New predictors of outcome in idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis. New therapies have improved the outcome of this condition; accordingly, the factors that determine outcome may have changed. We aimed to identify determinants of survival in a cohort of consecutive patients with PAH: which was idiopathic, familial, or associated with anorexigen use. We performed a retrospective cohort study of 84 consecutive patients with PAH who underwent initial evaluation at our center from January 1994 to June 2002. The primary outcome was death or lung transplantation. Survival at 1, 3, and 5 [corrected] years was 87%, 75%, and 61%, respectively. Multivariate analysis showed that being of African-American or Asian descent was associated with an increased risk of death. Warfarin use was associated with a reduced risk of death. Higher serum albumin and cardiac index and acute vasoreactivity were independently associated with improved survival. These data suggest that the determinants of outcome have changed. Race is identified as a new risk factor, which may be attributable to biologic or socioeconomic differences. Cardiac function and acute reactivity of the pulmonary vascular bed remain strong independent predictors of outcome.     

Urban Health Indicator Tools of the Physical Environment: a Systematic Review

Urban health indicator (UHI) tools provide evidence about the health impacts of the physical urban environment which can be used in built environment policy and decision-making. Where UHI tools provide data at the neighborhood (and lower) scale they can provide valuable information about health inequalities and environmental deprivation. This review performs a census of UHI tools and explores their nature and characteristics (including how they represent, simplify or address complex systems) to increase understanding of their potential use by municipal built environment policy and decision-makers. We searched seven bibliographic databases, four key journals and six practitioner websites and conducted Google searches between January 27, 2016 and February 24, 2016 for UHI tools. We extracted data from primary studies and online indicator systems. We included 198 documents which identified 145 UHI tools comprising 8006 indicators, from which we developed a taxonomy. Our taxonomy classifies the significant diversity of UHI tools with respect to topic, spatial scale, format, scope and purpose. The proportions of UHI tools which measure data at the neighborhood and lower scale, and present data via interactive maps, have both increased over time. This is particularly relevant to built environment policy and decision-makers, reflects growing analytical capability and offers the potential for improved understanding of the complexity of influences on urban health (an aspect noted as a particular challenge by some indicator producers). The relation between urban health indicators and health impacts attributable to modifiable environmental characteristics is often indirect. Furthermore, the use of UHI tools in policy and decision-making appears to be limited, thus raising questions about the continued development of such tools by multiple organisations duplicating scarce resources. Further research is needed to understand the requirements of built environment policy and decision-makers, public health professionals and local communities regarding the form and presentation of indicators which support their varied objectives.     

Genetic and molecular factors in drug-induced liver injury: a review

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic "dose-dependent" Type A reactions ii) "idiosyncratic" or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.     

Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome

BACKGROUND/AIMS: The aim of this study was to assess whether genetic polymorphism of three important candidate cytokine genes, IL-10 (-1082G/A, -819C/T, and -592C/A), IL-4 (-590C/T) and TNF-alpha (-308G/A), play a role in the susceptibility to developing drug-induced liver injury (DILI), and in determining its phenotypic expression and severity. METHODS: Cytokine genotyping was analysed using TaqMan 5' allelic discrimination assay in 140 DILI patients (mean age 51 y, range 13-82, with equal sex distribution) included in the Spanish Registry and 268 healthy controls. RESULTS: Genotypes, haplotypes and allele frequencies were similar for both cases and controls. The low IL-10 producing haplotype was more prevalent in DILI patients with the absence of peripheral blood eosinophilia (Pc=0.004, OR=5.29, 95% CI: 2.04-13.67), revealing significantly lower median eosinophil counts (0.19 x 10(9)L; P<0.0002) compared to the intermediate (0.24 x 10(9)L) and high (0.40 x 10(9)L) IL-10 haplotypes. All cases with serious DILI outcome carried low or intermediate IL-10 producing haplotype and had normal or low eosinophil counts. CONCLUSIONS: IL-10, IL-4 and TNF-alpha genetic polymorphisms were not related to the risk of developing DILI. Low IL-10 producing haplotype is associated with low eosinophil count, absence of eosinophilia and may be associated with worse clinical outcome from DILI.     

Determinants of Risky Sexual Behavior Among Injecting Drug Users (IDUs) in Georgia

Injection risk practices and risky sexual behaviors place injection drug users (IDUs) and their sexual partners particularly vulnerable to HIV. The purpose of the study was to describe and understand determinants of high-risk sexual behavior among IDUs in Georgia. A cross-sectional, anonymous survey assessed knowledge, behavior and HIV status in IDUs in five Georgian cities (Tbilisi, Gori, Telavi, Zugdidi, Batumi) in 2009. The study enrolled in total 1,127 (1,112 males, 15 females) IDUs. Results indicate that occasional sexual relationships are common among male IDUs, including married ones. A subsample of 661 male IDUs who reported having occasional and paid sex partners during the last 12 months was analyzed. Multivariate analysis shows that not having a regular partner in the last 12 month (adjusted odds ratio (aOR) 1.57, 95 % CI 1.04 2.37), and using previously used needles/syringes at last injecting (aOR 2.37, 95 % I 1.10–5.11) are independent correlates of inconsistent condom use with occasional and paid sexual partners among IDUs. Buprenorphine injectors have lower odds of inconsistent condom use with occasional and paid sexual partners compared to heroin injectors (aOR 0.47, 95 % CI 0.27–0.80), and IDUs who live in Telavi are twice more likely to engage in such risky sexual behavior than capital city residents (aOR 2.55, 95 % CI 1.46–4.48). More effective programs focused on sexual risk behavior reduction strategies should be designed and implemented.     

Prolonged cholestasis after raloxifene and fenofibrate interaction： A case report

Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistance of toxic cholestasis.     

Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands

Natural killer (NK) cells contribute to immunity and reproduction. Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.     

KIR2DS2 and KIR2DS4 promoter hypomethylation patterns in patients undergoing hematopoietic cell transplantation (HCT)

The killer cell Ig-like receptor (KIR)–MHC class I pathway is an integral part of natural killer cell immunity, and its role in host protection from both cancer and infection is important. In addition, we have shown elevated KIR2DS2 and 2DS4 expression in PBMCs of patients undergoing hematopoietic cell transplantation (HCT) [1]. Since all inhibitory KIR promoters are known to be heavily methylated, the question asked here is how and when KIR2DS2 and 2DS4 promoters had changed their methylation profile in association with HCT.