Does Debts Foster Economic Growth?: The Experience of Malaysia

The study examines the effect of different types of debts on the economic growth in Malaysia during the sample period 1970 - 2006. Using cointegration test, the findings suggest that all components of debts have a negative effect on long-run economic growth. In addition, the Granger causality test reveals the existence of a short-run causality linkage between all debt measures and economic growth in the shortrun. The policy conclusion is that an increase in foreign debt level adversely influences economic performance, whereas the decline in the rate of economic growth weakens the ability of the country to service its debt

A systematic review of current knowledge of HIV epidemiology and of sexual behaviour in Nepal

OBJECTIVE: To systematically review information on HIV epidemiology and on sexual behaviour in Nepal with a view to identifying gaps in current knowledge. METHODS: Systematic review covering electronic databases, web-based information, personal contact with experts and hand searching of key journals. RESULTS: HIV-1 seroprevalence has been rising rapidly in association with high-risk behaviours, with current levels of 40% amongst the nation's injecting drug users and approaching 20% amongst Kathmandu's female commercial sex workers (FCSWs). HIV seroprevalence remains low in the general population (0.29% of 15–49 year olds). There are significant methodological limitations in many of the seroprevalence studies identified, and these estimates need to be treated with caution. There are extensive migration patterns both within the country and internationally which provide the potential for considerable sexual networking. However, studies of sexual behaviour have focused on FCSWs and the extent of sexual networks within the general population is largely unknown. CONCLUSIONS: Whilst some of the ingredients are present for an explosive HIV epidemic in Nepal, crucial knowledge on sexual behaviour in the general population is missing. Research on sexual networking is urgently required to guide HIV control in Nepal. There is also a need for further good-quality epidemiological studies of HIV seroprevalence

First documented cure of a suggestive exogenous reinfection in polymyositis with same but multidrug resistant M. tuberculosis

BACKGROUND: MDR Mycobacterium tuberculosis is the major cause of treatment failure in tuberculosis patients, especially in immunosuppressed. We described a young polymyositis patient on immunosuppressive therapy who was started with antituberculosis therapy as a susceptible strain of M. tuberculosis was isolated from a single cutaneous abscess in his neck and from regional lymph nodes. CASE PRESENTATION: He had non-reactive miliary tuberculosis and multiple cutaneous abscesses 6 months later with the same strain, which was resistant this time to 9 antituberculosis drugs. We described clinical presentation, radiological and laboratory work-up, treatment and follow-up as the patient was cured after 1.5 years with 6 antituberculosis drugs. CONCLUSION: To our knowledge, this is the first reported case where an immunosuppressed patient with suggestive exogenous reinfection within 6 months with the same but MDR strain of M. tuberculosis was cured. Intense management and regular follow up were important since the patient was a potent source of MDR M. tuberculosis infection and there was limited choice for therapy

A study of empyema thoracis and role of intrapleural streptokinase in its management

BACKGROUND: Clinical spectrum, microbiology and outcome of empyema thoracis are changing. Intrapleural instillation of fibrinolytic agents is being increasingly used for management of empyema thoracis. The present study was carried out to describe the clinical profile and outcome of patients with empyema thoracis including those with chronic empyema and to study the efficacy and safety of intrapleural streptokinase in its management. METHODS: Clinical profile, etiological agents, hospital course and outcome of 31 patients (mean age 40 ± 16 years, M: F 25: 6) with empyema thoracis treated from 1998 to 2003 was analyzed. All patients were diagnosed on the basis of aspiration of frank pus from pleural cavity. Clinical profile, response to therapy and outcome were compared between the patients who received intrapleural streptokinase (n = 12) and those who did not (n = 19). RESULTS: Etiology was tubercular in 42% of the patients (n = 13) whereas the rest were bacterial. Amongst the patients in which organisms could be isolated (n = 13, 42%) Staphylococcus aureus was the commonest (n = 5). Intrapleural streptokinase was instilled in 12 patients. This procedure resulted in increase of drainage of pleural fluid in all patients. Mean daily pleural fluid drainage after streptokinase instillation was significantly higher for patients who received intrapleural streptokinase than those who did not (213 ml vs 57 ml, p = 0.006). Only one patient who was instilled streptokinase eventually required decortication, which had to be done in five patients (16.1%). Mean hospital stay was 30.2 ± 17.6 days whereas two patients died. CONCLUSIONS: Tubercular empyema is common in Indian patients. Intrapleural streptokinase appears to be a useful strategy to preserve lung function and reduce need for surgery in patients with late stage of empyema thoracis

