COX2, and iNOS genes and abnormal antioxidants to near normal. AA seems to bring about its beneficial actions against alloxan-induced cytotoxicity and type 1 DM by enhancing the production of LXA4. © 2016 BioFactors, 43(2):251-271, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

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

Ramos-Solano, Moisés, E-mail: mrsolano84@gmail.com; Programa de Doctorado en Ciencias Biomédica, Centro Universitario de Ciencias de la Salud; Meza-Canales, Ivan D., E-mail: imezacanales@ice.mpg.de

According to the multifactorial model of cervical cancer (CC) causation, it is now recognized that other modifications, in addition to Human papillomavirus (HPV) infection, are necessary for the development of this neoplasia. Among these, it has been proposed that a dysregulation of the WNT pathway might favor malignant progression of HPV-immortalized keratinocytes. The aim of this study was to identify components of the WNT pathway differentially expressed in CC vs. non-tumorigenic, but immortalized human keratinocytes. Interestingly, WNT7A expression was found strongly downregulated in cell lines and biopsies derived from CC. Restoration of WNT7A in CC-derived cell lines using a lentiviralmore » gene delivery system or after adding a recombinant human protein decreases cell proliferation. Likewise, WNT7A silencing in non-tumorigenic cells markedly accelerates proliferation. Decreased WNT7A expression was due to hypermethylation at particular CpG sites. To our knowledge, this is the first study reporting reduced WNT7A levels in CC-derived cells and that ectopic WNT7A restoration negatively affects cell proliferation and migration. - Highlights: • WNT7A is expressed in normal keratinocytes or cervical cells without lesion. • WNT7A is significantly reduced in cervical cancer-derived cells. • Restoration of WNT7A expression in HeLa decreases proliferation and cell migration. • Silencing of WNT7A in HaCaT induces an increased proliferation and migration rate. • Decreased WNT7A expression in this model is due to hypermethylation.« less

Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease.

PubMed

Lin, Ai-Ling; Jahrling, Jordan B; Zhang, Wei; DeRosa, Nicholas; Bakshi, Vikas; Romero, Peter; Galvan, Veronica; Richardson, Arlan

2017-01-01

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects. © The Author(s) 2015.

Chemically Induced Conditional Rescue of the Reduced Epidermal Fluorescence8 Mutant of Arabidopsis Reveals Rapid Restoration of Growth and Selective Turnover of Secondary Metabolite Pools1[C][OPEN

PubMed Central

Kim, Jeong Im; Ciesielski, Peter N.; Donohoe, Bryon S.; Chapple, Clint; Li, Xu

2014-01-01

The phenylpropanoid pathway is responsible for the biosynthesis of diverse and important secondary metabolites including lignin and flavonoids. The reduced epidermal fluorescence8 (ref8) mutant of Arabidopsis (Arabidopsis thaliana), which is defective in a lignin biosynthetic enzyme p-coumaroyl shikimate 3′-hydroxylase (C3′H), exhibits severe dwarfism and sterility. To better understand the impact of perturbation of phenylpropanoid metabolism on plant growth, we generated a chemically inducible C3′H expression construct and transformed it into the ref8 mutant. Application of dexamethasone to these plants greatly alleviates the dwarfism and sterility and substantially reverses the biochemical phenotypes of ref8 plants, including the reduction of lignin content and hyperaccumulation of flavonoids and p-coumarate esters. Induction of C3′H expression at different developmental stages has distinct impacts on plant growth. Although early induction effectively restored the elongation of primary inflorescence stem, application to 7-week-old plants enabled them to produce new rosette inflorescence stems. Examination of hypocotyls of these plants revealed normal vasculature in the newly formed secondary xylem, presumably restoring water transport in the mutant. The ref8 mutant accumulates higher levels of salicylic acid than the wild type, but depletion of this compound in ref8 did not relieve the mutant’s growth defects, suggesting that the hyperaccumulation of salicylic acid is unlikely to be responsible for dwarfism in this mutant. PMID:24381065

Neurological complications of lumbar artificial disc replacement and comparison of clinical results with those related to lumbar arthrodesis in the literature: results of a multicenter, prospective, randomized investigational device exemption study of Charité intervertebral disc. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004.

