Induced Hypothermia During Resuscitation from Hemorrhagic Shock Attenuates Microvascular Inflammation in the Rat Mesenteric Microcirculation

Introduction: Hemorrhagic shock is a major cause of morbidity and mortality in trauma patients. Microvascular inflammation occurs during resuscitation following hemorrhagic shock, and is a major cause of multiple organ dysfunction and late mortality. Hypothermia has traditionally been associated with poor outcomes in trauma patients, but pre-clinical evidence suggests that hypothermia may have some benefit in selected patients. Our objective was to evaluate the effect of induced hypothermia on microvascular inflammation during resuscitation from hemorrhagic shock. Methods: Intravital microscopy was used to visualize mesenteric venules of anesthetized rats in real time to evaluate leukocyte adherence per 100 μm venule length and mast cell degranulation. An optical Doppler velocimeter was used to measure centerline red blood cell velocity in order to calculate shear rate. Measurements were obtained at a baseline control period in all animals. Animals then were divided into normotensive or hypotensive groups. Animals in the shock group underwent mean arterial blood pressure reduction to 40-45 mmHg for 1 hour via blood withdrawal. During the first two hours of resuscitation, body temperature of the hypothermic group was maintained at 32-34°C, while the normothermic group was maintained between 36-38°C. The hypothermic group was then rewarmed for the final two hours of resuscitation. Results: Leukocyte adherence was significantly lower after 2 hours in hypothermic resuscitation (n=5) compared with normothermic resuscitation (n=6): (3.4±0.8 vs 8.3±1.3, p=0.011). Upon rewarming, leukocyte adherence was not significantly different between hypothermic and normothermic shock groups: (5.4±1.1 vs 9.5±1.6, p=0.081). No significant elevation was observed in normotensive normothermic (n=3) or hypothermic animals (n=4). Shear rate decreased significantly from the control period after normothermic resuscitation (p<0.05), with no other groups having significant changes. Mast cell degranulation was significantly decreased in the hypothermic (1.02±0.04) vs normothermic (1.22±0.07) shock groups (p=0.038) after the experiment compared to the control measures; no significant degranulation occurred in normotensive animals. Conclusions: Hypothermia during resuscitation attenuates microvascular inflammation in rat mesentery following hemorrhagic shock. Further study is needed to determine the underlying mechanisms of hypothermia in reducing microvascular inflammation during resuscitation, defining optimal degree of hypothermia, and the timing of this innovative therapy

Diet and Exercise Interventions Following Coronary Artery Bypass Graft Surgery: A Review and Call to Action

Coronary artery bypass graft (CABG) surgery has been used for the treatment of coronary artery disease (CAD) for approximately 50 years, and has been performed on millions of people globally. However, little is known about the impact of diet and exercise on long-term outcomes of patients who have undergone CABG surgery. Although clinical practice guidelines on the management of this patient population have been available for approximately 2 decades, evidence regarding secondary prevention behavioral interventions, lifestyle modifications and self-management to slow the progressive decline of CAD, reduce cardiac hospitalizations, and prevent reoperation remains virtually absent from the literature. Diet and exercise are modifiable factors that affect secondary CAD risk. This article reviews the relevant current literature on long-term diet and exercise outcomes in patients who underwent CABG. The limited available literature shows the positive impacts of exercise on psychosocial well-being and physical fitness. Current evidence indicates diet and exercise interventions are effective in the short-term, but effects fade over time. Potential age and sex differences were found across the reviewed studies; however, further research is needed with more rigorous designs to replicate and confirm findings, and to define optimal management regimens and cost-effective prevention strategies

