Many erythrocyte processes and pathways, including glycolysis, the pentose phosphate pathway (PPP), KCl cotransport, ATP release, Na+/K+-ATPase activity, ankyrin–band 3 interactions, and nitric oxide ...(NO) release, are regulated by changes in O2 pressure that occur as a red blood cell (RBC) transits between the lungs and tissues. The O2 dependence of glycolysis, PPP, and ankyrin–band 3 interactions (affecting RBC rheology) are controlled by O2-dependent competition between deoxyhemoglobin (deoxyHb), but not oxyhemoglobin (oxyHb), and other proteins for band 3. We undertook the present study to determine whether the O2 dependence of Na+/K+/2Cl− cotransport (catalyzed by Na+/K+/2Cl− cotransporter 1 NKCC1) might similarly originate from competition between deoxyHb and a protein involved in NKCC1 regulation for a common binding site on band 3. Using three transgenic mouse strains having mutated deoxyhemoglobin-binding sites on band 3, we found that docking of deoxyhemoglobin at the N terminus of band 3 displaces the protein with no lysine kinase 1 (WNK1) from its overlapping binding site on band 3. This displacement enabled WNK1 to phosphorylate oxidative stress-responsive kinase 1 (OSR1), which, in turn, phosphorylated and activated NKCC1. Under normal solution conditions, the NKCC1 activation increased RBC volume and thereby induced changes in RBC rheology. Because the deoxyhemoglobin-mediated WNK1 displacement from band 3 in this O2 regulation pathway may also occur in the regulation of other O2-regulated ion transporters, we hypothesize that the NKCC1-mediated regulatory mechanism may represent a general pattern of O2 modulation of ion transporters in erythrocytes.
We compared and validated the performance accuracy of simplified comorbidity evaluation compared to the Charlson Comorbidity Index (CCI) predicting COVID-19 severity. In addition, we also determined ...whether risk prediction of COVID-19 severity changed during different COVID-19 pandemic outbreaks.
We enrolled all patients whose SARS-CoV-2 PCR tests were performed at six different hospital Emergency Departments in 2020. Patients were divided into three groups based on the various COVID-19 outbreaks in the US (first wave: March–May 2020, second wave: June–September 2020, and third wave: October–December 2020). A simplified comorbidity evaluation was used as an independent risk factor to predict clinical outcomes using multivariate logistic regressions.
A total of 22,248 patients were included, for which 7023 (32%) patients tested COVID-19 positive. Higher percentages of COVID-19 patients with more than three chronic conditions had worse clinical outcomes (i.e., hospital and intensive care unit admissions, receiving invasive mechanical ventilations, and in-hospital mortality) during all three COVID-19 outbreak waves.
This simplified comorbidity evaluation was validated to be associated with COVID clinical outcomes. Such evaluation did not perform worse when compared with CCI to predict in-hospital mortality.
Homeless adolescents who used alcohol or illicit substances but were not seeking treatment (
n
= 54) were recorded during brief motivational interventions. Adolescent language during sessions was ...coded on the basis of motivational interviewing concepts (global ratings of engagement and affect, counts of commitment to change, statements about reasons for change, and statements about desire or ability to change), and ratings were tested as predictors of rates of substance use over time. Results indicate that statements about desire or ability against change, although infrequent (
M
= 0.61 per 5 min), were strongly and negatively predictive of changes in substance use rates (days of abstinence over the prior month) at both 1- and 3-month postbaseline assessment (
p
s < .001). Statements about reasons for change were associated with greater reductions in days of substance use at 1-month assessment (
p
< .05). Commitment language was not associated with outcomes. Results suggest that specific aspects of adolescent speech in brief interventions may be important in the prediction of change in substance use. These relationships should be examined within larger samples and other clinical contexts.
Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of ...microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field.
We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb).
We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases.
Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.
