Association of common BRCA1 variants with predisposition to breast tumors in Pakistan.

BRCA1 variants are extensively associated with increased risk of breast cancer. Early detection and screening of variants is still rare in developing countries. Here, we investigated six BRCA1 variants in 300 subjects from Pakistani population using tetra amplification-refractory mutation system (T-ARMS) PCR. Our results indicate significant association of BRCA1 variants rs8176237 (AA; OR 8.2, 95% CI 3.02-22.64, p < 0.0001), rs1060915 (CC; OR 4.29, 95% CI 1.94-9.48, p = 0.0003), and rs799912 (TT; OR 3.16, 95% CI 1.44-6.94, p = 0.004) with up to 8-fold increased odds of breast cancer under recessive model. Furthermore, BRCA1 haplotypes AGCACG and AGCCCT were associated with up to 18% breast cancer cases (p < 0.05). Additionally, we found association of these variants with up to 11-fold increased odds of benign breast tumors. Linkage disequilibrium (LD) block-wise analysis revealed haplotypes GCAC and ATAC were associated with significantly increased risk. To our knowledge, this is the first study that identifies the association of these BRCA1 variants with breast tumors in Pakistani population. In conclusion, BRCA1 variants investigated in the present study are associated with high odds of benign- and malignant breast tumors. Studies with bigger sample size may help early detection and screening to reduce the odds of breast cancer.

Somatic mutations in collagens are associated with a distinct tumor environment and overall survival in gastric cancer.

BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.

Multiple Stress Reduces the Advantage of Pesticide Adaptation.

Under global change scenarios, multistress conditions may occur regularly and require adaptation. However, the adaptation to one stressor might be associated with the increased sensitivity to another stressor. Here, we investigated the ecological consequences of such trade-off under multiple stress. We compared the pesticide tolerance of the crustacean Gammarus pulex from agricultural streams with populations from reference streams. Under optimum temperature, G. pulex from agricultural streams were considerably more tolerant to pesticides as compared to the reference populations. Here, we assume that the increased tolerance in agricultural populations is the combination of acclimation, epigenetic effect, and genetic evolution. After experimental pre-exposure to very low concentration (LC50/1000), reference populations showed increased pesticide tolerance. In contrast, pre-exposure did not further increase the tolerance of agricultural populations. Moreover, these populations were more sensitive to elevated temperature alone due to the hypothesized fitness cost of genetic adaptation to pesticides. However, both reference and agricultural populations showed a similar tolerance to the combined stress of pesticides and warming due to stronger synergistic effects in adapted populations. As a result, pesticide adaptation loses its advantage. The combined effect was predicted well using the stress addition model, developed for predicting the synergistic interaction of independent stressors. We conclude that under multistress conditions, adaptation to pesticides reduces the general stress capacity of individuals and trade-off processes increase the sensitivity to additional stressors. This causes strong synergistic effects of additional stressors on pesticide-adapted individuals.

Relationship of mildly increased albuminuria and coronary artery revascularization outcomes in patients with diabetes.

BACKGROUND: The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease. METHODS AND RESULTS: We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type-2 diabetes (BARI-2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin-creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR ≥10 mg/g < 30 mg/g), moderately (uACR ≥30 mg/g < 300 mg/g) and severely increased (uACR ≥300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow-up of 4.3 ± 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all-cause mortality. Additionally, nonwhites with type-II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all-cause mortality, and two times for (P = 0.015) MI during follow-up. CONCLUSIONS: Mildly increased albuminuria is a significant predictor of all-cause mortality in those with type-II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites.

Interaction between Albuminuria and Treatment Group Outcomes for Patients with Renal Artery Stenosis: The NITER Study.

PURPOSE: To perform a post-hoc analysis of the Nephropathy Ischemic Therapy (NITER) trial, which enrolled patients with atherosclerotic renal artery stenosis, to evaluate whether medical therapy plus stent placement is superior to medical therapy alone in patients without elevated albuminuria. MATERIALS AND METHODS: Data from 51 patients were analyzed and stratified into 2 cohorts by median urinary albumin (UAlb) levels: cohort 1 ("low albuminuria," UAlb ≤0.04 g/24h) and cohort 2 ("high albuminuria," UAlb >0.04g/24h). Interaction effect between treatment arms and UAlb cohorts was calculated using Cox regression analysis. Survival analysis was followed by test for effect size, power analysis, and construction of a Kaplan-Meier survival table. RESULTS: At study completion, 13 patients had an outcome event: 6 (23%) from cohort 1 and 7 (28%) from cohort 2. Patients in cohort 1 had event-free survival of 83% at 3.9 ± 0.3 years from the primary endpoints of all-cause mortality, dialysis, and cardiovascular events when treated with interventional therapy, compared to 45% when treated with medical therapy alone (P = .501), which showed a 62% treatment effect for stent placement. In cohort 2, event-free survival rates were 64% for medical therapy versus 52% for medical plus interventional therapy (P = .64). Using Cox regression analysis, the interaction effect between treatment arms and UAlb cohorts was not significant (P = .32). The power of the study to detect an interaction effect, if one existed, was only 15%. CONCLUSIONS: Inference cannot be drawn for similar populations because of inadequate sample size, but, in this sample, patients treated with stent placement who had low albuminuria had better outcomes than patients treated with medical therapy alone.

