Corticosteroid Levels Research Articles

Effect of dexamethasone on albendazole cysticidal activity in experimental cysticercosis by Taenia crassiceps in BALB/c mice: In vitro and in vivo evaluation

Taenia solium is a parasite whose larvae (cysticerci) can locate in the central nervous system of humans and cause neurocysticercosis (NC). The introduction of cysticidal drugs such as albendazole (ABZ) for the treatment of NC has significantly improved its prognosis. However, treatment is not always effective, and the high levels of corticosteroids used to prevent inflammatory complications in this disease could be, partly, the cause of this observation. In this context, this study investigated, using the experimental mouse model of intraperitoneal infection with Taenia crassiceps, the influence of corticosteroid administration on the therapeutic efficacy of ABZ. We evaluated and compared the effects of ABZ, dexamethasone (DXM) and their combination (ABZ + DXM) on cyst viability, both in vitro and in vivo. Serum levels of IL-4, IFN-gamma, IL-6 and IL-10 were evaluated in the in vivo study. Results showed that the treatment with ABZ, in vitro and in vivo, was associated with a high number of parasites deaths. Concomitant treatment with DXM did not alter ABZ in vitro cysticidal activity but reduced its effectiveness significantly in the in vivo experimental model. Cytokine serum levels did not change significantly in treated mice compared to the controls. The results of this study are relevant as they indicate a negative effect of corticosteroids on the efficacy of cysticidal therapy. In human neurocysticercosis, control of inflammation is of great importance to most patients in order to avoid complications. Corticosteroids are generally used for this purpose and the results of this study demonstrate the need to find other therapeutic strategies. Further studies are needed to better understand the mechanisms involved.

A novel ABCD1 gene mutation causes adrenomyeloneuropathy in a Chinese family

BackgroundAdrenomyeloneuropathy (AMN) is a rare genetic disease. In this study, a case of AMN was uncovered in a Chinese family.MethodsClinical manifestations were collected and observed through medical records, physical examination, laboratory tests, and magnetic resonance imaging (MRI). Generation sequencing of the ABCD1 gene was performed, and the pedigree of the family was analyzed.ResultsThe proband suffered from adrenocortical insufficiency at 8 years old and presented with a slowly progressive gait disorder at 21 years old. Physical examination, laboratory tests, and MRI showed that he had adult‐onset AMN manifestations, including spasticity and hyperactive tendon reflexes with Hoffman and Babinski signs in the limbs, difficulty in performing the heel‐to‐shin test, hyperpigmentation, increased levels of adrenocorticotropic hormone and very long‐chain fatty acids, decreased levels of corticosteroid and serum gesterol, and salient atrophy of the cervical and thoracic spinal cord. DNA analysis revealed a missense variant, c.290A>C (p.His97Pro) in exon 1 of the ABCD1 gene, in the proband. Sanger sequencing confirmed that the proband's mother was heterozygous for the same variant. The ABCD1 gene mutation transmitted in an X‐linked inheritance manner.ConclusionA novel missense mutation in the ABCD1 gene was identified in a Chinese family, which caused an unusual manifestation of adult‐onset AMN. This discovery is beneficial for the genetic counseling of patients with X‐linked adrenoleukodystrophy.

Huang Qin Hua Shi decoction for high-temperature- and high-humidity-induced cognitive-behavioral disorder in rats is associated with deactivation of the hypothalamic–pituitary–adrenal axis

ObjectiveTo investigate the effects of Huang Qin Hua Shi (HQ) decoction on the hypothalamic–pituitary–adrenal (HPA) axis in rats under high-temperature (hT)- and high-humidity (hH)-induced stress.MethodsMale rats were randomized into four groups: rats without stress; rats induced with hT (35 ± 1°C) and hH (85 ± 5% humidity); rats induced with hT and hH and treated with HQ decoction; and rats induced with hT and hH and treated with mifepristone. After 3 weeks, rats underwent the Morris water maze and open-field test. Rat hypothalami were analyzed pathologically using hematoxylin and eosin staining and glucocorticoid receptor (GR) mRNA expression was evaluated by in situ hybridization. Serum levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosteroid (CORT) were assessed by enzyme-linked immunosorbent assay.ResultsThe administration of mifepristone or HQ in stressed rats significantly improved their performance in the Morris water maze test and increased the central-to-peripheral ratio and incidence of deep rearing in the open-field test. Mifepristone and HQ also reversed histological changes in the hypothalami of stressed rats. Compared with control rats, GR mRNA expression in the hypothalamus and serum CRH, ACTH, and CORT were significantly elevated in rats stressed with hT and hH, and these changes were attenuated by mifepristone and HQ.ConclusionHQ decoction protects against hT- and hH-induced cognitive-behavioral disorder and its therapeutic effect is associated with decreased HPA axis activity.

Зміни активності ангіотензинперетворюючого ферменту в структурах гіпоталамо-гіпофізарно-адренокортикальної системи та функції кори надниркових залоз щурів під дією метанандаміду

Мета роботи — дослідити вплив метанандаміду — метаболічно стійкого похідного ендоканабіноїду N-арахідоноїлетаноламіну на активність ангіотензинперетворюючого ферменту (АПФ) у центрах регуляції гіпоталамо-гіпофізарно-адренокортикальної системи (ГГАС), а також на рівень кортикостероїдів у плазмі крові щурів. Матеріал і методи. Активність АПФ у гіпоталамусі, аденогіпофізі, надниркових залозах і плазмі крові щурів визначали за допомогою флуориметричного методу, використовуючи як субстрат Benzoyl-Gly-His-Leu (Sigma, США). Вміст 11-гідроксикортикостероїдів (11-ОКС) у плазмі крові щурів встановлювали із застосуванням флуориметричного мікрометоду. Результати. Через 1 годину після одноразового введення інтактним щурам метанандаміду в дозах 0,2 мг/кг і 0,02 мг/кг активність АПФ у центральних ланках ГГАС — гіпоталамусі та аденогіпофізі підвищувалася, активність АПФ унадниркових залозах та активність циркулюючого в крові ферменту знижувалися. Після одноразового введення інтактним щурам метанандаміду в дозі 0,2 мг/кг виявлено підвищення рівня 11-ОКС у плазмі крові щурів, введення метанандаміду в низькій дозі — 0,02 мг/кг не призводило до вірогідних змін рівня кортикостероїдів у крові тварин. Висновки. Екзогенні канабіноїди модулюють активність ангіотензинової системи в різних ланках ГГАС, стимулюючи активність АПФ у гіпоталамусі й аденогіпофізі та знижуючи активність ферментув надниркових залозах і плазмі крові через 1 годину після одноразового введення метанандаміду інтактним щурам. Через кортикотропін-рилізинг активність ангіотензинів гіпоталамуса та аденогіпофіза підвищення активності АПФ у цих структурах може бути одним із важливих чинників активації ГГАС, зокрема синтезу кортикостероїдів, спричиненого одноразовим введенням метанандаміду у високих дозах.

Expression of obesity-related adipokine genes during fasting in a naturally obese marine mammal.

Northern elephant seals (Mirounga angustirostris) are exceptional among fasting-adapted animals in coupling prolonged fasting with energetically costly activities, relying on oxidation of fat stores accrued during foraging to power metabolic demands of reproduction and molting. We hypothesized that high rates of energy expenditure, insulin resistance, and immune responses to colonial breeding in fasting seals are mediated by adipokines, or signaling molecules secreted by adipose tissue that are associated with obesity and inflammation in humans. We measured mRNA expression of 10 adipokine genes in blubber tissue of adult female elephant seals sampled early and late during their lactation and molting fasts and correlated gene expression with adiposity and circulating levels of corticosteroid and immune markers. Expression of adiponectin (ADIPOQ) and its receptor ADIPOR2, leptin receptor (LEPR), resistin (RETN), retinol binding protein 4 (RBP4), and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) was increased, whereas that of fat mass and obesity-associated protein (FTO) was decreased in late-fasted compared with early-fasted groups. Abundance of adipokine transcripts that increased in late fasting was negatively associated with body mass and positively associated with cortisol, suggesting that they may mediate local metabolic effects of cortisol in blubber during fasting. Expression of several adipokines was correlated with the immune markers IL-6, haptoglobin, IgM, and IgE, suggesting a potential role in modulating immune responses to colonial breeding and molting. Since many of these adipokines have not been measured in other wild animals, this study provides preliminary insights into their local regulation in fat tissue and targeted assays for future studies.