Chronic low-grade retinal inflammation is an essential contributor to the pathogenesis of diabetic retinopathy (DR). It is characterized by increased retinal cell expression and secretion of a ...variety of inflammatory cytokines; among these, IL-1β has the reputation of being a major driver of cytokine-induced inflammation. IL-1β and other cytokines drive inflammatory changes that cause damage to retinal cells, leading to the hallmark vascular lesions of DR; these include increased leukocyte adherence, vascular permeability, and capillary cell death. Nuclear factor of activated T-cells (NFAT) is a transcriptional regulator of inflammatory cytokines and adhesion molecules and is expressed in retinal cells. Consequently, it may influence multiple pathogenic steps early in DR. We investigated the NFAT-dependency of IL-1β-induced inflammation in human Müller cells (hMC) and human retinal microvascular endothelial cells (hRMEC). Our results show that an NFAT inhibitor, Inhibitor of NFAT-Calcineurin Association-6 (INCA-6), decreased IL-1β-induced expression of IL-1β and TNFα in hMC, while having no effect on VEGF, CCL2, or CCL5 expression. We also demonstrate that INCA-6 attenuated IL-1β-induced increases of IL-1β, TNFα, IL-6, CCL2, and CCL5 (inflammatory cytokines and chemokines), and ICAM-1 and E-selectin (leukocyte adhesion molecules) expression in hRMEC. INCA-6 similarly inhibited IL-1β-induced increases in leukocyte adhesion in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Finally, INCA-6 rescued IL-1β-induced permeability in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Taken together, these data demonstrate the potential of NFAT inhibition to mitigate retinal inflammation secondary to diabetes.
•In DR, retinal inflammation initiates, propagates, and sustains disease progression.•Targeting NFAT attenuates IL-1β-induced Müller cell inflammation.•NFAT inhibition reduces IL-1β-induced microvascular endothelial cell inflammation.•NFAT inhibition rescues vascular hyperpermeability and leukostasis.•Targeting NFAT has therapeutic potential for attenuating retinal inflammation.
The glycine receptor is a pentameric ligand-gated ion channel that is involved in fast inhibitory neurotransmission in the central nervous system. Zinc is an allosteric modulator of glycine receptor ...function, enhancing the effects of glycine at nanomolar to low-micromolar concentrations and inhibiting its effects at higher concentrations. Low-nanomolar concentrations of contaminating zinc in electrophysiological buffers are capable of synergistically enhancing receptor modulation by other compounds, such as ethanol. This suggests that, unless accounted for, previous studies of glycine receptor modulation were measuring the effects of modulator plus comodulation by zinc on receptor function. Since zinc is present in vivo at a variety of concentrations, it will influence glycine receptor modulation by other pharmacologic agents. We investigated the utility of previously described "zinc-enhancement-insensitive"
1 glycine receptor mutants D80A, D80G, and W170S to probe for interactions between zinc and other allosteric modulators at the glycine receptor. We found that only the W170S mutation conferred complete abolishment of zinc enhancement across a variety of agonist and zinc concentrations. Using
1 W170S receptors, we established that, in addition to ethanol, zinc interacts with inhalants, but not volatile anesthetics, to synergistically enhance channel function. Additionally, we determined that this interaction is abolished at higher zinc concentrations when receptor-enhancing binding sites are saturated, suggesting a mechanism by which modulators such as ethanol and inhalants are capable of increasing receptor affinity for zinc, in addition to enhancing channel function on their own.
Wound closure method in total hip and knee arthroplasty is a controversial topic with no differences in clinical outcomes between surgical staples (SS) and subcutaneous sutures with Dermabond (SCD). ...When clinically appropriate, providers should focus more on what the patient may prefer. This study aimed to collect data on patient preference between SS and SCD and analyze differences in preference based on gender and previous surgical histories.
Patients were surveyed on their wound closure preferences prior to surgery. The handout given collected preference and patient demographics. Risk ratios and risk difference with 95% confidence intervals (95% CI) were calculated along with Firth-corrected logistic regressions.
A total of 163 participants were analyzed (53% female) (average age = 63.8 years), in which 12 participants selected SS as their preferred method. Males demonstrated no difference in relative risk (risk ratio: 2.3 95% CI: 0.7, 7.3, P = .150) or absolute risk (risk difference: 5.9 −2.2, 14.1, P = .156) in choosing SS over SCD. Patients that previously sustained SS for other surgeries demonstrated no difference in adjusted odds (adjusted: 0.9 95% CI: 0.2, 3.2, P = .839) in choosing SS over SCD.
