Associations between physical activity and sedentary time on components of metabolic syndrome among adults with HIV

Recent data show that people living with HIV/AIDS (PLWHA) are at a greater risk of cardiovascular disease (CVD), which could possibly be explained by an increased prevalence of metabolic syndrome (MetSyn) due to the known toxicities associated with antiretroviral therapy (ART). The purpose of this study is to examine the relationships between physical activity (PA) and components of MetSyn in a sample of PLWHA taking ART. A total of 31 males and 32 females living with HIV and currently taking ART were enrolled in a home-based PA intervention aimed to reduce risk factors for CVD. Clinical assessments included measures of resting blood pressure (BP), waist circumference, height, weight, PA levels via accelerometer, and a fasted blood draw. Components of MetSyn were divided into three clusters (1 = 0–1; 2 = 2; 3 = 3 or more). A one-way analysis of variance was used to determine differences between clusters. Multiple linear regressions were used to identify significant associations between moderate intensity PA (MPA) and sedentary time among components of MetSyn. MPA was significantly lower across MetSyn clusters (p < 0.001), whereas sedentary time was significantly higher (p = 0.01). A multiple linear regression showed MPA to be a significant predictor of waist circumference after controlling for age, race, gender, and sedentary time. Routine PA can be beneficial in helping PLWHA reduce waist circumference ultimately leading to metabolic improvements. This in turn would help PLWHA self-manage known components of MetSyn, thus reducing their risk of CVD and mortality.     

A comprehensive framework for evaluating the environmental health and safety implications of engineered nanomaterials

Engineered nanomaterials (ENM) are a growing aspect of the global economy, and their safe and sustainable development, use, and eventual disposal requires the capability to forecast and avoid potential problems. This review provides a framework to evaluate the health and safety implications of ENM releases into the environment, including purposeful releases such as for antimicrobial sprays or nano-enabled pesticides, and inadvertent releases as a consequence of other intended applications. Considerations encompass product life cycles, environmental media, exposed populations, and possible adverse outcomes. This framework is presented as a series of compartmental flow diagrams that serve as a basis to help derive future quantitative predictive models, guide research, and support development of tools for making risk-based decisions. After use, ENM are not expected to remain in their original form due to reactivity and/or propensity for hetero-agglomeration in environmental media. Therefore, emphasis is placed on characterizing ENM as they occur in environmental or biological matrices. In addition, predicting the activity of ENM in the environment is difficult due to the multiple dynamic interactions between the physical/chemical aspects of ENM and similarly complex environmental conditions. Others have proposed the use of simple predictive functional assays as an intermediate step to address the challenge of using physical/chemical properties to predict environmental fate and behavior of ENM. The nodes and interactions of the framework presented here reflect phase transitions that could be targets for development of such assays to estimate kinetic reaction rates and simplify model predictions. Application, refinement, and demonstration of this framework, along with an associated knowledgebase that includes targeted functional assay data, will allow better de novo predictions of potential exposures and adverse outcomes.     

Members of the synaptobrevin/vesicle-associated membrane protein (VAMP) family in Drosophila are functionally interchangeable in vivo for neurotransmitter release and cell viability

Synaptobrevins or VAMPs are vesicle-associated membrane proteins, often called v-SNARES, that are important for vesicle transport and fusion at the plasma membrane. Drosophila has two characterized members of this gene family: synaptobrevin (syb) and neuronal synaptobrevin (n-syb). Mutant phenotypes and gene-expression patterns indicate that n-Syb is exclusively neuronal and required only for synaptic vesicle secretion, whereas Syb is ubiquitous and, as shown here, essential for cell viability. When the eye precursor cells were made homozygous for syb(-), the eye failed to develop. In contrast, n-syb(-) eye clones developed appropriately but failed to activate downstream neurons. To determine whether the two proteins are structurally specialized to accomplish these distinct in vivo functions, we have driven the expression of each gene in the absence of the other to look for phenotypic rescue. We find that expression of n-syb during eye development can rescue the cell lethality of the syb mutations, as can rat VAMP2 and cellubrevin. Expression of syb can restore synaptic transmission to n-syb mutants as assayed both by electroretinogram and recordings of excitatory junctional currents at the neuromuscular junction. Therefore, we find that Syb, which usually is not involved in synaptic function, can mediate Ca(2+)-triggered synaptic activity and that no particular specialization of the v-SNARE is required to differentiate synaptic exocytosis from other forms.     

Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure

BACKGROUND: This study describes the process and outcomes of continuous outpatient support with inotropes (COSI) in patients with Stage D heart failure (HF). Although Stage D HF has recently been defined as end-stage disease requiring special interventions for survival such as COSI or ventricular assist devices, concern has been raised regarding the safety, efficacy, mortality outcomes, and ethics of COSI. METHODS AND RESULTS: Inotrope dependence was defined as worsening of the patient's clinical status with attempted inotrope withdrawal such that the patient was deemed unlikely to survive to permit hospital discharge. A care process for COSI was designed; baseline and outcome variables were evaluated. COSI was administered to 36 inotrope-dependent patients (age 55.4 +/- 9.5 years, 24 males). Baseline characteristics (mean +/- SD) were consistent with Stage D HF: left ventricular ejection fraction 19.9 +/- 8.5, left ventricular end-diastolic dimension (LVEDD) 70 +/- 10 mm, systolic blood pressure 97.4 +/- 13.4 mm Hg, serum creatinine 1.5 +/- 0.6, serum sodium 131.7 +/- 5.3; 69 HF hospitalizations (mean 1.9 +/- 1.8) 6 months before COSI initiation. Symptomatic hypotension, increasing dyspnea, renal dysfunction, and hypoperfusion most commonly prevented inotrope withdrawal. Despite Stage D HF, patients were discharged with COSI ambulatory, oriented, and pain free. Rehospitalizations were 46; 6 subjects accounted for 24 hospitalizations; 23 had 0 or 1 rehospitalization. Median survival was 3.4 months (range 0.2-26.3 months); and 3-, 6-, and 12-month Kaplan Meier survival was 51%, 26%, and 6%, respectively. The majority of patients died at home and chose to not undergo resuscitation attempts. CONCLUSION: COSI may be an acceptable treatment option for Stage D HF.     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Green synthesis of new pyrrolidine-fused spirooxindoles via three-component domino reaction in EtOH/H2O

An efficient, green and sustainable approach for the synthesis of novel polycyclic pyrrolidine-fused spirooxindole compounds was developed. The synthesis included a one-pot, three-component, domino reaction of (E)-3-(2-nitrovinyl)-indoles, isatins and chiral polycyclic α-amino acids under catalyst-free conditions at room temperature in EtOH–H₂O. The salient features of this methodology are eco-friendliness, high yields and the ease of obtaining target compounds without the involvement of toxic solvents and column chromatography. These novel polycyclic pyrrolidine-fused spirooxindoles provide a collection of structurally diverse compounds that show promise for future bioassays and medical treatments.

An efficient, green and sustainable approach was developed for the synthesis of novel polycyclic pyrrolidine-fused spirooxindole compounds.     

The many weak instruments problem and Mendelian randomization

Instrumental variable estimates of causal effects can be biased when using many instruments that are only weakly associated with the exposure. We describe several techniques to reduce this bias and estimate corrected standard errors. We present our findings using a simulation study and an empirical application. For the latter, we estimate the effect of height on lung function, using genetic variants as instruments for height. Our simulation study demonstrates that, using many weak individual variants, two‐stage least squares (2SLS) is biased, whereas the limited information maximum likelihood (LIML) and the continuously updating estimator (CUE) are unbiased and have accurate rejection frequencies when standard errors are corrected for the presence of many weak instruments. Our illustrative empirical example uses data on 3631 children from England. We used 180 genetic variants as instruments and compared conventional ordinary least squares estimates with results for the 2SLS, LIML, and CUE instrumental variable estimators using the individual height variants. We further compare these with instrumental variable estimates using an unweighted or weighted allele score as single instruments. In conclusion, the allele scores and CUE gave consistent estimates of the causal effect. In our empirical example, estimates using the allele score were more efficient. CUE with corrected standard errors, however, provides a useful additional statistical tool in applications with many weak instruments. The CUE may be preferred over an allele score if the population weights for the allele score are unknown or when the causal effects of multiple risk factors are estimated jointly. © 2014 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.