No description available.

Cannabinoid (CB) receptors have been found in most vertebrates that have been studied. The location of various CB receptors in the body and brain are known, but their physiological functions are not fully understood. The effects CBs have on the cardiovascular system have been of growing interest in recent years. Increasing reports from emergency departments and law enforcement agencies detail acute cardiovascular and psychological effects from synthetic CB intoxication, such as JWH-018. This major health concern is substantiated by governmental agencies like the CDC and NIDA. This pilot study investigates the acute toxic effects of the synthetic CB, JWH-018, on the cardiovascular and neuroendocrine systems in Ictalurus punctatus (channel catfish). Research in organisms besides the traditional mammal models can provide new insights into CB function and physiology. Ictalurus punctatus lend multiple benefits as a model organism that permits researchers to investigate in vivo effects of both cardiovascular and neuroendocrine systems without much influence from traditional sampling methods, and further more provide ample size and tissue to perform specific cardiovascular experiments. Multiple methods were used to assess cardiovascular function and sympathetic nervous system activation. Two different doses, low (500 µg/kg) and high 1,500 µg/kg, of JWH-018 were evaluated in the study. Delivery of JWH-018, via dorsal aorta cannulation, was administered to channel catfish in order to measure cardiovascular functions and sample blood. Plasma levels of the hypothalamus-pituitary-adrenal/interrenal (HPA/I) biomarkers; ACTH, cortisol, epinephrine, and norepinephrine, were measured using ELISAs. Myocardial and neural tissue was collected after the exposures for rt-PCR analysis on β2 adrenergic and glucocorticoid receptor density change. Acute exposure of JWH-018 in undisturbed channel catfish yielded several findings: (1) High dose of JWH-018 was responsible for cardio depressor effects in catfish with a tendency to produce tachycardia, (2) rt-PCR results showed a 2.7 fold increase of glucocorticoid receptor mRNA density in catfish cardiomyocytes when exposed to each dose of JWH-018, (3) Catfish plasma ACTH levels were increased with high doses of JWH-018, while plasma cortisol was increased by low doses. Channel catfish is an excellent animal model to examine the effects of synthetic cannabinoids and cardiovascular function. Acute exposures to high levels of JWH-018 appear to produce cardiovascular dysfunction providing evidence that substantiates emergency department reports, in addition yields novel information about the interaction of CBs exposure and the increase of glucocorticoid receptors levels on cardiomyocytes. The channel catfish is a new animal model that can aid in further investigations of CB exposure and multiple physiological functions for health and toxicology studies. With relatively easy adjustments from this pilot study, the effects on CBs can be monitored on Ictalurus punctatus with confident results concerning human health.

No description available.

<p>  </p> <p>Heat stress affects breeder ducks raised in North America and other parts of the world, but the effects of such stress on the progenies is not known. Therefore, the objectives of this study were to investigate: 1) The objectives of this thesis were to first investigate the effect of heat stress or exposure to exogenous glucocorticoid (GC) on fertility, production performance, egg biochemistry, egg quality, and welfare of breeder Pekin ducks. 2) the effects of maternal GC on phenotypic plasticity and behavior of the F1 generation. Three studies were carried out to investigate these objectives.</p> <p>The first experiment was conducted to test the hypothesis that chronic treatment with low levels of either corticosterone or cortisol would alter heterophil to lymphocyte ratio (HLR) and immune organ morphometrics. Further, we wanted to determine if chronic treatment with either GC would elicit an increase in cortisol levels in egg albumen. To test our hypotheses, we implanted silastic capsules subcutaneously under the skin of the neck of adult ducks (n = 5/sex/dose) using propofol anesthesia. Capsules contained corticosterone, cortisol, or empty capsules as controls. Over the course of 2 weeks, blood serum, blood smears, body weights, and egg quality data were collected. After 2 weeks, ducks were euthanized using pentobarbital (FatalPlus, 396 mg/ml/kg) and body weight, weights of spleens, livers, and the number of active follicles were recorded. Blood smears were analyzed for HLR by a lab unaware of the treatment groups. Albumen GC levels were assessed using mass spectrometry. Data were analyzed using a 2- or 3-way ANOVA as appropriate and <em>post hoc </em>with Fishers protected least squares difference (PLSD). There were no treatment effects on egg quality measures or body weight. Corticosterone treatment did elicit an increase in serum corticosterone (p < 0.05), but not cortisol levels, compared to controls in both sexes. Both cortisol and corticosterone treatments increased (p < 0.05) serum levels of cortisol compared to controls. Relative spleen weights were higher (p < 0.05) in hens following corticosterone but not cortisol treatment. No other organs showed any differences among the treatment groups. Both GCs elicited an increase (p < 0.001) in HLR in hens at all time-points over the 2-week treatment period compared to controls. Cortisol, not corticosterone, elicited an increase in HLR for drakes (p < 0.05) compared to controls at day 1 after implants. Chronic treatment with cortisol, but not corticosterone, elicited an increase (p < 0.01) in egg albumen cortisol levels compared to other groups. Corticosterone was not detected in any albumen samples.</p> <p>The goal of our second experiment was to test the hypothesis that heat stress (HS) would alter welfare, egg quality, and morphometrics of breeder ducks. Furthermore, we wanted to test if HS would increase cortisol levels in egg albumen due to recent exciting findings that cortisol, not corticosterone, is isolated in egg albumen. To test our hypothesis, adult Pekin ducks were randomly assigned to two different rooms at 85% lay with 60 hens and 20 drakes per room. Baseline data including body weight, body condition scores (BCS) (such as footpad quality, eyes, nostrils, feather cleanliness, and feather quality scores), and egg production/quality were collected the week preceding heat treatment. Ducks were subjected to cyclic HS of 350C for 10h/day and to 29.50C for the remaining 14h/day for 3 weeks while the control room was maintained at 220C. Eggs were collected daily, and body weights were taken on days 0 and 21 relative to the onset of heat treatment. BCS were collected weekly. Eggs were collected weekly for quality assessment and albumen glucocorticoid (GCs) levels assessment using mass spectrometry. One week before the exposure to HS, 10 hens and 5 drakes were euthanized and the same number again after 3 weeks of HS or control exposures using pentobarbital and birds necropsied. Body weight, weights of the liver, spleen, and the number of maturing follicles were recorded. Data analyses were done by 2- or 3-way ANOVA as appropriate with a Tukey-Kramer post hoc test. BCS were analyzed using a chi-squared test. A p value ≤ 0.05 was considered significant. Circulating levels of corticosterone were significantly (p < 0.01) elevated at week 1 only in the HS hens while there was no significant difference in the circulating levels of corticosterone in drakes compared to the controls. The circulating levels of cortisol increased significantly at week 1 (p < 0.05), week 2 (p < 0.05), and week 3 (p < 0.01) in the hens and at week 2 and 3 only (p < 0.05) in the drakes compared to the controls. Feather quality scores (p < 0.01), feather cleanliness scores (p < 0.001) and footpad quality scores (p < 0.05) increased significantly in the HS group compared to controls, higher BCS indicate a decline in welfare. HS elicited a significant (p < 0.001) decrease in egg production at weeks 1 and 3 and a descriptive decrease in the number of fertile eggs upon candling at 10 days of incubation, numeric decrease hatchability and increase in the number of dead embryos in the HS group after the incubation period. Hens in the HS group showed a significantly decreased BW (p < 0.001), and number of ovarian follicles (p < 0.05) compared to controls. Shell weight decreased significantly at week 1 (p < 0.05) compared to controls. Yolk weight decreased significantly at week 3 (p < 0.01) compared to controls. HS elicited a significant increase in albumen cortisol levels at week 1 (p < 0.05) and week 3 (p < 0.05).</p> <p>The third experiment was conducted to determine if parental exposure to heat stress would impair performance, hypothalamic pituitary adrenal (HPA) axis response, welfare, or behavior of their offspring. To achieve these goals, we treated adult drakes and hens at peak lay to heat stress or control temperature for 3 weeks and incubated eggs collected from the last 3 days of the experiment. A total of 76 ducklings were placed into pens from each parental treatment group: control (CON-F1) and heat stress (HS-F1) and raised as grow-out ducks. Weekly data for body weights, body condition scores (BCS), and novel object test (NOT) were collected weekly. At 3 weeks of age, ducks (n = 6 per treatment group) were subjected to adrenocorticotropic hormone (ACTH) (ACTH/cosyntropin, 0.0625 mg/kg) challenge or vehicle as control. Blood samples were collected from the metatarsal vein into serum-separator tubes at 0, 1, 2, 3, and 4 hours relative to