Characteristics of Female Sex Workers in Southern India Willing and Unwilling to Participate in a Placebo Gel Trial

Respondent-driven sampling was used to recruit female sex workers (FSWs) for a community survey conducted in southern India. After survey completion, participants were given a brochure describing a clinical trial that entailed daily use of a placebo vaginal gel for four months. This study assessed predictors of screening among survey respondents, predictors of enrollment among those eligible for the trial, and predictors of visit attendance and retention among those enrolled. FSWs who reported having symptoms of sexually transmitted infections (STI), engaging in sex work in the past month, and living in a subdistrict easily accessible by public transportation with a high concentration of FSWs, were more likely to screen. FSWs who had never been tested for HIV were more likely to enroll. This analysis suggests that the primary reason FSWs participated in the trial was a desire for health care—not other factors hypothesized to be important, e.g., HIV risk perception and poverty status.     

Preventing contrast-induced nephropathy: problems, challenges and future directions

Contrast-induced nephropathy is an injury to the kidney occurring as a result of exposure to intravascular contrast media. It results in both short- and long-term adverse events including mortality. Since treatment of the injury after it has occurred is ineffective, efforts to prevent the injury are the focus of investigators and clinicians alike. In this commentary, the pathogenesis and clinical relevance of contrast-induced nephropathy are reviewed. Prophylactic strategies are discussed with a focus on the use of meta-analysis of small single-center trials.     

Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. IP6Ks convert IP6 to pyrophosphates such as diphosphoinositol pentakisphosphate (IP7) and bis-diphosphoinositol tetrakisphosphate (IP8). IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. The inositol hexakisphosphate kinase 2 (IP6K2) controls cellular apoptosis. To explore roles for IP6K2 in brain function, we elucidated its protein interactome in mouse brain revealing a robust association of IP6K2 with creatine kinase-B (CK-B), a key enzyme in energy homeostasis. Cerebella of IP6K2-deleted mice (IP6K2-knockout [KO]) produced less phosphocreatine and ATP and generated higher levels of reactive oxygen species and protein oxidative damage. In IP6K2-KO mice, mitochondrial dysfunction was associated with impaired expression of the cytochrome-c1 subunit of complex III of the electron transport chain. We reversed some of these effects by combined treatment with N-acetylcysteine and phosphocreatine. These findings establish a role for IP6K2–CK-B interaction in energy homeostasis associated with neuroprotection.

Inositol pyrophosphates are versatile messenger molecules that mediate a variety of cellular functions, including cell growth, apoptosis, endocytosis, and cell differentiation. The most extensively studied inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), displays a 5′-diphosphate (1, 2). IP7 is generated in mammals by a family of inositol hexakisphosphate kinases (IP6Ks) (3, 4). IP6Ks exists in three isoforms: IP6K1, IP6K2, and IP6K3. Inositol hexakisphosphate kinase-2 (IP6K2) sensitizes cells to apoptosis (5, 6). Mice with targeted deletion of IP6K2 display an increased incidence of aero-digestive tract carcinoma (7). Cell survival associated with heat shock protein 90 also involves IP6K2 (8, 9).We previously reported a major role for IP6K2 in the disposition of cerebellar granule cells as well as Purkinje cell morphology and motor coordination. The influence of IP6K2 upon cerebellar disposition involved protein 4.1N, both of which were highly expressed in cerebellar granule cells (10).To further assess the functions of IP6K2 in the brain, we explored its binding partners using coimmunoprecipitation and tandem liquid chromatography mass spectrometry (LC-MS/MS). Here, we report that IP6K2 robustly interacts with creatine kinase-B (CK-B), which regulates energy homeostasis of cells and exists in two forms, brain type (CK-B) and muscle type (CK-M). CK catalyzes the reversible transfer of the phosphate group of phosphocreatine to ADP to yield ATP (11, 12). A functional interplay between mitochondrial and cytosolic isoforms of CK regulates cellular energy homeostasis. Cytosolic CK rephosphorylates locally produced free ADP and increases creatine globally, while the mitochondrial enzyme catalyzes the conversion of creatine to phosphocreatine utilizing mitochondrial ATP (13–15).Here, we show that IP6K2 loss leads to decreased CK-B expression, reduced ATP levels, and diminished mitochondrial activity associated with increased oxidative stress. About 80 to 90% of ATP is generated in the mitochondria by oxidative phosphorylation, and diminished ATP levels are the immediate effect of mitochondrial dysfunction. Loss of IP6K2 and CK-B reflects the suppression of the mitochondrial cytochrome c1 expression, a component of complex III of the mitochondrial electron transport chain. In the present study, we report a physiologic association of CK-B and IP6K2, whose disruption impacts mitochondrial functions.Dendritic morphogenesis was reduced in IP6K2-deficient neurons and was rescued by restoring normal levels of ATP. These observations reveal an essential role of IP6K2 in the energy production of the brain. Our findings indicate that IP6K2 is a key regulator of mitochondrial homeostasis which promotes neuroprotection.     

Catheter ablation of hemodynamically compromising incessant atrioventricular tachycardia.