Effects of 17β-E2 on growth and gonad development of overwintering Whitmania pigra

The present study was conducted to explores the effects of short-term addition of 17β-E2 on the growth,gonad development and internal quality of overwintering Whitmania pigra. Before overwintering,0. 0,1. 0,10. 0,25. 0,50. 0,100. 0 μg·L~(-1) of 17β-E2 were added to the aquaculture water for 6 weeks and then hibernated for 60 days. The changes of growth performance,gonad index,morphological structure of spermary( ovary),endogenous steroid hormones level and internal quality were measured. The results showed that the body weight,weight gain rate,specific growth rate,female gonad index,oocyte development and endogenous estrogen level of the leech increased first and then decreased with the increase of the concentration of exogenous 17β-E2,which were higher than those of the control group. The body weight,weight gain rate and specific growth rate of the leech at the concentration of 25 μg·L~(-1)17β-E2 were significantly higher than those of the other groups( P<0. 05),oocyte development and endogenous estrogen levels were significantly higher than those of other groups at the concentration of 50 μg·L~(-1)( P<0. 05). When the concentration of exogenous 17β-E2 was higher than 50 μg·L~(-1),the levels of male gonad index,spermatocyte development,endogenous androgen and progesterone were significantly inhibited( P< 0. 05). There was no significant difference in endogenous corticosteroid levels among the groups. In conclusion,short-term addition of exogenous 17β-E2 of 10-25 μg·L~(-1) could promote the growth of overwintering leeches,oocyte development and antithrombin activity without inhibiting the development of male gonads.

Prenatal exposure to betamethasone causes intergenerational impairment of epididymal development in the rat

Studies on epididymal toxicology are scarce. Betamethasone (BM) is a glucocorticoid used in clinical practice for antenatal therapy. We previously reported changes to testicular morphology, altered sperm quality, and fertility in adult rats following intrauterine administration of BM. Given that high levels of corticosteroids during gestation lead to fetal androgen depletion, and the essential role of testosterone during epididymal development, here we investigated epididymal morphology and physiology in the F1 and F2 male offspring of female rats treated with BM during gestation. Pregnant rats were randomly divided into two experimental groups: control (saline vehicle, n=11) and BM-treated group (0.1mg/kg betamethasone 21-phosphate disodium, n=13). Rats received an intramuscular injection of vehicle or BM on gestational days 12, 13, 18, and 19. This encompasses the beginning of the critical window of male rat reproductive tract development. A subset of three males from each litter (n=5 litters/group) was used: One rat per litter was euthanized at puberty, one was euthanized at adulthood, while the others were mated with a non-treated female to obtain the F2 generation. The same protocol described for the F1 was applied for F2, except for the mating protocol. In both F1 and F2 generations, prenatal BM exposure resulted in delayed differentiation of the cauda epididymal epithelium, characterized by increased cribriform appearance on PND 45, and displayed weaker or non-detectable Cx43 immunostaining. Furthermore, in the F1 generation only, immunostaining of TP63, a transcription factor expressed in basal cells, appeared more intense with a greater number of TP63-positive cells observed in the cauda epididymis. In adults, the epithelial area was reduced in the F1 BM rats. The contractile activity of isolated epididymal ducts was comparable between groups. Prenatal BM exposure leads to intergenerational impairment in the development and structure of the rat epididymis.

276-LB: Constitutive Activation of PKA Signaling in POMC-Expressing Cells Improves Systemic Glucose Metabolism