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.Funding support for this project was obtained from the European Research Council (project number 250157) and BGI. The study was also supported by TwinsUK, which is funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013); and also receives support from the National Institute for Health Research (NIHR) BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas' NHS Foundation Trust and King’s College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. M.M. is the holder of Wellcome Trust Senior Investigator Award (Wellcome 098381). T.D.S. is the holder of an ERC Advanced Principal Investigator award (ERC 250157). A.P.M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Skeletal muscle 450k methylation project is supported by European Community's Seventh Framework Programme (FP7/2007-2013) under DEXLIFE project (grant agreement no. HEALTH-F2-2011-279228)

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell–like phenotypes shown by many tumors

Survival Differences by Race/Ethnicity and Treatment for Localized Hepatocellular Carcinoma Within the United States

Racial differences among hepatocellular carcinoma survival have been reported, but the etiology behind these disparities remains unclear. Using multi-variable logistic regression analysis, our restrospective cohort study investigated the demographic disparities in survival among localized hepatocellular carcinoma in the United States. From 1998 to 2001, 2,776 cases of localized hepatocellular carcinoma were identified. Significant racial/ethnic disparities in overall survival and utilization of therapies were identified. Compared with non-Hispanic white males, black females were 56% less likely to survive 3 years (OR 0.44; 95% CI 0.21–0.93). Treatment-specific models also demonstrated disparities, e.g., compared with non-Hispanic whites, Asians receiving transplantation were 77% more likely to survive 3 years (OR, 1.77; 95% CI 1.28–2.44). There are significant racial/ethnic disparities in 3-year survival among patients with localized hepatocellular carcinoma. These differences are partially explained by demographic differences in utilization of therapy and in stage-specific survival for each therapy

Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel–Haenszel χ2 test, Kaplan–Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (P<0.0001). Similarly, Kaplan–Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2–10.2; P<0.0001 for progression; relative risk 7.1; 95% CI 4.7–10.9; P<0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma

Nuclear ING2 expression is reduced in human cutaneous melanomas

Cutaneous malignant melanoma is a severe and sometimes life-threatening cancer. The molecular mechanism of melanomagenesis is incompletely understood. Deregulation of apoptosis is probably one of the key factors contributing to the progression of melanoma. The inhibitor of growth (ING) family proteins are candidate tumour suppressors which play important roles in apoptosis. Downregulated expression of ING proteins have been reported in several tumour types, including the loss of nuclear expression of p33ING1b in melanoma. As ING2 exhibits 58.9% homology with p33ING1b, we hypothesized that the aberrant expression of ING2 may be involved in melanomagenesis. Here, we used tissue microarray technology and immunohistochemistry to examine ING2 expression in human nevi and melanoma biopsies. Our data showed that nuclear ING2 expression was significantly reduced in radial growth phase (RGP), vertical growth phase (VGP), and metastatic melanomas compared with dysplastic nevi (P<0.05). Our data also revealed that nuclear ING2 expression was not associated with patient's gender, age or tumour thickness, ulceration, American Joint Committee on Cancer (AJCC) stage, tumour subtype, location and 5-year survival (P>0.05). Taken together, our results suggest that nuclear ING2 expression is significantly reduced in human melanomas and that reduced ING2 may be an important molecular event in the initiation of melanoma development

Dissecting the Relation between a Nuclear Receptor and GATA: Binding Affinity Studies of Thyroid Hormone Receptor and GATA2 on TSHβ Promoter

Background: Much is known about how genes regulated by nuclear receptors (NRs) are switched on in the presence of a ligand. However, the molecular mechanism for gene down-regulation by liganded NRs remains a conundrum. The interaction between two zinc-finger transcription factors, Nuclear Receptor and GATA, was described almost a decade ago as a strategy adopted by the cell to up-or down-regulate gene expression. More recently, cell-based assays have shown that the Zn-finger region of GATA2 (GATA2-Zf) has an important role in down-regulation of the thyrotropin gene (TSH beta) by liganded thyroid hormone receptor (TR). Methodology/Principal Findings: In an effort to better understand the mechanism that drives TSH beta down-regulation by a liganded TR and GATA2, we have carried out equilibrium binding assays using fluorescence anisotropy to study the interaction of recombinant TR and GATA2-Zf with regulatory elements present in the TSH beta promoter. Surprisingly, we observed that ligand (T3) weakens TR binding to a negative regulatory element (NRE) present in the TSH beta promoter. We also show that TR may interact with GATA2-Zf in the absence of ligand, but T3 is crucial for increasing the affinity of this complex for different GATA response elements (GATA-REs). Importantly, these results indicate that TR complex formation enhances DNA binding of the TR-GATA2 in a ligand-dependent manner. Conclusions: Our findings extend previous results obtained in vivo, further improving our understanding of how liganded nuclear receptors down-regulate gene transcription, with the cooperative binding of transcription factors to DNA forming the core of this process.Medical Research Council (MRC), UKConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazi