The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of ...TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI.
The last decade saw major advances in understanding the metabolism of Coenzyme A (CoA) thioesters (acyl-CoAs) and related inborn errors (CoA metabolic diseases, CAMDs). For diagnosis, acylcarnitines ...and organic acids, both derived from acyl-CoAs, are excellent markers of most CAMDs. Clinically, each CAMD is unique but strikingly, three main patterns emerge: first, systemic decompensations with combinations of acidosis, ketosis, hypoglycemia, hyperammonemia and fatty liver; second, neurological episodes, particularly acute “stroke-like” episodes, often involving the basal ganglia but sometimes cerebral cortex, brainstem or optic nerves and third, especially in CAMDs of long chain fatty acyl-CoA metabolism, lipid myopathy, cardiomyopathy and arrhythmia. Some patients develop signs from more than one category. The pathophysiology of CAMDs is not precisely understood. Available data suggest that signs may result from CoA sequestration, toxicity and redistribution (CASTOR) in the mitochondrial matrix has been suggested to play a role. This predicts that most CAMDs cause deficiency of CoA, limiting mitochondrial energy production, and that toxic effects from the abnormal accumulation of acyl-CoAs and from extramitochondrial functions of acetyl-CoA may also contribute. Recent progress includes the following. (1) Direct measurements of tissue acyl-CoAs in mammalian models of CAMDs have been related to clinical features. (2) Inborn errors of CoA biosynthesis were shown to cause clinical changes similar to those of inborn errors of acyl-CoA degradation. (3) CoA levels in cells can be influenced pharmacologically. (4) Roles for acetyl-CoA are increasingly identified in all cell compartments. (5) Nonenzymatic acyl-CoA-mediated acylation of intracellular proteins occurs in mammalian tissues and is increased in CAMDs.
Introduction
Adult patients with epilepsy (PWE) have an 18% prevalence of comorbid attention deficit hyperactivity disorder (ADHD) compared to a prevalence of 2%–5% in the general population. ...Recognition of this dual diagnosis is important since stimulant therapy is both safe and effective in this population.
Methods
Here, we aim to determine if PWE have adequate documentation for comorbid ADHD when being admitted to the Epilepsy Monitoring Unit (EMU). A retrospective review was conducted at the Baylor St. Luke's Medical Center EMU for patients presenting between July 2017 and November 2020. Patients were divided into two groups: Group I—patients without a documented ADHD diagnosis or ADHD medications and Group II—patients with a documented ADHD diagnosis and/or taking medications indicated specifically for ADHD.
Results
Of 524 individual patients who presented to the EMU, only 25 patients (4.8%) had documentation of a diagnosis of ADHD and/or ADHD medications (Group II). The proportion of patients in Group II did not significantly differ based on the EMU diagnosis. However, there was a significantly greater number of other psychiatric diagnoses (p = .005) and a greater number of psychiatric medications prescribed (p < .001) in patients in Group II.
Conclusion
Our study suggests that ADHD is underrecognized and underdiagnosed in patients presenting to the EMU, and screening tools may be useful to help clinicians address seizure comorbidities such as ADHD.
Graphical
Nanonization is a simple and effective method to improve dissolution rate and oral bioavailability of drugs with poor water solubility. There is growing interest to downscale the nanocrystal ...production to enable early preclinical evaluation of new drug candidates when compound availability is scarce. The purpose of the present study was to investigate laser fragmentation to form nanosuspensions in aqueous solution of the insoluble model drug megestrol acetate (MA) using very little quantities of the drug. Laser fragmentation was obtained by focusing a femtosecond (fs) or nanosecond (ns) laser radiation on a magnetically stirred MA suspension in water or aqueous solution of a stabilizing agent. The size distribution and physicochemical properties of the drug nanoparticles were characterized, and the
in vitro dissolution and
in vivo oral pharmacokinetics of a laser fragmented formulation were evaluated. A MA nanosuspension was also prepared by media milling for comparison purpose. For both laser radiations, smaller particles were obtained as the laser power was increased, but at a cost of higher degradation. Significant nanonization was achieved after a 30-min
fs laser treatment at 250
mW and a 1-h
ns laser treatment at 2500
mW. The degradation induced by the laser process of the drug was primarily oxidative in nature. The crystal phase of the drug was maintained, although partial loss of crystallinity was observed. The
in vitro dissolution rate and
in vivo bioavailability of the laser fragmented formulation were similar to those obtained with the nanosuspension prepared by media milling, and significantly improved compared to the coarse drug powder. It follows that this laser nanonization method has potential to be used for the preclinical evaluation of new drug candidates.