Constitutive Proopiomelanocortin (POMC)-expressing cells are mainly found in the hypothalamic arcuate nucleus, brainstem solitary tract nucleus, and pituitary gland. The cAMP-dependent protein kinase A (PKA) critically transduces signaling pathways of many important hormones and neurotransmitters including glucagon, GLP-1, α-MSH, dopamine and catecholamine. We generated the mice deleting PKA regulatory subunit R1A (Prkar1a) in POMC-expressing cells to induce constitutive activation of PKA signaling in POMC cells. These mice exhibited interesting phenotypes similar to human Cushing's syndrome; thin skin, hair loss, increased fat mass but reduced muscle and bone mass, female infertility, retarded linear growth, hump and insulin resistance. Moreover, they had increased corticosterone levels both in urine and plasma along with adrenal cortical hypertrophy. Interestingly, despite severe insulin resistance and obesity, plasma glucose concentrations were significantly lower in both fasting and post-glucose loading conditions. These mice showed enhanced insulin-independent glucose disposal. FDG-PET scanning and 2DG uptake tests revealed increased glucose uptake in the brain and the kidney. Normalization of corticosteroid levels by bilateral adrenalectomy and corticosteroid replacement could not normalize blood glucose. Collectively, our hypothesis is that abnormal activation of PKA signaling in pituitary POMC cells causes human Cushing’s syndrome-like phenotype whereas unusual activation of PKA signaling in hypothalamic POMC neurons enhances glucose disposal in the brain and the kidney. Disclosure J. Choi: None. S. Min: None. G. Kang: None. J. Kim: None. M. Kim: None. Funding National Research Foundation of Korea

Bovine Herpesvirus 1 Counteracts Immune Responses and Immune-Surveillance to Enhance Pathogenesis and Virus Transmission.

Infection of cattle by bovine herpesvirus 1 (BoHV-1) can culminate in upper respiratory tract disorders, conjunctivitis, or genital disorders. Infection also consistently leads to transient immune-suppression. BoHV-1 is the number one infectious agent in cattle that is associated with abortions in cattle. BoHV-1, as other α-herpesvirinae subfamily members, establishes latency in sensory neurons. Stressful stimuli, mimicked by the synthetic corticosteroid dexamethasone, consistently induce reactivation from latency in latently infected calves and rabbits. Increased corticosteroid levels due to stress have a two-pronged effect on reactivation from latency by: (1) directly stimulating viral gene expression and replication, and (2) impairing antiviral immune responses, thus enhancing virus spread and transmission. BoHV-1 encodes several proteins, bICP0, bICP27, gG, UL49.5, and VP8, which interfere with key antiviral innate immune responses in the absence of other viral genes. Furthermore, the ability of BoHV-1 to infect lymphocytes and induce apoptosis, in particular CD4+ T cells, has negative impacts on immune responses during acute infection. BoHV-1 induced immune-suppression can initiate the poly-microbial disorder known as bovine respiratory disease complex, which costs the US cattle industry more than one billion dollars annually. Furthermore, interfering with antiviral responses may promote viral spread to ovaries and the developing fetus, thus enhancing reproductive issues associated with BoHV-1 infection of cows or pregnant cows. The focus of this review is to describe the known mechanisms, direct and indirect, by which BoHV-1 interferes with antiviral immune responses during the course of infection.

Fetal exposure to high levels of maternal glucocorticoids alters reelin signaling in the prefrontal cortex of rat pups

Maternal stress (MS) is associated with various neuropsychiatric disorders and cognitive impairment in the offspring. However, it is unclear how early life stress alters the pup’s brain development and how it contributes to the pathology of neuropsychiatric disorders later in life. Reelin is a large extracellular matrix glycoprotein that plays essential roles in early brain development such as neural migration, synaptic development, and maturation. Dysregulation of reelin and its signaling proteins is associated with the emergence of neuropsychiatric disorders in adulthood. This study examined the effect of repeated maternal Carbenoxolone (CBX) injection during late gestation on reelin signaling in the prefrontal cortex (PFC) of rat pups. CBX is a selective 11β-HSD2 enzyme inhibitor that promotes the direct transfer of maternal corticosteroids (CORT) to the fetus. Therefore, treatment with CBX can mimic the animal model of early life exposure to high levels of maternal stress hormone. In this study, pregnant rats were injected daily with either saline or CBX during gestation day (GD) 14–21, and the levels of reelin and its signaling proteins were examined in the PFC of rat pups at different postnatal age from P0-P21. The main result of this study is the repeated maternal CBX injections during GD14-21 acutely increase reln mRNA and protein expression in the PFC of rat pups at birth (P0) and follow by a significant decrease during P7-P14. The treatment also causes long term decreases in the amount of VLDLR and Dab1 which are the downstream signaling proteins for the reelin pathway, at least until P21. Our results indicated that fetal exposure to high levels of maternal CORT interferes with reelin signaling which might have profound effects on cortical development associated with neuropsychiatric disorders later in life.

Is There a Relation Between Lateral Epicondylitis and Total Cholesterol Levels?