Revealing the cascade of pesticide effects from gene to community.

Global pesticide exposure in agriculture leads to biodiversity loss, even at ultra-low concentrations below the legal limits. The mechanisms by which the effects of toxicants act at such low concentrations are still unclear, particularly in relation to their propagation across the different biological levels. In this study, we demonstrate, for the first time, a cascade of effects from the gene to the community level. At the gene level, agricultural pesticide exposure resulted in reduced genetic diversity of field-collected Gammarus pulex, a dominant freshwater crustacean in Europe. Additionally, we identified alleles associated with adaptations to pesticide contamination. At the individual level, this genetic adaptation to pesticides was linked to a lower fecundity, indicating related fitness costs. At the community level, the combined effect of pesticides and competitors caused a decline in the overall number and abundance of pesticides susceptible macroinvertebrate competing with gammarids. The resulting reduction in interspecific competition provided an advantage for pesticide-adapted G. pulex to dominate macroinvertebrate communities in contaminated areas, despite their reduced fitness due to adaptation. These processes demonstrate the complex cascade of effects, and also illustrate the resilience and adaptability of biological systems across organisational levels to meet the challenges of a changing environment.

Exploring BPA alternatives - Environmental levels and toxicity review.

Bisphenol A alternatives are manufactured as potentially less harmful substitutes of bisphenol A (BPA) that offer similar functionality. These alternatives are already in the market, entering the environment and thus raising ecological concerns. However, it can be expected that levels of BPA alternatives will dominate in the future, they are limited information on their environmental safety. The EU PARC project highlights BPA alternatives as priority chemicals and consolidates information on BPA alternatives, with a focus on environmental relevance and on the identification of the research gaps. The review highlighted aspects and future perspectives. In brief, an extension of environmental monitoring is crucial, extending it to cover BPA alternatives to track their levels and facilitate the timely implementation of mitigation measures. The biological activity has been studied for BPA alternatives, but in a non-systematic way and prioritized a limited number of chemicals. For several BPA alternatives, the data has already provided substantial evidence regarding their potential harm to the environment. We stress the importance of conducting more comprehensive assessments that go beyond the traditional reproductive studies and focus on overlooked relevant endpoints. Future research should also consider mixture effects, realistic environmental concentrations, and the long-term consequences on biota and ecosystems.

Impact of Cadmium Contamination on Fertilizer Value and Associated Health Risks in Different Soil Types Following Anaerobic Digestate Application.

Cadmium (Cd) contamination in the soil potentially hampers microbial biomass and adversely affects their services such as decomposition and mineralization of organic matter. It can reduce nitrogen (N) metabolism and consequently affect plant growth and physiology. Further, Cd accumulation in plants can pose health risks through vegetable consumption. Here, we investigated consequences of Cd contamination on fertilizer value and associated health risks following the application of biogas residues (BGR) to various soil types. Our results indicate that the application of BGR to all soil types significantly increased dry matter (DM) yield and N uptake. However, the Cd contamination negatively affected DM yield and N recovery from BGR in a dose-dependent manner. Organic N mineralization from BGR also decreased in Cd-contaminated soils. The highest DM yield and N recovery were recorded in sandy soil, whereas the lowest values were observed in clay soil. Cadmium was accumulated in spinach, and health risk index (HRI) associated with its dietary intake revealed that consuming spinach grown in Cd-contaminated soil, with or without BGR, is unsafe. Among the soil types, values of daily intake of metals (DIM) and HRI were lowest in clay soil and highest in sandy soil. However, the application of BGR curtailed HRI across all soil types. Notably, the application of BGR alone resulted in HRI values < 1, which are under the safe limit. We conclude that soil contamination with Cd reduces fertilizer value and entails implications for human health. However, the application of BGR to the soil can decrease Cd effects.

Lung Findings in a Patient with a History of Nicotine Vaping and Cannabis Smoking.