More patients favored SCD over SS. There was no difference in preferences based on gender or previous surgical history. Current literature shows that successful wound closure is achieved with minimized risks for infection and other complications using both methods. Providers should adopt a patient-centric approach and perform the closure method that most patients prefer when medically warranted.
Emergency physicians often rely on a "triple-rule-out" computed tomography (CT) where image acquisition is timed to obtain image quality equivalent to dedicated coronary CT angiography, pulmonary CT ...angiography, and thoracic aorta CT angiography. This case highlights the importance of obtaining CT angiography dedicated to the aorta in the setting of high clinical suspicion for aortic disease if initial CT pulmonary angiogram is negative for aortic disease.
The water discharged by hydropower facilities is a matter of increasing concern due to poor downstream water quality. The use of auto-venting hydroturbines has been suggested as one of the best ways ...to mitigate low dissolved oxygen levels in the downstream water. Much of the design of auto-venting hydroturbines is currently performed with computational fluid dynamics (CFD) simulations. However, there is little information available to test and verify the performance of these simulations regarding gas transfer and bubble size distribution. This paper investigates the performance of a water tunnel test-bed for CFD simulations of an auto-venting hydroturbine through the use of a ventilated hydrofoil. Bubble size distributions are measured by a shadow imaging technique and found to have a Sauter mean diameter of 0.9mm for a reference case. Higher liquid velocities, a lower airflow rate and a higher angle of attack all resulted in a greater number of small bubbles and a lower weighted mean bubble size. Bubble-water oxygen transfer is measured by the disturbed equilibrium technique. The gas transfer model of Azbel (1981) is utilized to characterize the liquid film coefficient for oxygen transfer, with one scaling coefficient to reflect the fact that characteristic turbulent velocity is replaced by cross-sectional mean velocity. The value of the coefficient is found to stay constant at a particular hydrofoil configuration while it varied over a narrow range of 0.52–0.60 for different hydrofoil angles of attack. This suggests that it is an appropriate coefficient for flow over a ventilated hydrofoil and possibly other flow situations. These results can be used by investigators to test and verify their CFD model against known bubble size distributions and gas transfer in a water tunnel flow that has important similarities to an auto-venting hydroturbine.
Background
Initial reports of the FUNC score suggest that it may accurately identify those patients suffering from intracerebral hemorrhage (ICH) with an ultra low chance of functional neurologic ...recovery. This study’s aim is to validate the FUNC score and determine if it accurately identifies the cohort of patients with an ultra low chance of survival with good neurologic recovery.
Methods
Retrospective review of 501 consecutive primary ICH patients admitted from the Emergency Department to a large healthcare system. Performance of the FUNC, ICH-GS, and oICH scores was determined by calculating areas under the receiver-operator-characteristic curves. Patients with a predicted 100 % chance of poor neurologic outcome (PNO) (FUNC
<
4 and ICH-GS
>
10) scores were evaluated to determine if DNR impacted 90 day survival or rate of survival with a Glasgow Outcome Score of
<
3.
Results
In 366 cases of primary ICH who presented during the study period, 222(61 %) survived to discharge. Both the FUNC (AUC: 0.873) and ICH-GS (AUC: 0.888) outperformed the oICH (AUC: 0.743) in predicting 90-day mortality (
p
= <0.001). Of 68 patients with a FUNC score
<
4, 67 (98.5 %) had PNO at discharge. The presence of DNR was not associated with a significant difference in the rate of PNO at discharge (40/40 = 100 % vs. 27/28 = 96.4 %
p
= 0.42) or 90-day mortality (40/40 = 100 % vs. 21/28 = 75 %,
p
= 0.06).
Conclusion
The FUNC and ICH-GS appear superior to the oICH in predicting outcome in patients with primary ICH. In addition, the FUNC score appears to accurately identify patients with low chance of functional neurologic recovery at discharge.
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