To investigate whether high total cholesterol (TC) levels are associated with lateral epicondylitis (LE). We retrospectively reviewed all patients with LE who presented to our institution between 2011 and 2015. The inclusion criteria were a diagnosis of LE based on clinical history and physical examination findings and age between 40 and 55years. For healthy controls, we obtained data from a national cohort (sixth Korean National Health and Nutrition Examination Survey) aged between 40 and 55years. We compared TC levels between the groups, determined the incidence of hypercholesterolemia (TC level ≥ 240mg/dL) according to the occurrence of LE, and calculated odds ratios for the occurrence of LE. We also evaluated whether cholesterol levels were associated with clinical findings of LE, such as pain level, onset age, symptom duration, and number of corticosteroid injections. The study comprised 289 patients with LE (mean age, 47.9years) and 1,077 healthy individuals (mean age, 47.7years). TC levels were significantly higher in patients with LE than in healthy individuals (205.0mg/dL vs 194.6mg/dL, P < .001). The mean difference of 10.4mg/dL was clinically meaningful because a change of 10mg/dL with medical intervention is considered significant. The incidence of hypercholesterolemia was higher in LE patients than in healthy controls (16.6% vs 9.0%, P < .001). After adjustment for age, sex, body mass index, and glucose level, patients with hypercholesterolemia (TC level ≥ 240mg/dL) were 2.47 (95% confidence interval, 1.65-3.70) times more likely to experience LE than those with normal cholesterol levels (<200mg/dL). TC levels correlated with pain level, onset age, and number of corticosteroid injections. A clinically meaningful difference in TC levels was found between LE patients and healthy controls. Inaddition, the incidence of hypercholesterolemia was higher in LE patients than in controls. The present findings suggest a potential association between high TC levels and LE. Level III, case-control study.

Loss of the glucocorticoid receptor in zebrafish improves muscle glucose availability and increases growth.

Chronic stress and the associated elevation in corticosteroid levels increase muscle protein catabolism. We hypothesized that the glucocorticoid receptor (GR)-regulated restriction of muscle glucose availability may play a role in the increased protein catabolism during chronic stress. To test this, we generated a ubiquitous GR knockout (GRKO) zebrafish to determine the physiological consequence of glucocorticoid stimulation on muscle metabolism and growth. Adult GRKO zebrafish had higher body mass, and this corresponded to an increased protein and lipid, but not carbohydrate, content. GRKO fish were hypercortisolemic, but they elicited a higher cortisol response to an acute stressor. However, the stressor-induced increase in plasma glucose level observed in the wild type was completely abolished in the GRKO fish. Also, the muscle, but not liver, capacity for glucose uptake was enhanced in the GRKO fish, and this corresponded with a higher hexokinase activity in the mutants. Zebrafish lacking GR also showed a higher capacity for protein synthesis, including increased phosphorylation of eukaryotic initiation factor 4B, higher expression of heat shock protein cognate 70, and total protein content. A chronic fasting stressor reduced body mass and muscle protein content in adult zebrafish, but this decrease was attenuated in the GRKO compared with the wild-type fish. Metabolomics analysis revealed that the free pool of amino acid substrates used for oxidation and gluconeogenesis were lower in the fasted GRKO fish muscle compared with the wild type. Altogether, chronic stressor-mediated GR signaling limits muscle glucose uptake, and this may play a role in protein catabolism, leading to the growth suppression in fish.

Comparision of intra-articular corticosteroid and low level laser therapy in idiopathic adhesive capsulitis of shoulder

Objective: To compare the relative effectiveness of intra-articular corticosteroid and low level laser therapy in idiopathic adhesive capsulitis of shoulder among 80 patients with the complaints of pain in shoulder joint and on clinical examination suspected of idiopathic adhesive capsulitis.Methods: A total number of 80 patients with Adhesive capsulitis were divided into 2 groups of 40 each. One group received intra articular injection Triamcinolone while other group received Low level laser therapy. Pre and post intervention range of movements of shoulders and SRQ scores were recorded at 6 months.Results: The improvement in abduction, external rotation and overhead elevation movement was significantly higher in steroid injection study group (37.30, 15.25, 57.75 degrees) as compared to Low laser therapy group (20.62, 7.12, 33.37 degrees) (P-value