treatment for the determination of serum glucocorticoids. Blood smears were also produced from these same samples to determine heterophil to lymphocyte ratios (HLR). All injected birds were euthanized with pentobarbital on the second day relative to ACTH administration, spleen and bursa were removed and weighed immediately. Duck level analyses were completed using 1-, or 2 -way ANOVA as appropriate. BCS were analyzed using a chi-squared test. We observed that HS-F1 had a lower hatch weight (p < 0.05) compared to CON-F1. However, growth rates during the 5-week grow-out period were not significantly different between the two flocks. NOT (N = 4) analyses showed that the HS-F1 had a greater fear response (P< 0.001) compared to CON-F1. Similarly, an ACTH stimulation test showed that the HS-F1 ducks had significantly heightened corticosterone and HLR responses compared to CON-F1 ducks (p < 0.05). The HS-F1 showed altered baseline and ACTH-stimulated levels of cortisol compared to controls.</p> <p>In conclusion, GC elicit differential effects and although corticosterone has been stated to be the predominant GC in avian species, cortisol may provide critical information to further understand and improve welfare. HS decreased performance, fertility, and productivity of breeder ducks. In addition, HS and exogenous GC elicited a selective deposition of cortisol, not corticosterone, in the egg albumen. The maternal cortisol deposited in eggs alter the hypothalamic-pituitary adrenal (HPA) axis and behavioral responses of the F1 generation. This suggests that maternal hormones can alter the phenotypic plasticity of the offspring and can be used to produce offspring that have better adaptation to the rising temperatures as a result of climate change. Finally, the measure of cortisol in egg albumen can be used as a non-invasive marker of stress.</p>

The successful regeneration of muscle tissue is dependent upon the infiltration of phagocytic CD14++CD16- monocytes that support the proliferation and differentiation of myogenic precursor cells. Physiologically, the magnitude of the cellular response following resistance exercise is dictated by the level of receptor expression on the plasma membrane of the monocyte, as well as the secretion of their cognate ligands from tissue resident cells. However, it remains unclear whether the innate pro-inflammatory immune response varies with different resistance training protocols, and how it may impact recovery and the muscle remodeling process. Therefore, the purpose of this investigation was to examine temporal changes in the expression of chemotactic and adhesion receptors following an acute bout of high-volume, moderate-intensity (VOL) versus high-intensity, low-volume (HVY) lower-body resistance exercise in experienced, resistance trained men. Changes in receptor expression were assessed in conjunction with plasma concentrations of MCP-1, TNF?, and cortisol. Ten resistance-trained men (90.1 ± 11.3 kg; 176.0 ± 4.9 cm; 24.7 ± 3.4 yrs; 14.1 ± 6.1% body fat) performed each resistance exercise protocol in a random, counterbalanced order. Blood samples were obtained at baseline (BL), immediately (IP), 30 minutes (30P), 1 hour (1H), 2 hours (2H), and 5 hours (5H) post-exercise. Analysis of target receptor expression on CD14++CD16- monocytes was completed at BL, IP, 1H, 2H and 5H time points via flow cytometric analysis. Plasma concentrations of myoglobin, and LDH AUC were significantly greater following HVY compared to VOL (p = 0.003 and p = 0.010 respectively). Changes in plasma TNF?, MCP-1, and expression of CCR2, CD11b, and GCR on CD14++CD16- monocytes were similar following HVY and VOL. When collapsed across groups, TNF? was significantly increased at IP, 30P, 1H and 2H post-exercise (p = 0.001 – 0.004), while MCP-1 was significantly elevated at all post-exercise time points (p = 0.002 – 0.033). CCR2 expression was significantly lower at IP, 1H, 2H and 5H post-exercise (p = 0.020 – 0.040). In contrast, CD11b receptor expression was significantly greater at 1H relative to BL (p = 0.001), while GCR expression was not significantly different from baseline at any time point. As expected, plasma cortisol concentrations were significantly higher following VOL compared to HVY (p = 0.001), although this did not appear to be related to changes in receptor expression. Plasma testosterone concentrations and TNFr1 receptor expression did not appear to be affected by resistance exercise. Our results do not support a role for cortisol in the modulation of CCR2 receptors in vivo, while the degree of muscle damage does not appear to influence plasma concentrations of TNF?, or MCP-1. It is therefore likely that both HVY and VOL protocols constitute an exercise stimulus that is sufficient enough to promote a robust pro-inflammatory response, which is similar in timing and magnitude.