PubMed

Geisler, Fred H; Blumenthal, Scott L; Guyer, Richard D; McAfee, Paul C; Regan, John J; Johnson, J Patrick; Mullin, Bradford

2004-09-01

Arthrodesis is the gold standard for surgical treatment of lumbar degenerative disc disease (DDD). Solid fusion, however, can cause stress and increased motion in the segments adjacent to the fused level. This may initiate and/or accelerate the adjacent-segment disease process. Artificial discs are designed to restore and maintain normal motion of the lumbar intervertebral segment. Restoring and maintaining normal motion of the segment reduces stresses and loads on adjacent level segments. A US Food and Drug Administration Investigational Device Exemptions multicentered study of the Charité artificial disc was completed. The control group consisted of individuals who underwent anterior lumbar interbody fusion involving BAK cages and iliac crest bone graft. This is the first report of Class I data in which a lumbar artificial disc is compared with lumbar fusion. Of 304 individuals enrolled in the study, 205 were randomized to the Charité disc-treated group and 99 to the BAK fusion-treated (control) group. Neurological status was equivalent between the two groups at 6, 12, and 24 months postoperatively. The number of patients with major, minor, or other neurological complications was equivalent. There was a greater incidence of both major and minor complications in the BAK fusion group at 0 to 42 days postoperatively. Compared with data reported in the lumbar fusion literature, the Charité disc-treated patients had equivalent or better mean changes in visual analog scale and Oswestry Disability Index scores. The Charité artificial disc is safe and effective for the treatment of single-level lumbar DDD, resulting in no higher incidence of neurological complications compared with BAK-assisted fusion and leading to equivalent or better outcomes compared with those obtained in the control group and those reported in the lumbar fusion literature.

Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway.

PubMed

Dong, Ying; Gao, Guirong; Fan, Hongyan; Li, Shengxian; Li, Xuhang; Liu, Wei

2015-01-01

Activation of Liver X receptors (LXRs), key transcriptional regulators of glucose metabolism, normalizes glycemia and improves insulin sensitivity in rodent models with insulin resistance. However, the molecular mechanism is unclear. This study is aimed to elucidate the mechanism of LXRs-mediated liver glucose metabolic regulation in vitro and in vivo. Db/db mice were used as an in vivo model of diabetes; palmitate (PA)-stimulated HepG2 cells were used as an in vitro cell model with impairment of insulin signaling. TO901317 (TO) was chosen as the LXRs agonist. We demonstrated that TO treatment for 14 days potently improved the hepatic glucose metabolism in db/db mice, including fasting blood glucose, fasting insulin level, and HOMA-IR. TO had no effect on the glucose metabolism in normal WT mice. TO-mediated activation of hepatic LXRs led to strong inhibition of ROS production accompanied by inactivation of JNK pathway and re-activation of Akt pathway. TO also suppressed the expression of gluconeogenic genes such as PEPCK and G-6-pase in db/db mice, but not in WT mice. In HepG2 cells, TO almost completely restored PA-induced Akt inactivation, and suppressed PA-stimulated ROS production and JNK activation. Interestingly, basal level of ROS was also inhibited by TO in HepG2 cells. TO significantly inhibited PA-stimulated expressions of gluconeogenic genes. Finally, we found that anti-oxidative genes, such as Nrf2, were up-regulated after LXRs activation by TO. These results strongly support the notion that activation of LXRs is critical in suppression of liver gluconeogenesis and improvement of insulin sensitivity in diabetic individuals. At molecular levels, the mode of action appears to be as fellows: under diabetic condition, ROS production is increased, JNK is activated, and Akt activity is inhibited; TO-mediated LXR activation potently inhibits ROS production, increases anti-oxidative gene expressions, suppresses JNK activation, and restores Akt activity. Our data provide new evidence to support LXRs as promising therapeutic targets for anti-diabetic drug development.

Hepatoprotective potential of ethanolic extract of Ziziphus oenoplia (L.) Mill roots against antitubercular drugs induced hepatotoxicity in experimental models.

PubMed

Rao, Ch V; Rawat, A K S; Singh, Anil P; Singh, Arpita; Verma, Neeraj

2012-04-01

To evaluate the hepatoprotective potential of ethanolic (50%) extract of Ziziphus oenoplia (L.) Mill (Z. oenoplia) root against isoniazid (INH) and rifampicin (RIF) induced liver damage in animal models. Five groups of six rats each were selected for the study. Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin (100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups. The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), and bilirubin were estimated along with activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione peroxidase, and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver. The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards normal in a dose dependent manner after the treatment with ethanolic extract of Z. oenoplia roots. Meanwhile, the decreased activities of superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependently. In addition, ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethanolic extract of Z. oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Lactobacillus plantarum HY7712 ameliorates cyclophosphamide-induced immunosuppression in mice.