Activation of infralimbic cortical glutamate neurons increases motivation and sociability, reduces stress reactivity, and prevents the cardiac consequences of chronic stress

Stress, a real or perceived threat to homeostasis or well‐being, has a considerable role in the pathogenesis of mood and anxiety disorders. Moreover, prolonged stress and mood disorders are significant risk factors for numerous cardiometabolic conditions that further burden health‐related quality of life. The neurobiological mechanisms of stress‐related health detriments remain elusive; however, we have identified a specific population of glutamate neurons in the infralimbic cortex (IL) that regulate multiple aspects of stress responding. To test the hypothesis that IL glutamate neurons integrate affective processes with the cardiovascular consequences of chronic stress, we used optogenetics to stimulate these cells while investigating mood‐related behaviors and physiological stress reactivity. Additionally, we investigated whether increased IL neuronal activity mitigates chronic stress‐induced cardiac changes. These hypotheses were addressed in two experiments in which male rats received intra‐IL injections of adeno‐associated virus containing a construct coding for the light‐sensitive cation channel, channelrhodopsin‐2, or a control construct expressing yellow fluorescent protein. Both constructs were expressed under the calcium/calmodulin‐dependent protein kinase IIa promoter, permitting the activation of IL glutamate neurons via targeted blue light stimulation. Parameters of optical stimulation (power, frequency, and pulsatility) were optimized with whole‐cell recordings from prefrontal slices. In the first experiment, animals were tested in the real‐time place preference assay and three‐chambered social motivation paradigm, followed by restraint stress to measure stress‐evoked plasma glucose and corticosteroid levels. For the second experiment, after rats were instrumented for optogenetics, electrocardiography‐enabled radiotelemeters were implanted to examine cardiovascular stress reactivity and cardiac autonomic balance during novel environment exposure. Additionally, these animals underwent echocardiographic assessment of cardiac function during IL optic stimulation, both before and after chronic variable stress. Our results indicated that activation of IL glutamate neurons induced place preference and increased social motivation; further, these behavioral effects were coupled with reduced endocrine stress reactivity. IL activation also decreased novel environment stress‐induced effects on heart rate and sympathovagal balance. Moreover, chronic variable stress increased left ventricular fractional shortening, consistent with a chronic elevation of sympathetic tone driving cardiac contractility and load; however, this effect was prevented by IL optical stimulation. Collectively, these studies highlight IL cortical neurons as a critical component of the neural network(s) integrating behavioral and affective processes with physiological responses to stress. These findings also provide a neurobiological mechanism for the relationship between stress, affective disorders, and cardiovascular health outcomes.Support or Funding InformationNIH grant R00 HL122454 to B. MyersThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15.

Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. Physical, emotional, and chemical stresses are linked to increasing the incidence of reactivation from latency, but the mechanism of action is not well understood. In general, stress increases corticosteroid levels, leading to activation of the glucocorticoid receptor (GR), a pioneer transcription factor. Consequently, we hypothesized that stress-mediated activation of the GR can stimulate productive infection and viral gene expression. New studies demonstrated that the GR-specific antagonist (CORT-108297) significantly reduced HSV-1 productive infection in mouse neuroblastoma cells (Neuro-2A). Additional studies demonstrated that the activated GR and Krüppel-like transcription factor 15 (KLF15) cooperatively transactivated the infected cell protein 0 (ICP0) promoter, a crucial viral regulatory protein. Interestingly, the synthetic corticosteroid dexamethasone and GR or KLF15 alone had little effect on ICP0 promoter activity in transfected Neuro-2A or Vero cells. Chromatin immunoprecipitation (ChIP) studies revealed that the GR and KLF15 occupied ICP0 promoter sequences important for transactivation at 2 and 4 h after infection; however, binding was not readily detected at 6 h after infection. Similar results were obtained for cells transfected with the full-length ICP0 promoter. ICP0 promoter sequences lack a consensus "whole" GR response element (GRE) but contain putative half-GREs that were important for dexamethasone induced promoter activity. The activated GR stimulates expression of, and interacts with, KLF15; consequently, these data suggest KLF15 and the GR form a feed-forward loop that activates viral gene expression and productive infection following stressful stimuli.IMPORTANCE The ability of herpes simplex virus 1 (HSV-1) to periodically reactivate from latency results in virus transmission and recurrent disease. The incidence of reactivation from latency is increased by chronic or acute stress. Stress increases the levels of corticosteroids, which bind and activate the glucocorticoid receptor (GR). Since GR activation is an immediate early response to stress, we tested whether the GR influences productive infection and the promoter that drives infected cell protein 0 (ICP0) expression. Pretreatment of cells with a GR-specific antagonist (CORT-108297) significantly reduced virus replication. Although the GR had little effect on ICP0 promoter activity alone, the Krüppel-like transcription factor 15 (KLF15) cooperated with the GR to stimulate promoter activity in transfected cells. In transfected or infected cells, the GR and KLF15 occupied ICP0 sequences important for transactivation. Collectively, these studies provide insight into how stress can directly stimulate productive infection and viral gene expression.