C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation

International audienceVoltage-gated Na(+) (NaV) channels are key regulators of myocardial excitability, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in NaV1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of NaV1.5 subunits associated with these arrhythmogenic disorders and the associated channel regulatory defects remain unknown. Here, we undertook phosphoproteomic analyses to identify and quantify in situ the phosphorylation sites in the NaV1.5 proteins purified from adult WT and failing CaMKIIδc-overexpressing (CaMKIIδc-Tg) mouse ventricles. Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. We then tested the hypothesis that phosphorylation at these two sites impairs fibroblast growth factor 13 (FGF13)-dependent regulation of NaV1.5 channel inactivation. Whole-cell voltage-clamp analyses in HEK293 cells demonstrated that FGF13 increases NaV1.5 channel availability and decreases late Na(+) current, two effects that were abrogated with NaV1.5 mutants mimicking phosphorylation at both sites. Additional co-immunoprecipitation experiments revealed that FGF13 potentiates the binding of calmodulin to NaV1.5 and that phosphomimetic mutations at both sites decrease the interaction of FGF13 and, consequently, of calmodulin with NaV1.5. Together, we have identified two novel native phosphorylation sites in the C terminus of NaV1.5 that impair FGF13-dependent regulation of channel inactivation and may contribute to CaMKIIδc-dependent arrhythmogenic disorders in failing hearts

A Comprehensive Clinical Genetics Approach to Critical Congenital Heart Disease in Infancy

Objective: To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. Study design: A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1 month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. Results: Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P = .0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P = .003) and brain (P = .0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P = .0061), as was presence of dysmorphic features (P = .0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. Conclusions: The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations

Goal consensus in selected community colleges

The purpose of this study was to identify the priority goal rankings at four selected community colleges in the North Central Accreditation Region by 42 administrators, 185 full-time faculty, and 548 full-time students. The colleges were similar in governance pattern, publically financed, comprehensive in program, similar in student enrollment, and co-educational with similar perceived mission;Research questions included (1) What is the rank order of perceived (is) and preferred (should be) goals of all of the participants, of administrators, of full-time faculty, of full-time students, and of each college in the study? (2) Do significant differences exist between the perceived (is) and preferred (should be) perceptions of each goal by each group? (3) Do significant differences exist in the rank order of perceived (is) goals and preferred (should be) goals?;The Community College Goals Inventory, the survey instrument, required that respondents utilize a five-point rating scale, (1) of no importance, or not applicable, (2) of low importance, (3) of medium importance, (4) of high importance, and recorded two judgments: how important the goal "is" presently at the campus and how important the goal "should be.";Data analysis yielded goals as summaries rank ordered by "is" and "should be" means for all administrators, faculty and students as well as by each college. Paired t-tests compared the "is" and "should be" responses for each goal for administrators, faculty, students, and for each college. Kendall's W analysis of rank-difference correlation of goals of administrators, faculty, and students and colleges was reported. An SPSSX program for statistical analysis was used;In the paired t-test, statistical differences between perceived and preferred responses exist at the .01 level in every goal area at each college. Goal analysis of colleges and groups using Kendall's W shows close agreement on all goal rankings;The findings of this study are similar to those of the Cross study using the CCGI.</p

membrane and acrosome integrity in freeze-thawed Merino ram sperm

The aim of this study was to determine the effects of curcumin, ellagic acid and methionine on sperm parameters following the freeze-thawing of Merino ram semen. Ejaculates were collected via an artificial vagina from four Merino rams, evaluated microscopically and pooled at 37 degrees C. The pooled semen samples were diluted in a Tris-based extender and separated into groups containing curcumin (1, 2, 4mM), ellagic acid (1, 2, 4mM), methionine (1, 2, 4mM) and no antioxidant (control). The diluted semen was cooled to 5 degrees C slowly and equilibrated for 3 h. After the equilibration, the samples were frozen in liquid nitrogen vapour, and plunged into liquid nitrogen (-196 degrees C) for storage. Frozen straws were thawed at 37 degrees C for 30 s in a water bath for microscopic sperm evaluation, individually. All antioxidants led to a higher percentage of sperm motility in comparison to the control group. The freezing extender supplemented with methionine (1mM), curcumin (1 and 2mM) and ellagic acid (1 and 2mM) led to higher percentage of sperm plasma membrane integrity when compared to other groups (P < 0.05). Antioxidant supplementation also resulted in a higher percentage of sperm acrosome integrity in comparison to the control. Methionine, curcumin and ellagic acid (1mM: 27.7 +/- 2.4, 28.0 +/- 2.1 and 26.8 +/- 2.0) groups provided higher protection in terms of sperm mitochondrial activity when compared to other groups (P < 0.05). The findings of this study show that varying concentrations of curcumin, methionine and ellagic acid have markedly different effects on the spermatological variables under study