PubMed

Jang, Se-Eun; Joh, Eun-Ha; Lee, Ho-Yong; Ahn, Young-Tae; Lee, Jung-Hee; Huh, Chul-Sung; Han, Myung Joo; Kim, Dong-Hyun

2013-03-01

Lactic acid bacteria (LAB) in fermented foods have attracted considerable attention recently as treatment options for immune diseases, the incidence of which has been increasing worldwide. The ability of 500 strains of LAB, isolated from kimchi, to induce TNF--α production in peritoneal macrophages was investigated. Lactobacillus plantarum HY7712 most strongly induced TNF--α production as well as NF-κB activation. However, HY7712 inhibited NF-κB activation in LPS-stimulated peritoneal macrophages. When HY7712 was orally treated in cyclophosphamide (CP)-immunosuppressed mice for 5 or 15 days, it reversed the body and spleen weights, blood RBC and WBC levels, and splenocyte and bone marrow cells that were reduced by CP. Orally administered HY7712 increased concanavalin A-induced T cell proliferation to 84.5% of the normal group on day 15, although treatment with CP alone markedly reduced it to 53.7% of the normal group. Furthermore, orally administered HY7712 significantly induced the expressions of IL-2 and IFN-γ in ConA-induced splenic cytotoxic T cells of CP-treated mice. Orally administered HY7712 restored the CP-impaired phagocytosis of macrophages in mice. Orally administered HY7712 also restored the cytotoxicity of NK and cytotoxic T cells derived from spleen and bone marrow against YAC-1 in CP-immunosuppressed mice. Based on these findings, orally administered HY7712 may accelerate the recovery of cyclophosphamide-caused immunosuppression, without evident side effects, by immunopotentiating NK and Tc cells, and may provide a mechanistic basis for using HY7712 as an alternative means in lessening chemotherapyinduced immunosuppression in cancer patients.

Glucose and Insulin Secretory Response Patterns Following Diet and Tolazamide Therapy in Diabetes

PubMed Central

Turtle, J. R.

1970-01-01

Glucose and insulin secretory response patterns during glucose tolerance tests were determined in 28 maturity-onset diabetics, and the sequential effects of diet and a sulphonylurea, tolazamide, were assessed. Untreated diabetics showed hyperglycaemia, increased serum immunoreactive insulin response patterns, delayed insulin release, and relative insulin deficiency. Diet alone partially corrected the hyperglycaemia and serum immunoreactive insulin response but had no effect on the delayed insulin release or relative insulin deficiency. Tolazamide plus diet restored all values towards normal. The net effect of maintenance tolazamide therapy was to (1) restore the insulin secretory response pattern to normal, (2) reduce total pancreatic insulin output, and (3) improve the efficiency of insulin secretion. The results suggest that there is a rational basis for the use of sulphonylurea in all maturity-onset diabetics, including patients with mild carbohydrate intolerance and those who are apparently controlled by diet alone. PMID:5470087

Viscoelastic analysis of a dental metal-ceramic system

NASA Astrophysics Data System (ADS)

Özüpek, Şebnem; Ünlü, Utku Cemal

2012-11-01

Porcelain-fused-to-metal (PFM) restorations used in prosthetic dentistry contain thermal stresses which develop during the cooling phase after firing. These thermal stresses coupled with the stresses produced by mechanical loads may be the dominant reasons for failures in clinical situations. For an accurate calculation of these stresses, viscoelastic behavior of ceramics at high temperatures should not be ignored. In this study, the finite element technique is used to evaluate the effect of viscoelasticity on stress distributions of a three-point flexure test specimen, which is the current international standard, ISO 9693, to characterize the interfacial bond strength of metal-ceramic restorative systems. Results indicate that the probability of interfacial debonding due to normal tensile stress is higher than that due to shear stress. This conclusion suggests modification of ISO 9693 bond strength definition from one in terms of the shear stress only to that accounting for both normal and shear stresses.

Estimation of the failure risk of a maxillary premolar with different crack depths with endodontic treatment by computer-aided design/computer-aided manufacturing ceramic restorations.