Le stress en début de vie (ELS) est associé à une susceptibilité accrue au développement de troubles liés au stress, tels que le trouble dépressif majeur (TDM). L'amygdale latérale (AL), une région du cerveau importante pour la régulation des comportements émotionnels et cognitifs, est vulnérable aux effets du ELS. Cependant, les mécanismes par lesquels l'ELS altère le comportement ne sont pas très bien définis. Auparavant, de nombreuses études se sont concentrées sur les mécanismes neuronaux qui sous-tendent les troubles comportementaux induits par le stress, mais le rôle des cellules gliales dans ce circuit reste indéterminé. Pourtant, les astrocytes, un type de cellule gliale, sont des déterminants clés du comportement. Nous avons donc cherché à identifier le rôle des astrocytes dans les effets de l'ELS sur le comportement dépendant de l'AL. Pour ce faire, nous avons utilisé un modèle de rongeur avec séparation maternelle, limitation de la litière et de la nidification pour reproduire les effets de l'ELS sur le cerveau en développement afin d’évaluer ses effets à long terme sur les astrocytes et le comportement dépendant de l'amygdale latérale. Bien que l'ELS n'ait pas eu d'influence sur le comportement anxieux des souris, ce dernier a altéré de manière significative la détection des menaces, un processus cognitif qui implique la capacité de distinguer avec précision un son menaçant précédemment appris (le stimulus conditionné) d'un son non menaçant dans un contexte nouveau. De plus, la diminution de la sensibilité au stress des astrocytes par la suppression des récepteurs glucocorticoïdes astrocytaires a amélioré de manière significative la fonction cognitive chez les souris ELS et naïves. Globalement, nos résultats suggèrent que les astrocytes jouent un rôle central dans la régulation des effets de l'ELS sur les troubles cognitifs. Ces données soulignent l'importance des astrocytes comme cibles thérapeutiques potentielles pour atténuer le dysfonctionnement cognitif, un symptôme omniprésent de la psychopathologie. / Early Life Stress (ELS) is associated with an enhanced susceptibility to the development of stress-related disorders, such as major depressive disorder (MDD). The lateral amygdala (LA), a brain region important for the regulation of emotive and cognitive behaviours is vulnerable to the effects of ELS. However, the mechanisms by which ELS impairs behaviour are poorly defined. Previously, research has focused on the neuronal mechanisms underlying stress-induced behavioural impairments, however the role of glial cells in this circuitry remains undetermined. Astrocytes, a type of glial cell, are key determinants of behaviour. Hence, we aimed to identify the role of astrocytes in the effects of ELS on LA-dependent behaviour. To accomplish this, we used a rodent model of maternal separation and limited bedding and nesting to replicate the effects of ELS on the developing brain by assessing its long-term effects on astrocytes and lateral-amygdala dependent behaviour. Although ELS did not influence anxiety-like behaviour in mice, ELS significantly impaired threat-detection, a cognitive process involving the ability to accurately distinguish between a previously learned threatening tone (the conditioned stimulus) and a non-threatening tone in a novel context. Additionally, decreasing astrocyte stress sensitivity by deleting astrocyte glucocorticoid receptors significantly enhanced cognitive function in both ELS and naïve mice. Overall, our results suggest that astrocytes are pivotal in the regulation of the effects of ELS on cognitive impairment. This data highlights the importance of astrocytes as potential therapeutic targets for mitigating cognitive dysfunction, a pervasive symptom of psychopathology.

No description available.

