39 research outputs found
Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition
<p>Abstract</p> <p>Background</p> <p>Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol.</p> <p>Results</p> <p>Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with <it>p</it>-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues.</p> <p>Conclusion</p> <p>Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence, the present findings should strengthen the notion that modulation of brain phosphatidylinositide signaling probably contributes to the molecular mechanism of diverse antidepressant medications.</p
Low vitamin D status is associated with systemic and gastrointestinal inflammation in dogs with a chronic enteropathy
Vitamin D is traditionally known for its role in calcium homeostasis and bone metabolism.
However, it has been demonstrated that numerous types of cells express the vitamin D
receptor and it is now clear that the physiological roles of vitamin D extend beyond the
maintenance of skeletal health. Vitamin D insufficiency, which is typically assessed by
measuring the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has
been associated with a number of disorders in people including hypertension, diabetes,
cardiovascular diseases, cancer, autoimmune conditions and infectious diseases. Meta-analyses
have demonstrated that serum 25(OH)D concentrations are an important predictor
of survival in people with a wide variety of illnesses and have been linked to all-cause
mortality in the general human population.
The role of vitamin D in non-skeletal disorders in cats and dogs is poorly understood. This is
surprising since cats and dogs could act as excellent models for probing the biology of
vitamin D. Vitamin D status in people is largely dependent on cutaneous production of
vitamin D. This is influenced by many factors such as season, latitude and exposure to
ultraviolet (UV) radiation. The interpretation of human studies investigating the effects
vitamin D status on disease outcomes are therefore influenced by a number of confounding
variables. Unlike humans, domesticated cats and dogs do not produce vitamin D cutaneously
and obtain vitamin D only from their diet. The physiological functions and regulation of
vitamin D are otherwise similar to humans. Most pets are fed commercial diets containing a
relatively standard amount of vitamin D. Consequently, companion animals are attractive
model systems in which to examine the relationship vitamin D status and health outcomes.
Furthermore, spontaneously occurring model systems which did not require disease to be
induced in healthy animals would allow the numbers of animals used in scientist research to
be reduced.
This thesis aimed to define vitamin D homeostasis in companion animals in three disease
settings; in cats with feline immunodeficiency virus (FIV) infection, dogs with chronic
enteropathies (CE) and in hospitalised ill cats. Additional aims were to assess the prognostic
significance of serum 25(OH)D concentrations in companion animals and the relationship
between serum 25(OH)D concentrations and markers of inflammation. The hypothesis of
this thesis was that vitamin status D would negatively correlate with presence of disease,
markers of inflammation and disease outcomes. As similar findings have been demonstrated
in human medicine, the hypothesis was that cats and dogs would be suitable models to
investigate the role of vitamin D in human disease.
This thesis demonstrates that in dogs with a CE serum 25(OH)D concentrations are
negatively correlated with inflammation and are predictive of clinical outcomes. Vitamin D
status was also lower in cats with FIV and importantly vitamin D status was predictive of
short term mortality in hospitalised ill cats. This research will be of interest to veterinary
surgeons and opens the possibility for clinical trials which examine if low vitamin D status is
causally associated with ill health and whether vitamin D supplementation results in superior
treatment outcomes in companion animals. This thesis also demonstrates the potential of cats
and dogs as model systems in which to examine the role of vitamin D in human health
A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)
Meeting abstrac
Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019
Five insights from the Global Burden of Disease Study 2019
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe
Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress
A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmunemediated
peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development
and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain–Barre´ syndrome. Adult
male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day 3 weeks) prior to
P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day
12.3 0.2 and reaching peak severity on day 17.0 0.3 (N ¼ 12). By comparison, forced-exercise preconditioned rats
exhibited a similar monophasic course but with significant (p <.05) reduction of disease severity. Analysis of popliteal
lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared
with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive
leukocytes. The percentage distribution of pro-inflammatory (Th1) lymphocytes retained in the nodes from sedentary EAN
rats (5.1 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats
(2.9 0.6%) or from adjuvant controls (2.0 0.3%). In contrast, the percentage of anti-inflammatory (Th2) lymphocytes
(7–10%) and that of cytotoxic T lymphocytes ( 20%) remained unaltered by forced exercise preconditioning. These data do
not support an exercise-inducible shift in Th1:Th2 cell bias. Rather, preconditioning with forced exercise elicits a sustained
attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (Th1) lymphocytes
from draining lymph nodes.
Key