PubMed

Lin, Chun-Li; Chang, Yen-Hsiang; Hsieh, Shih-Kai; Chang, Wen-Jen

2013-03-01

This study evaluated the risk of failure for an endodontically treated premolar with different crack depths, which was shearing toward the pulp chamber and was restored by using 3 different computer-aided design/computer-aided manufacturing ceramic restoration configurations. Three 3-dimensional finite element models designed with computer-aided design/computer-aided manufacturing ceramic onlay, endocrown, and conventional crown restorations were constructed to perform simulations. The Weibull function was incorporated with finite element analysis to calculate the long-term failure probability relative to different load conditions. The results indicated that the stress values on the enamel, dentin, and luting cement for endocrown restorations exhibited the lowest values relative to the other 2 restoration methods. Weibull analysis revealed that the overall failure probabilities in a shallow cracked premolar were 27%, 2%, and 1% for the onlay, endocrown, and conventional crown restorations, respectively, in the normal occlusal condition. The corresponding values were 70%, 10%, and 2% for the depth cracked premolar. This numeric investigation suggests that the endocrown provides sufficient fracture resistance only in a shallow cracked premolar with endodontic treatment. The conventional crown treatment can immobilize the premolar for different cracked depths with lower failure risk. Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Hepatoprotective effect of Bacoside-A, a major constituent of Bacopa monniera Linn.

PubMed

Sumathi, T; Nongbri, A

2008-10-01

Bacoside-A (B-A) was evaluated for its hepatoprotective activity against d-GalN induced liver injury in rats. B-A is a major constituent isolated from the plant Bacopa monniera Linn. B-A (10mg/kg of body weight) was administered orally once daily for 21 days and then d-GalN (300 mg/kg of body weight) was injected on 21st day after final administration of B-A. B-A reduces the elevated levels of serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (gamma-GT), lactate dehydrogenase (LDH), 5'nucleotidase (5'ND). In addition B-A also significantly restored towards normalization of the decreased levels of Vit-C, and Vit-E induced by d-GalN both in liver and plasma. These results suggest that B-A has hepatoprotective effect against d-GalN induced hepatotoxicity in rats.

Effect of N-acetylcysteine administration on the expression and activities of antioxidant enzymes and the malondialdehyde level in the blood of lead-exposed workers.

PubMed

Kasperczyk, Sławomir; Dobrakowski, Michał; Kasperczyk, Aleksandra; Machnik, Grzegorz; Birkner, Ewa

2014-03-01

We investigated whether treatment with N-acetylcysteine (NAC) reduces oxidative stress intensity and restores the expression and activities of superoxide dismutase (Sod1, SOD), catalase (Cat, CAT) and glutathione peroxidase (Gpx1, GPx) in lead-exposed workers. The exposed population was divided randomly into two groups. Workers in the first group (reference group, n=49) were not administered any drugs, while workers in the second group (n=122) were treated with NAC at three doses for 12 weeks (200 mg, 400 mg, 800 mg/day). NAC administered orally to lead-exposed workers normalized antioxidant enzyme activities in blood cells. Oxidative stress intensity measured as malondialdehyde (MDA) levels in serum, leukocytes and erythrocytes significantly decreased after NAC administration. NAC may be an alternative therapy for chronic lead intoxication. Copyright © 2014 Elsevier B.V. All rights reserved.

Aluminium and hydrogen ions inhibit a mechanosensory calcium-selective cation channel

NASA Technical Reports Server (NTRS)

Ding, J. P.; Pickard, B. G.

1993-01-01

The tension-dependent activity of mechanosensory calcium-selective cation channels in excised plasmalemmal patches from onion bulb scale epidermis is modulated by pH in the physiologically meaningful range between 4.5 and 7.2. It is rapidly lowered by lowering pH and rapidly raised by raising pH. Channel activity is effectively inhibited by low levels of aluminium ions and activity can be partially restored by washing for a few minutes. We suggest that under normal conditions the sensitivity of the mechanosensory channels to pH of the wall free space plays important roles in regulation of plant activities such as growth. We further suggest that, when levels of acid and aluminium ions in the soil solution are high, they might inhibit similar sensory channels in cells of the root tip, thus contributing critically to the acid soil syndrome.