Stress in captive Blue-fronted parrots (Amazona aestiva): the animalists' tale.

Understanding stress physiology is crucial for species management because high levels of stress can reduce reproduction and the individual's ability to face threats to survive. One of the most popular methods for non-invasive monitoring of animal endocrine status is the glucocorticoid (GC) metabolite measurements, which can provide important information about how animals are affected by their surrounding environment. Here, we carried out the biological validation of corticosterone enzyme immunoassays (EIAs), which together with a cortisol EIA was used to quantified the concentrations of urofaecal GC metabolites (uGCMs) in wild and captive Blue-fronted amazon parrots (Amazona aestiva). Urofaecal GC concentrations were significantly higher (P < 0.05) in free-living parrots (157.9 ± 18.5ng cortisol/g and 61.14 ± 23.5ng corticosterone/g dry urofaecal sample) than in those kept in captivity, which showed the comparable levels of GC metabolites independently of the management system applied. The higher uGCM levels obtained in the wild population point to an adaptive response for survival and species propagation in a more challenging environment, in comparison with captive animals. Furthermore, the lower uGCM concentrations in captive parrots may indicate an adaptive capacity of the species A. aestiva to captivity and its potential as a legal pet. The corticosterone EIA applied in this study proved to be an effective technique for the adrenocortical activity monitoring in this species. We discuss our findings considering the management and destiny given to wild-caught birds that are kept in confinement or returned to nature.

Probiotics: A Potential Immunotherapeutic Approach for the Treatment of Schizophrenia.

Probiotics are in use for physiological boosting, health supplement, and for treatment since historical time. Recently, the to-and-fro pathways linking the gut with the brain, explaining the indirect communication via modulation of immune function and levels of various neurotransmitters, have been discovered, but how precisely these modulations alter the levels of neurotransmitters contributing to the cognitive and other symptom improvements in patients with schizophrenia remains a new arena of research for psychiatry and psychology professionals. The germ-free mice experiments have been the game changer in the mechanistic exploration. The antimicrobial usage alters the local gut flora and hence is associated with psychiatric side effects that strengthen the association further. The changes in the genetics of these bacteria with different types of diet and its correlation with neurotransmitters production capacity and the psyche of the individual are indeed an emerging field for schizophrenia research. Redressal of issues such as manufacturing, the shelf life of probiotics, and stability of probiotics in the gut milieu, in the presence of food, secretions, and exact volume needed for particular age group will help in refining the dose duration of probiotic therapy. Clinical trials are underway for evaluating safety and efficacy in schizophrenia. The gut microorganism transplant and pharmacovigilance of probiotics are important areas yet to be addressed accurately. This paper elucidates the pathways, clinical studies, availability of probiotics in the Indian market with their composition, regulatory issues in India about the probiotic use, and future of probiotic research in schizophrenia.

Behavioral and endocrine correlates of dominance in captive female Jackson's hartebeest (Alcelaphus buselaphus).