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Insulin activates PI3-kinase (PI3K)/AKT to regulate glucose homeostasis in the peripheral tissues and the mediobasal hypothalamus (MBH) of rodents. We report that insulin infusion into the MBH or ...dorsal vagal complex (DVC) activated insulin receptors. The same dose of insulin that activated MBH PI3K/AKT did not in the DVC. DVC insulin instead activated Erk1/2 and lowered glucose production in rats and mice. Molecular and chemical inhibition of DVC Erk1/2 negated, while activation of DVC Erk1/2 recapitulated, the effects of DVC insulin. Circulating insulin failed to inhibit glucose production when DVC Erk1/2 was inhibited in normal rodents, while DVC insulin action was disrupted in high-fat-fed rodents. Activation of DVC ATP-sensitive potassium channels was necessary for insulin-Erk1/2 and sufficient to inhibit glucose production in normal and high-fat-fed rodents. DVC is a site of insulin action where insulin triggers Erk1/2 signaling to inhibit glucose production and of insulin resistance in high-fat feeding.
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► DVC insulin activates Erk1/2 → KATP to inhibit glucose production ► Circulating insulin inhibits glucose production via DVC Erk1/2 signaling ► DVC insulin-Erk1/2 fails to lower glucose production in high-fat-fed rodents ► DVC insulin resistance is bypassed by a direct activation of DVC KATP channels
Groundwater depletion threatens global freshwater resources, necessitating urgent water management and policies to meet current and future needs. However, existing data-intensive approaches to ...assessments do not fully account for the complex human, climate, and water interactions within transboundary groundwater systems. Here, we present the design of and findings from a pilot participatory modeling workshop aiming to advance understanding of the hydrologic–human–climate feedback loops underpinning groundwater systems. Using participatory modeling tools and methods from the system dynamics tradition, we captured the mental models of researchers from water, social, data, and systems sciences. A total of 54 feedback loops were identified, demonstrating the potential of this methodology to adequately capture the complexity of groundwater systems. Based on the workshop outcomes, as an illustrative example, we discuss the value of participatory system modeling as a conceptualization tool, bridging perspectives across disciplinary silos. We further discuss how outcomes may inform future research on existing knowledge gaps around groundwater issues, and in doing so, advance interdisciplinary, use-inspired research for water decision-making more broadly.
Prolonged elevation of glucose can adversely affect beta-cell function. In vitro studies have linked glucose-induced beta-cell dysfunction to oxidative stress; however, whether oxidative stress plays ...a role in vivo is unclear. Therefore, our objective was to investigate the role of oxidative stress in an in vivo model of glucose-induced beta-cell dysfunction.
Wistar rats were infused intravenously with glucose for 48 h to achieve 20 mmol/l hyperglycemia with/without co-infusion of one of the following antioxidants: taurine (2-amino ethanesulfonic acid) (TAU), an aldehyde scavenger; N-acetylcysteine (NAC), a precursor of glutathione; or tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (TPO), a superoxide dismutase mimetic. This was followed by islet isolation or hyperglycemic clamp.
A 48-h glucose infusion decreased glucose-stimulated insulin secretion (GSIS) and elevated reactive oxygen species (ROS), total superoxide, and mitochondrial superoxide in freshly isolated islets. TPO prevented the increase in total and mitochondrial superoxide and the beta-cell dysfunction induced by high glucose. However, TAU and NAC, despite completely normalizing H(2)DCF-DA (dihydro-dichlorofluorescein diacetate)-measured ROS, did not prevent the increase in superoxide and the decrease in beta-cell function induced by high glucose. TPO but not TAU also prevented beta-cell dysfunction induced by less extreme hyperglycemia (15 mmol/l) for a longer period of time (96 h). To further investigate whether TPO is effective in vivo, a hyperglycemic clamp was performed. Similar to the findings in isolated islets, prolonged glucose elevation (20 mmol/l for 48 h) decreased beta-cell function as assessed by the disposition index (insulin secretion adjusted for insulin sensitivity), and co-infusion of TPO with glucose completely restored beta-cell function.
These findings implicate superoxide generation in beta-cell dysfunction induced by prolonged hyperglycemia.
Abstract Objective Primary care screening programs for mental health disorders are designed to detect patients who might benefit from treatment. As such, the utility of these programs is predicated ...on the actions that take place in response to a positive screen. Our objective was to characterize the cascade of care delivery steps following a positive screen for a mental health disorder. Method We examined the care received by primary care patients over the year following a new positive screen for depression, posttraumatic stress disorder (PTSD) or alcohol misuse. We characterized whether the care adhered to practice guidelines for related mental health disorders and whether involvement of mental health specialists led to higher use of guideline-adherent practices. Results Many patients received appropriate treatment in the primary care setting and those whose scores were consistent with more severe illness were more likely to receive care in a mental health setting. Patients with positive screens for depression and PTSD who went on to be seen in mental health clinics received care that was consistent with treatment guidelines for the related disorder most of the time. In the case of patients with positive screens for alcohol misuse, few received guideline-recommended medications in any setting. However, a substantial portion of patients received some alcohol-related counseling from their primary care physicians during the visit in which their alcohol misuse was detected. Conclusion It appears that the treatment system for mental health problems, which extends from primary care settings to mental health subspecialty settings, can provide adequate care when patients' mental health problems are identified through screening. The care provided in all settings can be improved, and additional steps to enhance the quality of care are warranted. This should include additional efforts to align screening and treatment.
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