PubMed Central

Descarreaux, Martin; Blouin, Jean-Sébastien; Normand, Martin C; Hudon, Daniel

2001-01-01

Background: Ankylosing spondylitis (AS) produces gradual ossification in articular components of the sacro-iliac joints, spine, thoracic and scapular region. This pathology features a diminution of range of motion, muscle force and extensibility as well as functional capacities. Actual treatment of ankylosing spondylitis includes exercise program aimed at pain control, restoration of normal muscle force and extensibility and improvement in functional capacities. These programs are designed to adapt to the special characteristics of ankylosing spondylitis population. Case study: We present the case of a 30 years old man suffering from AS who participated in a 10 week exercise program based on his personal characteristics. We evaluated changes in trunk and hip muscle force and extensibility, pain level (visual pain scale) and disability level (Modified Oswerstry questionnaire). Conclusion: He showed improvement of some physical characteristics that were deficient in the initial evaluation. Improvement were noted in trunk range of motion, some muscular group forces and extensibility of certain muscles too.

AT1 receptor blocker azilsartan medoxomil normalizes plasma miR-146a and miR-342-3p in a murine heart failure model.

PubMed

Kaneko, Manami; Satomi, Tomoko; Fujiwara, Shuji; Uchiyama, Hidefumi; Kusumoto, Keiji; Nishimoto, Tomoyuki

Our study measured circulating microRNA (miRNA) levels in the plasma of calsequestrin (CSQ)-tg mouse, a severe heart failure model, and evaluated whether treatment with angiotensin II type 1 receptor blocker, azilsartan medoxomil (AZL-M) influenced their levels using miRNA array analysis. MiR-146a, miR-149, miR-150, and miR-342-3p were reproducibly reduced in the plasma of CSQ-tg mice. Among them, miR-146a and miR-342-3p were significantly restored by AZL-M, which were associated with improvement of survival rate and reduction of congestion. These results suggest that miRNA, especially miR-146a and miR-342-3p, could be used as potential biomarkers for evaluating the efficacy of anti-heart failure drugs.

Intravenous human umbilical cord blood improves electrophysiological and metabolic properties in ISO induced myocardial necrosis in rats.

PubMed

Mohan, Mahalaxmi; Rokade, Rahul; Kasturet, Sanjay

2013-03-01

Rats treated with isoproterenol (ISO, 85 mg/kg, sc, twice at an interval of 24 h) showed a significant increase in heart rate, mean arterial blood pressure, pressure rate index, ST elevation on ECG, and a significant increase in the levels of cardiac marker enzymes- lactate dehydrogenase, and creatine kinase in serum and a significant reduction in superoxide dismutase, and catalase and increase in thiobarbituric acid reactive substance activity in heart tissue. Treatment with Human umbilical cord blood (hUCBC; 500 and 1000 microL, iv, via the tail vein; 2 h after the second dose of ISO) significantly restored back to normal levels and showed a lesser degree of cellular infiltration and infarct size in histopathological and planimetry studies respectively. Thus, hUCBC ameliorates cardiotoxic effects of isoproterenol and may be of value in the treatment of myocardial infarction.

Transgenic rescue demonstrates involvement of the Ian5 gene in T cell development in the rat.

PubMed

Michalkiewicz, Mieczyslaw; Michalkiewicz, Teresa; Ettinger, Ruth A; Rutledge, Elizabeth A; Fuller, Jessica M; Moralejo, Daniel H; Van Yserloo, Brian; MacMurray, Armand J; Kwitek, Anne E; Jacob, Howard J; Lander, Eric S; Lernmark, Ake

2004-10-04

A single point mutation in a novel immune-associated nucleotide gene 5 (Ian5) coincides with severe T cell lymphopenia in BB rats. We used a transgenic rescue approach in lymphopenic BB-derived congenic F344.lyp/lyp rats to determine whether this mutation is responsible for lymphopenia and to establish the functional importance of this novel gene. A 150-kb P1 artificial chromosome (PAC) transgene harboring a wild-type allele of the rat Ian5 gene restored Ian5 transcript and protein levels, completely rescuing the T cell lymphopenia in the F344.lyp/lyp rats. This successful complementation provides direct functional evidence that the Ian5 gene product is essential for maintaining normal T cell levels. It also demonstrates that transgenic rescue in the rat is a practical and definitive method for revealing the function of a novel gene.

A Simplified Decision Support Approach for Evaluating Wetlands Ecosystem Services

EPA Science Inventory

State-level managers and restoration advocates have expressed a desire for approaches that address wetlands services and benefits for two purposes: to demonstrate the benefits of money budgeted for restoration, and to compare proposals when awarding restoration funds for specific...