Impairment of mucociliary clearance with reduced airway fluid secretion leads to chronically inflamed airways. Cystic fibrosis transmembrane conductance regulator (CFTR) is crucially involved in airway fluid secretion and dexamethasone (dexa) has previously been shown to elevate CFTR activity in airway epithelial cells. However, the pathway by which dexa increases CFTR activity is largely unknown. We aimed to determine whether the increase of CFTR activity by dexa is achieved by non-genomic signaling and hypothesized that the phosphoinositide 3-kinase (PI3K) pathway is involved in CFTR stimulation. Primary rat airway epithelial cells and human bronchial submucosal gland-derived Calu-3 cells were analyzed in Ussing chambers and kinase activation was determined byWestern blots. Results demonstrated a critical involvement of PI3K and protein kinase B (AKT) signaling in the dexa-induced increase of CFTR activity, while serum and glucocorticoid dependent kinase 1 (SGK1) activity was not essential. We further demonstrated a reduced neural precursor cell expressed, developmentally downregulated 4-like (NEDD4L) ubiquitin E3 ligase activity induced by dexa, possibly responsible for the elevated CFTR activity. Finally, increases of CFTR activity by dexa were demonstrated within 30 min accompanied by rapid activation of AKT. In conclusion, dexa induces a rapid stimulation of CFTR activity which depends on PI3K/AKT signaling in airway epithelial cells. Glucocorticoids might thus represent, in addition to their immunomodulatory actions, a therapeutic strategy to rapidly increase airway fluid secretion.

Despite the continued development of specialized immunosuppressive therapies in the form of monoclonal antibodies, glucocorticoids remain a mainstay in the treatment of rheumatological and auto-inflammatory disorders. Therapeutic glucocorticoids are unmatched in the breadth of their immunosuppressive properties and deliver their anti-inflammatory effects at unparalleled speed. However, long-term exposure to therapeutic doses of glucocorticoids decreases bone mass and increases the risk of fractures – particularly in the spine – thus limiting their clinical use. Due to the abundant expression of glucocorticoid receptors across all skeletal cell populations and their respective progenitors, therapeutic glucocorticoids affect skeletal quality through a plethora of cellular targets and molecular mechanisms. However, recent evidence from rodent studies, supported by clinical data, highlights the considerable role of cells of the osteoblast lineage in the pathogenesis of glucocorticoid-induced osteoporosis: it is now appreciated that cells of the osteoblast lineage are key targets of therapeutic glucocorticoids and have an outsized role in mediating their undesirable skeletal effects. As part of this article, we review the molecular mechanisms underpinning the detrimental effects of supraphysiological levels of glucocorticoids on cells of the osteoblast lineage including osteocytes and highlight the clinical implications of recent discoveries in the field.

Objetivos: Avaliar a estatura final, mineralização e marcadores de mineralização óssea de adultos com síndrome nefrótica (SN) idiopática corticossensível na infância e adolescência e analisar a influência da doença, suas comorbidades e do alvo de estatura no crescimento e mineralização destes pacientes. Casuística: Avaliamos a estatura final de 60 pacientes (41 masculinos e 19 femininos) com idade mínima de dezenove anos ou desenvolvimento genital P4G4 nos masculinos e menarca nos femininos portadores de SN corticossensível na infância e adolescência. Realizamos a densitometria óssea (DMO=g/cm2) em 26 destes pacientes e em 35 controles, com análise concomitante dos níveis séricos de 25 OH vitamina D3 (25(OH)D), Paratormônio (PTH), telopéptido carboxiterminal do colágeno tipo 1( (CTx), Propeptídeo Aminoterminal do Colágeno Tipo I (P1NP) e Osteocalcina (OC) Resultados: A idade média inicial dos 60 pacientes foi de 5a3m e final de 20a5m, com acompanhamento médio de 15a2m. A dose média de prednisona utilizada foi de 1264 mg/kg. O Zscore médio da estatura inicial (-0,60; SD: 1,0) e final (0,64; SD: 0,92), não diferiu significativamente (Teste T: p=0,72) entre si. O Zscore estatura na idade adulta se correlacionou significativamente apenas com o Zscore estatura inicial e com o Zscore alvo de estatura. Seis pacientes atingiram Zscore estatura < -2 na idade adulta e este achado demonstrou forte correlação com o Zscore estatura inicial e com o Zscore alvo de estatura. A DMO e Zscore DMO de L1L4, Cabeça do fêmur e do Fêmur total dos pacientes e controles não diferiram significativamente. 