For species that form dominance hierarchies, such as group-living ungulates, aggressive interactions can pose a challenge to successful captive management. For example, Jackson's hartebeest (Alcelaphus buselaphus), a rare antelope of east Africa, can be difficult to maintain in captivity because aggression within female dominance hierarchies can lead to injury and death. We quantified behavioral and endocrine correlates of dominance in a captive herd of ten female hartebeest with the goal of understanding how to minimize dangerous interactions. We observed hartebeest for 18 months in a 4-ha enclosure on St. Catherines Island, Georgia. We quantified type of agonistic behavior, initiator and recipient of the behavior, who displaced whom, and age and relative size of participants. We also used fecal steroid analysis to take weekly measurements of corticoids, a hormonal correlate of stress. Hartebeest maintained a stable, linear dominance hierarchy. Only 5.9% of interactions were reversals of established rank. Most dominance interactions were low intensity, but 17.3% of interactions carried a high risk of injury (chase, horn butt, horn clash, horn clash on knees, and head push). High-ranking individuals usually initiated interactions. Most interactions were between animals of similar rank, and animals of intermediate rank participated in the highest number of interactions. The frequency of high-intensity interactions was unrelated to rank. Rank was correlated with age, but not size. There was no relationship between rank and fecal corticoid levels. Dominance interactions in hartebeest are not a function of social instability, and the frequency of dangerous interactions is not a function of rank.

New reagents for poultry research: preparation, purification, and in vitro evaluation of non-PEGylated and mono-PEGylated chicken prolactin

Recombinant chicken prolactin (chPRL), expressed in Escherichia coli and purified as a monomer, was successfully PEGylated and purified to homogeneity as a mono-PEGylated protein (PEG-chPRL). Its biological activity was estimated by its ability to interact with human prolactin receptor extracellular domain (hPRLR-ECD) and stimulate PRLR-mediated proliferation in Nb2-11C cells. PEG-chPRL activity in a cell bioassay was 10-fold lower than that of non-PEGylated chPRL, but only 2-fold lower in a binding assay to hPRLR-ECD. The CD spectra of non-PEGylated and PEGylated chPRL were almost identical and similar to that of hPRL, indicating proper refolding. Although the PEGylation of chPRL resulted in lower activity in vitro, PEG-chPRL was absorbed more slowly than chPRL, remained in the circulation 16h longer. Furthermore the effects of PEG-chPRL injections in chickens on subsequent corticosteroid levels in blood were significantly profound compared to chPRL. These favorable PEGylation-induced pharmacokinetic alterations should improve efficacy of PEG-chPRL in in vivo experiments, as dosing frequency can be reduced due to its prolonged persistence in the circulation, and thus reduce the frequency of dosing. Furthermore, hydrophobic interaction chromatography was successfully adopted to isolate PEG-chPRL as a better alternative for separation of PEGylated PRL, and is likely to be successfully applicable to other proteins.

Sex-dependent responses to exertional heat stroke in mice.

With increasing participation of females in endurance athletics and active military service, it is important to determine if there are inherent sex-dependent susceptibilities to exertional heat injury or heat stroke. In this study we compared responses of male and female adult mice to exertional heat stroke (EHS). All mice were instrumented for telemetry core temperature measurements and were exercise-trained for 3 wk before EHS. During EHS, environmental temperature was 37.5°C (35% RH) while the mice ran on a forced running wheel, using incremental increases in speed. The symptom-limited endpoint was loss of consciousness, occurring at ~42.2°C core temperature. Females ran greater distances (623 vs. 346 m, P < 0.0001), reached faster running speeds (7.2 vs. 5.1 m/min, P < 0.0001), exercised for longer times (177 vs. 124 min, P < 0.0001), and were exposed to greater internal heat loads (240 vs.160°C·min; P < 0.0001). Minimum Tc during hypothermic recovery was ~32.0°C in both sexes. Females lost 9.2% body weight vs. 7.5% in males ( P < 0.001). Females demonstrated higher circulating corticosterone (286 vs 183 ng/ml, P = 0.001, at 3 h), but most plasma cytokines were not different. A component of performance in females could be attributed to greater body surface area/mass and greater external power performance. However, there were significant and independent effects of sex alone and a crossed effect of "sex × power" on performance. These results demonstrate that female mice have greater resistance to EHS during exercise in hyperthermia and that these effects cannot be attributed solely to body size. NEW & NOTEWORTHY Female mice are surprisingly more resistant to exertional heat stroke than male mice. They run faster and longer and can withstand greater internal heat loads. These changes cannot be fully accounted for by increased body surface/mass ratio in females or on differences in aerobic performance. Although the stress-immune response in males and females was similar, females exhibited markedly higher plasma corticosteroid levels, which were sustained over 14 days of recovery.