Small Amounts of α-Myosin Heavy Chain Isoform Expression Significantly Increase Power Output of Rat Cardiac Myocyte Fragments

The publisher's version of this article may be found at http://circres.ahajournals.org/cgi/content/abstract/90/11/1150?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1049671889562_931&stored_search=&FIRSTINDEX=0&volume=90&firstpage=1150&search_url=http%3A%2F%2Fcircres.ahajournals.org%2Fcgi%2Fsearch&journalMyocardial performance is likely affected by the relative expression of the two myosin heavy chain (MyHC) isoforms, namely {alpha}-MyHC and ß-MyHC. The relative expression of each isoform is regulated developmentally and in pathophysiological states. Many pathophysiological states are associated with small shifts in the relative expression of each MyHC isoform, yet the functional consequence of these shifts remains unclear. The purpose of this study was to determine the functional effect of a small shift in the relative expression of {alpha}-MyHC. To this end, power output was measured in rat cardiac myocyte fragments that expressed {approx}12% {alpha}-MyHC and in myocyte fragments that expressed {approx}0% {alpha}-MyHC, as determined in the same cells by SDS-PAGE analysis after mechanical experiments. Myocyte fragments expressing {approx}12% {alpha}-MyHC developed {approx}52% greater peak normalized power output than myocyte fragments expressing {approx}0% {alpha}-MyHC. These results indicate that small amounts of {alpha}-MyHC expression significantly augment myocyte power output.This work was supported by National Heart, Lung, and Blood Institute Grant HL-57852 (K.S.M.) and a predoctoral fellowship granted by the Heartland Affiliate of the American Heart Association (T.J.H.)

Power Output Is Increased After Phosphorylation of Myofibrillar Proteins in Rat Skinned Cardiac Myocytes

This work was supported by American Heart Association Beginning Grant-in-Aid 9914291 and NIH Grant HL57852.The publisher's version may be found at http://circres.ahajournals.org/cgi/content/full/89/12/1184ß-Adrenergic stimulation increases stroke volume in mammalian hearts as a result of protein kinase A (PKA)-induced phosphorylation of several myocyte proteins. This study investigated whether PKA-induced phosphorylation of myofibrillar proteins directly affects myocyte contractility. To test this possibility, we compared isometric force, loaded shortening velocity, and power output in skinned rat cardiac myocytes before and after treatment with the catalytic subunit of PKA. Consistent with previous studies, PKA increased phosphorylation levels of myosin binding protein C and troponin I, and reduced Ca2+ sensitivity of force. PKA also significantly increased both maximal force (25.4±8.3 versus 31.6±11.3 µN [P<0.001, n=12]) and peak absolute power output (2.48±1.33 versus 3.38±1.52 µW/mg [P<0.05, n=5]) during maximal Ca2+ activations. Furthermore, PKA elevated power output at nearly all loads even after normalizing for the increase in force. After PKA treatment, peak normalized power output increased {approx}20% during maximal Ca2+ activations (n=5) and {approx}33% during half-maximal Ca2+ activations (n=9). These results indicate that PKA-induced phosphorylation of myofibrillar proteins increases the power output-generating capacity of skinned cardiac myocytes, in part, by speeding the step(s) in the crossbridge cycle that limit loaded shortening rates, and these changes likely contribute to greater contractility in hearts after ß-adrenergic stimulation

Developing Systems for Cyber Situational Awareness

In both military and commercial settings, the awareness of Cyber attacks and the effect of those attacks on the mission space of an organization has become a targeted information goal for leaders and commanders at all levels. We present in this paper a defining framework to understand situational awareness (SA)—especially as it pertains to the Cyber domain—and propose a methodology for populating the cognitive domain model for this realm based on adversarial knowledge involved with Cyber attacks. We conclude with considerations for developing Cyber SA systems of the future

Increased brain activation during working memory processing after pediatric mild traumatic brain injury (mTBI).