6 pacientes e 2 controles apresentaram Zscore DMO < -2 (massa óssea reduzida) enquanto 2 pacientes e 1 controle demonstraram , Zscore DMO < -2,5 (osteoporose). Pacientes com massa óssea reduzida receberam 2189 mg/kg de prednisona durante 13 anos e aqueles com osteoporose, 2510 mg/kg durante 14 anos. Estes valores, comparados com aqueles de pacientes com massa óssea normal, mostraram significância estatística (p=0,01). Não houve correlação significativa entre as demais variáveis analisadas e a DMO. Os marcadores 25(OH)D, PTH, CTx, P1NP e OC dos pacientes e controles não diferiram significativamente. Quando analisados em relação à doença e suas comorbidades, DMO e estatura final não apresentaram significação estatística. Conclusões: 1. Os valores de Zscore estatura inicial e final se correlacionaram fortemente com o alvo de estatura. 2. Não houve associação entre as características clinicas da doença e a aquisição do alvo de estatura, neste grupo de pacientes. 3. A massa óssea e os marcadores de mineralização dos pacientes não diferiram quando comparados aos controles. 4. Os 6 pacientes com massa óssea reduzida (2 com osteoporose) utilizaram dose total e tempo de uso da prednisona significativamente maior que aqueles com massa óssea adequada 5. Não houve correlação entre os níveis séricos dos marcadores de mineralização óssea e a doença e suas comorbidades, a estatura final e a DMO dos pacientes adultos com SN na infância e adolescência / Objectives: The aim of the present study was to evaluate the final height, bone mineral density (BMD) and bone mineralization markers of adults with steroid responsive Idiopathic Nephrotic Syndrome (NS) in childhood and adolescence and to examine the influence of the disease, its co-morbidities and the patients\' target height in the final height and mineralization results. Patients and Methods: We have analyzed initial and final anthropometric data of 60 patients (41 male and 19 females) and / or their records, with a minimum age of nineteen years or fully developed pubertal status (P4G4 in males and menarche in females). BMD (g/cm2) was evaluated in 26 patients and in 35 controls, with a concomitant analysis, of serum levels of 25-OH Vitamin D (25(OH)D), Parathyroid Hormone (PTH); C-terminal telopeptide of type I collagen (CTx) and aminoterminal propeptide of type 1 procollagen (P1NP) and Osteocalcin (OC) Results: Mean age at first consultation was 5.3 years (SD: 2.4 yrs) and at last consultation was 20.4 yrs (SD: 3.0 yrs). The mean cumulative dose of prednisone was 1254 mg/kg (SD: 831.39 mg/kg). The mean initial height SDS was -0.60; (SD: 1.0) the final height SDS was -0.64; (SD: 0.92), (t-test: p=0.72). The final height SDS showed correlated significantly only with the initial height SDS and the target height SDS. Six patients achieved a final height SDS <-2 and this finding showed a strong correlation to the initial height SDS and to the target height SDS in the male patients. The patients\' and control subjects L1L4 head of the femur and the total femur BMD and BMD SDS did not differ significantly. 6 patients and 2 control subjects showed a BMD SDS <-2 (low bone mass) while 2 patients and 1 control subjects showed a BMD SDS <-2.5 (osteoporosis). Patients with BMD SDS <-2 received 2189 mg / kg of prednisone over 13 years while those with a BMD SDS <-2.5 received 2510 mg / kg prednisone for 14 years (p = 0.01 vs BMD SDS -2 ). No other studied variable correlated significantly with BMD. The studied bone biomarkers showed similar results in patients and control subjects without a significant correlation with disease activity, co-morbidities, and BMD or height parameters. Conclusion: 1. the initial and final height SDS were strongly correlated to the height target. 2. INS and its co-morbidities did not prevent the patients to reach their target height 3. The patients\' BMD and bone mineralization markers did not differ when compared to controls. 4. The 6 patients with low bone mass (2 with osteoporosis) used a total dose of prednisone for a longer period of time in relation to those with an adequate BMD 5. There was no correlation between bone mineralization markers, disease activity and its co-morbidities, final height and BMD of adult patients with INS in childhood and adolescence