Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure

Objective: Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. Methods: Retrospective analysis of patient records at the Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients [median (25th-75th percentile)] [age 65 (56-72) years; 79% males; LVEF 34 (31-37) %] were included. Patients underwent a symptomlimited, maximal CPET on a treadmill. During a median follow up of 8.6 ± 2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable's predictive strength. Model coefficients were converted to a risk score. Results: Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell’s C-statistic, but the optimal combination of EOV + VE/VCO2 slope + OUES + VEqCO2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the Heart Failure Survival Score (AUC=0.70;

Nutritional physiology of life-history trade-offs: How food protein–carbohydrate content influences life-history traits in the wing-polymorphic cricket \u3ci\u3eGryllus firmus\u3c/i\u3e

Although life-history trade-offs result from the differential acquisition and allocation of nutritional resources to competing physiological functions, many aspects of this topic remain poorly understood. Wing-polymorphic insects, which possess alternative morphs that trade off allocation to flight capability versus early reproduction, provide a good model system for exploring this topic. In this study, we used the wing-polymorphic cricket Gryllus firmus to test how expression of the flight capability versus reproduction trade-off was modified across a heterogeneous protein–carbohydrate nutritional landscape. Newly molted adult female long- and short-winged crickets were given one of 13 diets with different concentrations and ratios of protein and digestible carbohydrate; for each cricket, we measured consumption patterns, growth and allocation to reproduction (ovary mass) versus flight muscle maintenance (flight muscle mass and somatic lipid stores). Feeding responses in both morphs were influenced more by total macronutrient concentration than by protein–carbohydrate ratio, except at high-macronutrient concentration, where protein– carbohydrate balance was important. Mass gain tended to be greatest on protein-biased diets for both morphs, but was consistently lower across all diets for long-winged females. When long-winged females were fed high-carbohydrate foods, they accumulated greater somatic lipid stores; on high-protein foods, they accumulated greater somatic protein stores. Food protein–carbohydrate content also affected short-winged females (selected for early reproductive onset), which showed dramatic increases in ovary size, including ovarian stores of lipid and protein, on protein-biased foods. This is the first study to show how the concentration and ratio of dietary protein and carbohydrate affects consumption and allocation to key physiological features associated with the reproduction–dispersal life-history trade-off

PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex

The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4(+) T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation

Structural Insight into KCNQ (Kv7) Channel Assembly and Channelopathy

SummaryKv7.x (KCNQ) voltage-gated potassium channels form the cardiac and auditory IKs current and the neuronal M-current. The five Kv7 subtypes have distinct assembly preferences encoded by a C-terminal cytoplasmic assembly domain, the A-domain Tail. Here, we present the high-resolution structure of the Kv7.4 A-domain Tail together with biochemical experiments that show that the domain is a self-assembling, parallel, four-stranded coiled coil. Structural analysis and biochemical studies indicate conservation of the coiled coil in all Kv7 subtypes and that a limited set of interactions encode assembly specificity determinants. Kv7 mutations have prominent roles in arrhythmias, deafness, and epilepsy. The structure together with biochemical data indicate that A-domain Tail arrhythmia mutations cluster on the solvent-accessible surface of the subunit interface at a likely site of action for modulatory proteins. Together, the data provide a framework for understanding Kv7 assembly specificity and the molecular basis of a distinct set of Kv7 channelopathies

The Effects of Previous Childhood Trauma on Dissociative Symptoms in Adult Survivors of Recent Trauma

This presentation aims to examine the effects of previous childhood abuse (e.g. physical or sexual abuse) on the dissociative symptoms experienced by adult survivors of recent traumas (e.g. physical or sexual assaults). The aims of this study are to examine the self-reports of the participants regarding childhood experiences of trauma, their current dissociative experiences and the severity of those experiences, and physiological markers such as skin conductance and heart rate that may play a significant role in their experiences of dissociation. The hypothesis of this research is that previous childhood abuse will significantly increase the likelihood and severity of the adult survivor reporting dissociative experiences, and that their physiological data will indicate a significant difference between individuals who experienced childhood trauma and those who did not

A predominance of R5-like HIV genotypes in vaginal secretions is associated with elevated plasma HIV-1 RNA levels and the absence of anti-retroviral therapy