Purpose: The neural substrate of post-concussive symptoms following the initial injury period after mild traumatic brain injury (mTBI) in pediatric populations remains poorly elucidated. This study examined neuropsychological, behavioral, and brain functioning in adolescents post-mTBI to assess whether persistent differences were detectable up to a year post-injury. Methods: Nineteen adolescents (mean age 14.7 years) who experienced mTBI 3–12 months previously (mean 7.5 months) and 19 matched healthy controls (mean age 14.0 years) completed neuropsychological testing and an fMRI auditory-verbal N-back working memory task. Parents completed behavioral ratings. Results: No between-group differences were found for cognition, behavior, or N-back task performance, though the expected decreased accuracy and increased reaction time as task difficulty increased were apparent. However, the mTBI group showed significantly greater brain activation than controls during the most difficult working memory task condition. Conclusion: Greater working memory task-related activation was found in adolescents up to one year post-mTBI relative to controls, potentially indicating compensatory activation to support normal task performance. Differences in brain activation in the mTBI group so long after injury may indicate residual alterations in brain function much later than would be expected based on the typical pattern of natural recovery, which could have important clinical implications

Fluvoxamine for outpatient management of COVID-19 to prevent hospitalization: A systematic review and meta-analysis

Importance: Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization. Objective: To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19. Data Sources: World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Study Selection: Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included. Data Extraction and Synthesis: The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool and a bayesian random effects meta-analysis with different estimates of prior probability was conducted: a weakly neutral prior (50% chance of efficacy with 95% CI for risk ratio [RR] between 0.5 and 2.0) and a moderately optimistic prior (85% chance of efficacy). A frequentist random-effects meta-analysis was conducted as a senstivity analysis, and the results were contextualized by estimating the probability of any association (RR ≤ 1) and moderate association (RR ≤ 0.9) with reduced hospitalization. Main Outcomes and Measures: All-cause hospitalization. Results: This systematic review and meta-analysis of 3 randomized clinical trials and included 2196 participants. The RRs for hospitalization were 0.78 (95% CI, 0.58-1.08) for the bayesian weakly neutral prior, 0.73 (95% CI, 0.53-1.01) for the bayesian moderately optimistic prior, and 0.75 (95% CI, 0.58-0.97) for the frequentist analysis. Depending on the scenario, the probability of any association with reduced hospitalization ranged from 94.1% to 98.6%, and the probability of moderate association ranged from 81.6% to 91.8%. Conclusions and Relevance: In this systematic review and meta-analysis of data from 3 trials, under a variety of assumptions, fluvoxamine showed a high probability of being associated with reduced hospitalization in outpatients with COVID-19. Ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates. Meanwhile, fluvoxamine could be recommended as a management option, particularly in resource-limited settings or for individuals without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals

Transdermal blood sampling for C-peptide is a minimally invasive, reliable alternative to venous sampling in children and adults with type 1 diabetes

Objective: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limit their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. Research Design and methods: Ninety-one individuals (71 type 1 diabetes, 20 controls; type 1 diabetes: aged median 14.8 years[interquartile range 9.1-17.1]; diabetes duration 4.0 years[1.5-7.7]; controls 42.2 years[38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Type 1 diabetes participants also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200pmol/L) was compared along with agreement in levels using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies using established thresholds. Acceptability was assessed by age-appropriate questionnaire.Results: Transdermal sampling took a mean of 2.35minutes (SD 1.49). Median sample volume was 50 µl(IQR 40-50) with 3/91(3.3%) failures, and 13/88(14.7%) <35 µL). TCB C-peptide showed good agreement to venous plasma (mean venous ln(C-peptide) – TCB ln(C-peptide) = 0.008, 95% CI(-0.23, 0.29), with 100%(36/36) sensitivity/100%(50/50) specificity to detect venous C-peptide ≥ 200pmol/L. Where venous serum in multiple autoantibody positive TCB plasma agreed in 22/32 (sensitivity 69%), comparative specificity was 35/36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs 7%; 30% undecided). Conclusions: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling, TCB sampling for islet autoantibodies needs further assessment

Transdermal Blood Sampling for C-peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes

OBJECTIVE:C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative.RESEARCH DESIGN AND METHODS:Ninety-one individuals (71 with type 1 diabetes, 20 controls; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1–17.1], diabetes duration 4.0 years [1.5–7.7]; controls: 42.2 years [38.0–52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire.RESULTS:Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40–50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) &lt;35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] – TCB ln[C-peptide] = 0.008, 95% CI [−0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided).CONCLUSIONS:Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment

Decreased cerebral blood flow in chronic pediatric mild TBI: an MRI perfusion study

We evaluated cerebral blood flow (CBF) in chronic pediatric mild traumatic brain injury (mTBI) using arterial spin labeling (ASL) magnetic resonance imaging perfusion. mTBI patients showed lower CBF than controls in bilateral frontotemporal regions, with no between-group cognitive differences. Findings suggest ASL may be useful to assess functional abnormalities in pediatric mTBI