Multimorbidity in South Asian adults: prevalence, risk factors and mortality.

Background: We report the prevalence, risk factors and mortality associated with multimorbidity in urban South Asian adults. Methods: Hypertension, diabetes, heart disease, stroke and chronic kidney disease were measured at baseline in a sample of 16 287 adults ages ≥20 years in Delhi, Chennai and Karachi in 2010-11 followed for an average of 38 months. Multimorbidity was defined as having ≥2 chronic conditions at baseline. We identified correlates of multimorbidity at baseline using multinomial logistic models, and we assessed the prospective association between multimorbidity and mortality using Cox proportional hazards models. Results: The adjusted prevalence of multimorbidity was 9.4%; multimorbidity was highest in adults who were aged ≥60 years (37%), consumed alcohol (12.3%), body mass index ≥25 m/kg2 (14.1%), high waist circumference (17.1%) and had family history of a chronic condition (12.4%). Compared with adults with no chronic conditions, the fully adjusted relative hazard of death was twice as high in adults with two morbidities (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.6, 3.3) and thrice as high in adults with ≥3 morbidities (HR = 3.1; 95% CI: 1.9, 5.1). Conclusion: Multimorbidity affects nearly 1 in 10 urban South Asians, and each additional morbidity carries a progressively higher risk of death. Identifying locally appropriate strategies for prevention and coordinated management of multimorbidity will benefit population health in the region

MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines

Cystic fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung, caused by mutations in the CFTR gene. IL-8 and other proinflammatory mediators are elevated in the CF airway, and the immediate mechanism may depend on disease-specific stabilization of IL-8 mRNA in CF lung epithelial cells. MAPK signaling pathways impact directly on IL-8 protein expression in CF cells, and we have hypothesized that the mechanism may also involve stabilization of the IL-8 mRNA. To test this hypothesis, we have examined the effects of pharmacological and molecular inhibitors of p38, and downstream MK2, ERK1/2, and JNK, on stability of IL-8 mRNA in CF lung epithelial cells. We previously showed that tristetraprolin (TTP) was constitutively low in CF and that raising TTP destabilized the IL-8 mRNA. We therefore also tested these effects on CF lung epithelial cells stably expressing TTP. TTP binds to AU-rich elements in the 3′-UTR of the IL-8 mRNA. We find that inhibition of p38 and ERK1/2 reduces the stability of IL-8 mRNA in parental CF cells. However, neither intervention further lowers TTP-dependent destabilization of IL-8 mRNA. By contrast, inhibition of the JNK-2 pathway has no effect on IL-8 mRNA stability in parental CF cell, but rather increases the stability of the message in cells expressing high levels of TTP. However, we find that inhibition of ERK1/2 or p38 leads to suppression of the effect of JNK-2 inhibition on IL-8 mRNA stability. These data thus lend support to our hypothesis that constitutive MAPK signaling and proteasomal activity might also contribute, along with aberrantly lower TTP, to the proinflammatory phenotype in CF lung epithelial cells by increasing IL-8 mRNA stability and IL-8 protein expression

Essential tremor and essential tremor plus are essentially similar electrophysiologically

BACKGROUND: The merits of classifying the heterogeneous group of essential tremors into essential tremor (ET) and essential tremor plus (ETP) is debated. OBJECTIVES: We studied the electrophysiological and spiral characteristics of tremor in ET and ETP. METHODS: We reviewed standardized videos from a tremor database and clinically classified patients into ET, ETP or dystonic tremor (DT). The following variables were derived from combined tri‐axial accelerometry‐surface electromyography‐ peak frequency, total power, peak power, full width half maximum, tremor stability index and EMG‐coherence. We analysed hand‐drawn spirals to derive mean deviation, tremor variability, inter‐ and intra‐loop widths. We compared these variables among the groups. RESULTS: We recruited 72 participants (81.9% male) with mean age 47.7±16.1years and Fahn‐Tolosa‐Marin Tremor Rating Scale (FTM‐TRS) total score 31.1±14.1. Patients with ET were younger (p=0.014) and had less severe tremor (p=0.020) compared to ETP and DT. In ETP group, 48.6% had subtle dystonia. Peak frequency was greater in ETP (7.3±0.3 Hz) compared to DT (6.1±0.4 Hz; p=0.024). Peak power was greater in ETP and DT for postural tremor. Rest tremor was recordable on accelerometry in 26.7% of ET. Other variables were similar among the groups. CONCLUSION: Electrophysiological evaluation revealed postural tremor of frequency 6‐7 Hz in ET, ETP and DT with subtle differences‐ more severe tremor in ETP and DT, and higher frequency in ETP compared to DT. Our findings suggest a similar tremor oscillator in these conditions, supporting the view that these entities are part of a spectrum of tremor disorders, rather than distinct etiological entities

Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells

Cystic fibrosis (CF) is due to mutations in the CFTR gene and is characterized by hypersecretion of the proinflammatory chemokine IL-8 into the airway lumen. Consequently, this induces the highly inflammatory cellular phenotype typical of CF. Our initial studies revealed that IL-8 mRNA is relatively stable in CF cells compared with those that had been repaired with [WT]CFTR (wild-type CFTR). Relevantly, the 3′-UTR of IL-8 mRNA contains AU-rich sequences (AREs) that have been shown to mediate posttranscriptional regulation of proinflammatory genes upon binding to ARE-binding proteins including Tristetraprolin (TTP). We therefore hypothesized that very low endogenous levels of TTP in CF cells might be responsible for the relative stability of IL-8 mRNA. As predicted, increased expression of TTP in CF cells resulted in reduced stability of IL-8 mRNA. An in vitro analysis of IL-8 mRNA stability in CF cells also revealed a TTP-induced enhancement of deadenylation causing reduction of IL-8 mRNA stability. We conclude that enhanced stability of IL-8 mRNA in TTP-deficient CF lung epithelial cells serve to drive the proinflammatory cellular phenotype in the CF lung