A 27-year-old woman was admitted to the Georgetown University Hospital with refractory hemodynamically compromising incessant atrioventricular tachycardia. A single left-sided accessory pathway was identified and successfully modified acutely. Endocardial delivery of direct current energy provided an extremely effective therapeutic intervention resulting in termination of atrioventricular tachycardia and restoration of stable hemodynamic status. Although a second ablation procedure was necessary to permanently interrupt accessory pathway conduction, the patient has remained free of symptoms without medications for 13 months.     

The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India

We investigated the safety, tolerability and effectiveness of locally produced generic highly active antiretroviral therapy (HAART) regimens with a chart review conducted at YRG CARE, a tertiary HIV referral centre in India. A total of 333 patients had been on Indian-manufactured generic HAART for at least 3 months. In this cohort, generic HAART was safe, well tolerated and effective at increasing CD4 T-lymphocyte counts in patients with advanced HIV, comparable to the experience with proprietary HAART.     

Three-question set from Michigan Neuropathy Screening Instrument adds independent prognostic information on cardiovascular outcomes: analysis of ALTITUDE trial

Aims/hypothesis

The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes.

Methods

In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set.

Results

In the training set, three questions (‘Are your legs numb?’, ‘Have you ever had an open sore on your foot?’ and ‘Do your legs hurt when you walk?’) were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell’s C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007).

Conclusions/interpretation

We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes.

     

Influence of conduction disturbances on clinical outcome in patients with acute myocardial infarction receiving thrombolysis (results from the ARGAMI-2 study)

Right bundle branch block and complete atrioventricular (AV) block are conduction disorders (CDs) that have been observed in 14% of patients admitted with ST-elevation acute myocardial infarction. CDs carry a poor prognosis, with a threefold increase in the mortality rate, mainly due to cardiogenic shock and recurrent fatal myocardial infarction at 1-year follow-up. According to multivariable analysis, CD was the second strongest predictor of death, after high Killip class. Compared with patients without CD, the 1-year outcome of patients with CD was identically worse, irrespective of whether CD appeared during admission, disappeared, or remained constant. Similar adverse outcomes were seen in patients with complete AV block and right bundle branch block.     

What Do Patients Want?

PURPOSE: Clinicians often make decisions for their patients, despite evidence that suggests that correspondence between patient and clinician decision making is poor. The management of colorectal cancer presents difficult decisions because the impact of treatment on quality of life might overshadow its survival efficacy. This study investigated whether patients are able to trade survival for quality of life as a means to express their preference for treatment options and to compare their preferences with those expressed by clinicians. METHODS: Patients undergoing curative surgery for colorectal cancer were interviewed postoperatively to elicit their preferences in four hypothetical treatment scenarios. A questionnaire was mailed to all Australian colorectal surgeons and medical oncologists that asked them to respond as if they themselves were patients. RESULTS: One hundred patients (91 percent), 43 colorectal surgeons (77 percent), and 103 medical oncologists (50 percent) participated. In all four scenarios, patients were able to trade survival for quality of life. Patients' responses varied between scenarios, both in willingness to trade and the average amount traded. There were significant differences between patients and clinicians. Clinicians were more willing than patients to trade survival to avoid a permanent colostomy in favor of chemoradiotherapy. Patients' strongest preference was to avoid chemotherapy, more than to avoid a permanent colostomy. CONCLUSIONS: Patients are able to trade survival as a measure of preference for quality of life and can do so differentially between treatment scenarios. Patients' preferences do not always accord with those of clinicians. Unless patients' preferences are explicitly sought and incorporated into clinical decision making, patients may not receive the treatment that is best for them.     

Nutritional status and serum cytokine profiles in children, adolescents, and young adults with Schistosoma japonicum-associated hepatic fibrosis, in Leyte, Philippines

In a cross-sectional study of 641 Schistosoma japonicum-infected individuals in Leyte, Philippines, who were 7-30 years old, we determined the grade of hepatic fibrosis (HF) by ultrasound and used anthropometric measurements and hemoglobin levels to assess nutritional status. Serum levels of interleukin (IL)-1, IL-6, and IL-10; tumor-necrosis factor (TNF)-alpha; soluble TNF- alpha receptor I; and C-reactive protein (CRP) were measured to examine the association between these markers of inflammation and HF grade. HF was present in 8.9% of the cohort; the majority of cases were mild (grade I), and severe (grade II or grade III) cases occurred only in male individuals. Compared with individuals without HF, those with severe HF--and, to a lesser degree, those with mild HF--had a significantly lower body-mass index (BMI) and BMI z-score, a higher prevalence of anemia, and a higher level of CRP and were more likely to produce IL-6; furthermore, those with severe HF had a significantly higher level of IL-1, compared with those either without HF or with mild HF. These findings suggest that even mild HF is associated with nutritional morbidity and underscore the importance of early recognition and treatment. In addition, our data are consistent with the hypothesis that, by systemically increasing the levels of the proinflammatory cytokines IL-1 and IL-6, HF causes undernutrition and anemia.