Therapeutic effect of ozone and rutin on adriamycin-induced testicular toxicity in an experimental rat model.

PubMed

Salem, E A; Salem, N A; Hellstrom, W J

2017-02-01

To evaluate the cytoprotective effects of rutin, ozone and their combination on adriamycin (ADR)-induced testicular toxicity, 50 male albino rats were classified into five groups of ten animals each as follows: placebo group; ADR group; ADR + rutin group; ADR + ozone group and ADR + rutin + ozone group. Sperm functions, testosterone (T), luteinising hormone (LH), follicle stimulating hormone (FSH), testicular enzymes, oxidant/antioxidant status, C-reactive protein, monocyte chemoattractant proteins-1 and leukotriene B4 were determined. After ADR injection, a decline in sperm functions was observed. FSH and LH levels were increased, T level and testicular enzymes were decreased, significant enhancement in oxidative stress with subsequent depletion in antioxidants was detected and inflammatory markers were significantly elevated. Treatment with rutin and/or ozone, however, improved the aforementioned parameters. Ozone therapy alone almost completely reversed the toxic effects of ADR and restored all parameters to normal levels. © 2016 Blackwell Verlag GmbH.

Chronic sleep deprivation markedly reduces coagulation factor VII expression

PubMed Central

Pinotti, Mirko; Bertolucci, Cristiano; Frigato, Elena; Branchini, Alessio; Cavallari, Nicola; Baba, Kenkichi; Contreras-Alcantara, Susana; Ehlen, J. Christopher; Bernardi, Francesco; Paul, Ketema N.; Tosini, Gianluca

2010-01-01

Chronic sleep loss, a common feature of human life in industrialized countries, is associated to cardiovascular disorders. Variations in functional parameters of coagulation might contribute to explain this relationship. By exploiting the mouse model and a specifically designed protocol, we demonstrated that seven days of partial sleep deprivation significantly decreases (−30.5%) the thrombin generation potential in plasma evaluated upon extrinsic (TF/FVIIa pathway) but not intrinsic activation of coagulation. This variation was consistent with a decrease (−49.8%) in the plasma activity levels of factor VII (FVII), the crucial physiologicalal trigger of coagulation, which was even more pronounced at the liver mRNA level (−85.7%). The recovery in normal sleep conditions for three days completely restored thrombin generation and FVII activity in plasma. For the first time, we demonstrate that chronic sleep deprivation on its own reduces, in a reversible manner, the FVII expression levels, thus influencing the TF/FVIIa activation pathway efficiency. PMID:20418241

Cadmium inhibits mouse sperm motility through inducing tyrosine phosphorylation in a specific subset of proteins.

PubMed

Wang, Lirui; Li, Yuhua; Fu, Jieli; Zhen, Linqing; Zhao, Na; Yang, Qiangzhen; Li, Sisi; Li, Xinhong

2016-08-01

Cadmium (Cd) has been reported to impair male fertility, primarily by disrupting sperm motility, but the underlying molecular mechanism remains unclear. Here we investigated the effects of Cd on sperm motility, tyrosine phosphorylation, AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, and ATP levels in vitro. Our results demonstrated that Cd inhibited sperm motility, GAPDH activity, AMPK activity and ATP production, and induced tyrosine phosphorylation of 55-57KDa proteins. Importantly, all the parameters affected by Cd were restored to normal levels when incubated with 10μM Cd in the presence of 30μM ethylene diamine tetraacetic acid (EDTA). Interestingly, changes of tyrosine phosphorylation levels of 55-57KDa proteins are completely contrary to that of other parameters. These results suggest that Cd-induced tyrosine phosphorylation of 55-57KDa proteins might act as an engine to block intracellular energy metabolism and thus decrease sperm motility. Copyright © 2016 Elsevier Inc. All rights reserved.

Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex.

PubMed

Prüss, Harald; Tedeschi, Andrea; Thiriot, Aude; Lynch, Lydia; Loughhead, Scott M; Stutte, Susanne; Mazo, Irina B; Kopp, Marcel A; Brommer, Benedikt; Blex, Christian; Geurtz, Laura-Christin; Liebscher, Thomas; Niedeggen, Andreas; Dirnagl, Ulrich; Bradke, Frank; Volz, Magdalena S; DeVivo, Michael J; Chen, Yuying; von Andrian, Ulrich H; Schwab, Jan M

2017-11-01

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.