HIV expressed in genital secretions provides the inoculum from which transmitting variants are selected, both in sexual transmission and mother-to-infant transmission during partuition. Characterization of HIV levels and genotypes found in vaginal secretions and the impact of anti-retroviral therapy (ART) on this virus can provide valuable insight for the prevention of HIV transmission. Vaginal HIV was evaluated in a cohort of 43 women attending a New Orleans HIV outpatient clinic. Predominant vaginal genotypes were characterized as R5- or X4-like by heteroduplex tracking analyses of the envelope V3 region. Most women (67.4%) shed R5-like genotypes in vaginal secretions which was associated with elevated plasma HIV levels (≥ 10,000 copies HIV-RNA/mL) and absence of ART. Because R5-like genotypes are more frequently associated with transmission, these observations suggest that the majority of women shedding HIV in genital secretions present a transmission risk. The levels of vaginal virus were similar between both groups, but shedding of X4-like genotypes was associated with lower plasma viral loads and the use of ART, suggesting that ART use may impact the genotypes of virus found in the female genital compartment

Autonomous docking ground demonstration

The Autonomous Docking Ground Demonstration is an evaluation of the laser sensor system to support the docking phase (12 ft to contact) when operated in conjunction with the guidance, navigation, and control (GN&C) software. The docking mechanism being used was developed for the Apollo/Soyuz Test Program. This demonstration will be conducted using the 6-DOF Dynamic Test System (DTS). The DTS simulates the Space Station Freedom as the stationary or target vehicle and the Orbiter as the active or chase vehicle. For this demonstration, the laser sensor will be mounted on the target vehicle and the retroflectors will be on the chase vehicle. This arrangement was chosen to prevent potential damage to the laser. The laser sensor system, GN&C, and 6-DOF DTS will be operated closed-loop. Initial conditions to simulate vehicle misalignments, translational and rotational, will be introduced within the constraints of the systems involved

Autonomous docking ground demonstration (category 3)

The NASA Johnson Space Center (JSC) is involved in the development of an autonomous docking ground demonstration. The demonstration combines the technologies, expertise and facilities of the JSC Tracking and Communications Division (EE), Structures and Mechanics Division (ES), and the Navigation, Guidance and Control Division (EG) and their supporting contractors. The autonomous docking ground demonstration is an evaluation of the capabilities of the laser sensor system to support the docking phase (12ft to contact) when operated in conjunction with the Guidance, Navigation and Control Software. The docking mechanism being used was developed for the Apollo Soyuz Test Program. This demonstration will be conducted using the Six-Degrees of Freedom (6-DOF) Dynamic Test System (DTS). The DTS environment simulates the Space Station Freedom as the stationary or target vehicle and the Orbiter as the active or chase vehicle. For this demonstration the laser sensor will be mounted on the target vehicle and the retroreflectors on the chase vehicle. This arrangement was used to prevent potential damage to the laser. The sensor system. GN&C and 6-DOF DTS will be operated closed-loop. Initial condition to simulate vehicle misalignments, translational and rotational, will be introduced within the constraints of the systems involved. Detailed description of each of the demonstration components (e.g., Sensor System, GN&C, 6-DOF DTS and supporting computer configuration) including their capabilities and limitations will be discussed. A demonstration architecture drawing and photographs of the test configuration will be presented

Nutritional physiology of life-history trade-offs: how food protein-carbohydrate content influences life-history traits in the wing-polymorphic cricket Gryllus firmus

AbstractAlthough life-history trade-offs result from the differential acquisition and allocation of nutritional resources to competing physiological functions, many aspects of this topic remain poorly understood. Wing-polymorphic insects, which possess alternate morphs that trade off allocation to flight capability versus early reproduction, provide a good model system for exploring this topic. In this study we used the wing-polymorphic cricket Gryllus firmus to test how expression of the flight capability vs. reproduction trade-off was modified across a heterogeneous protein-carbohydrate nutritional landscape. Newly molted adult female crickets were given one of 13 diets with different concentrations and ratios of protein and digestible carbohydrate; for each cricket we measured consumption patterns, growth, and allocation to reproduction (ovary mass) vs. flight muscle maintenance (flight muscle mass and somatic lipid stores). Feeding responses in both morphs were influenced more by total macronutrient concentration than protein-carbohydrate ratio, except at high macronutrient concentration, where protein-carbohydrate balance was important. Mass gain tended to be greatest on protein-biased diets for both morphs, but was consistently lower across all diets for long-winged females. When long-winged females were fed high-carbohydrate foods they accumulated greater somatic lipid stores; on high-protein foods they accumulated greater somatic protein stores. Food protein-carbohydrate content also affected short-winged females (selected for early reproductive onset), which showed dramatic increases in ovary size, including ovarian stores of lipids and protein, on protein-biased foods. This is the first study to show how the concentration and ratio of dietary protein and carbohydrate affects consumption and allocation to key physiological features associated with the reproduction-dispersal life-history trade-off.</jats:p