We report a collection of lung findings in a patient with a remote history of cigarette smoking, but now engaged in heavy nicotine vaping with daily edible and combustible cannabis use. Computed tomography (CT) imaging demonstrated numerous, small, and bilateral nodules with ground-glass appearance. The largest nodule is demonstrated in the right upper lung lobe. Clinically the differential diagnosis at this time included hypersensitivity pneumonitis and sarcoidosis. Atypical infection, particularly of a fungal etiology, and metastatic malignancy were also considered. Initial pathology of the right lung needle biopsy revealed alveolar septal thickening with associated atypical pneumocyte proliferation, suggestive of atypical adenomatous hyperplasia (AAH). Subsequently the patient underwent wedge resection of the right upper, middle and lower lobes. Pathology examination revealed pulmonary Langerhans cell histiocytosis (PLCH) in the upper and lower lobes, with CD1a staining highlighting the aggregates of Langerhans cells. Vascular changes were also present including intimal thickening of muscular pulmonary arteries, consistent with pulmonary hypertensive changes. Background lung parenchyma demonstrated respiratory bronchiolitis, smoking-related interstitial fibrosis, an organizing thrombus in muscular artery and associated pneumocyte hyperplasia.

Pesticide-induced metabolic changes are amplified by food stress.

In natural ecosystems, long-term detrimental effects of pesticides may occur at very low concentrations, below those considered safe by the governmental risk assessment. Mechanisms potentially responsible for this unexpected sensitivity include environmental stress-factors such as food deficiency. To understand this so called "effect-paradox", we investigated how food stress interacts with insecticide-induced biochemical fingerprints. Therefore, we measured metabolomic perturbations in Daphnia magna following a 24 h exposure to esfenvalerate under high and low food conditions. In total, 160 metabolites covering the groups of amino acids, fatty acids, lipids, and sugars were analyzed. At 0.001 µg/L esfenvalerate - a factor of >200 below the acute lethal concentration (LC50) - the endogenous metabolome was significantly affected. Further, the effect under low food conditions was considerably stronger compared to high food conditions. Individual metabolites showed up to 7-fold stronger effects under low food conditions. In general, the metabolomic changes were largely dose-specific and increased over seven days after contamination. We conclude that the metabolic profiles are altered for at least seven days after a pulse exposure, and therefore might be a key process to understanding population level changes at ultra-low pesticide concentrations in the field.

Doege-Potter Syndrome with a Benign Solitary Fibrous Tumor: A Case Report and Literature Review.

Doege-Potter syndrome is a rare paraneoplastic syndrome that is often diagnosed incidentally during the workup of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia secondary to excessive production of partially processed IGF-II hormone from a solitary fibrous tumor (SFT). Often these tumors are intrathoracic, benign, and asymptomatic. Occasionally they present as a paraneoplastic event; hypertrophic osteoarthropathy in Pierre-Marie-Bamberger syndrome and hypoglycemia in Doege-Potter syndrome. The NAB2-STAT6 gene fusion is the hallmark of the SFT. Complete surgical resection of the tumor often results in resolution of symptoms and cure in most cases. Here we present the case of an 83-year-old non-diabetic female with recurrent syncopal events who was diagnosed with the Doege-Potter syndrome secondary to a SFT of pleura. Her tumor was positive for NAB2-STAT6 gene fusion on RT-PCR. Following the resection of the giant tumor mass, she became symptom-free within 24 h, and has remained asymptomatic at 4 months follow-up.

Insecticides in agricultural streams exert pressure for adaptation but impair performance in Gammarus pulex at regulatory acceptable concentrations.

Pesticide exposure in agricultural streams requires non-target species to adapt. However, pesticides may reduce performance in between exposure events due to long-term effects and physiological fitness costs of adaptation. Here, we investigated the long-term consequences of pesticide exposure to low concentrations in the widespread crustacean Gammarus pulex. We collected populations from six German streams covering no to moderate agricultural pesticide exposure. Peak concentrations ranged up to 1/400 of their acute median lethal concentration (Toxic Unit = -2.6), resulting in significant changes in the macroinvertebrate community composition (SPEARpesticides = up to 0.12). Acute toxicity tests revealed up to 2.5-fold increased tolerance towards the most frequently found insecticide clothianidin compared to populations from non-contaminated streams. However, populations showing increased insecticide tolerance were characterized by reduced survival, per capita growth and mating when cultured under pesticide-free conditions in the laboratory for three months. We conclude that pesticide pollution triggers adaptation both at the species and the community level even at concentrations considered to be safe according to the European pesticide legislation. In G. pulex, exposure and adaptation are associated with impaired performance which potentially affects ecosystem functions such as leaf litter degradation. These long-term impairments need to be considered in deriving safe concentrations.

Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience.

BACKGROUND: Drug-induced liver injury (DILI) and herbal/dietary supplements (HDS) related liver injury present unique diagnostic challenges. Collaboration between the clinician and the pathologist is required for an accurate diagnosis and management. AIM: To report our experience on the clinical-pathological findings of hepatic injury caused by drugs/HDS. METHODS: A retrospective review of clinically proven cases of DILI/HDS who presented to our institution from January 1, 2013 to December 31, 2017 was performed. Slides were reviewed for histopathological patterns of injury and correlated with the causative agent. Out of 600 patients presenting with unexplained rise in liver enzymes undergoing biopsy, 107 were suspected to have DILI/HDS. Of these, 53 had a directly linked exposure to drug/herbal supplements. Fifteen patients were excluded for concurrent known liver disease. Thirty-eight patients with clinically proven DILI/HDS were finally included. RESULTS: Thirty-eight cases of DILI/HDS with a male:female of 1:1.5 and mean age of 51 ± 3 years were identified. DILI was identified in 84.2% cases while HDS injury in 15.8%. Acute hepatitis (42.1%) was the most common pattern of injury while granulomatous hepatitis (2.6%) was the least common. We found one case of acute-cholestasis due to rivaroxaban and two cases of cholestatic-hepatitis due to rizatriptan and trimethobenzamide-hydrochloride that, to the best of our knowledge, have not been previously reported. One case of steatohepatitis due to trimethoprim-sulfamethoxazole and three unusual cases of cholestatic-hepatitis with bile duct injury and steatosis due to dronedarone, C4-Extreme and hydroxycut, were also seen. Of our cohort, 81.6% of the patients fared well with discontinuation of drug and 18.4% underwent transplant; of which 42.9% were deceased. CONCLUSION: We describe the clinical findings, histopathological patterns of injury and clinical outcomes caused by drugs. In particular, we report a few previously unreported/ rarely observed clinical and histopathological patterns of hepatic injury.

Noble Metal Based Alloy Nanoframes: Syntheses and Applications in Fuel Cells.

Noble metal nanostructures are being used broadly as catalysts for energy conversion in fuel cells. To overcome the future energy crises, fuel cells are anticipated as clean energy sources because they can be operated at low temperature, their energy conversion is high and their carbon release is almost zero. However, an active and stable electrocatalyst is essential for the electrochemical reactions in fuel cells. Therefore, properties of the nanostructures greatly depend on the shape of the nanostructures. Individual as well as interaction properties are greatly affected by changes in the surface area of the nanostructures. By shape controlled synthesis, properties of the nanostructures could be further enhanced by increasing the surface area or active sites for electrocatalysts. Therefore, an efficient approach is needed for the fabrication of nanostructures to increase their efficiency, activity, or durability in fuel cells by reducing the usage of noble metals. Different types of hollow nanostructures until now have been prepared including nanoboxes, nanocages, nanoshells, nanoframes (NFs), etc. NFs are the hollow unique three-dimensional structure which have no walls-they only contain corners or edges so they have large surface area. In electrocatalytic reactions, the molecules involved in the reaction can easily reach the inner surface of the nanoframes, thus noble metals' utilization efficiency increases. NFs usually have high surface area, greater morphological and compositional stabilities, allowing them to withstand harsh environmental conditions. By considering the current challenges in fabrication of noble metal based alloy NFs as electrocatalysts, this review paper will highlight recent progress, design, and fabrication of noble metal alloy NFs through different strategies-mainly photocatalytic template, electrodeposition, Kirkendall effect, galvanic replacement, chemical/oxidative etching, combination of both and other methods. Then, electrochemical applications of NFs in fuel cells toward formic acid, methanol, ethanol, oxygen reduction reaction as well as bifunctional catalyst will also be highlighted. Finally, we will summarize different challenges in the fabrication of highly proficient nanocatalysts for the fuel cells with low cost, high efficiency and high durability, which are the major issues for the highly commercial use of fuel cells in the future.

Breast cancer risk associated with BRCA1/2 variants in the Pakistani population.

BACKGROUND: Majority of the BRCA1 and BRCA2 mutations are associated with the risk of sporadic and familial breast cancer. Since these genes are significant in DNA repair mechanisms, we focused homology-directed DNA repair (HDDR) and BRCA complex. METHODS: We selected BRCA1 variant (rs80356932, 4491C/T) and BRCA2 variant (rs80359182, 319T/C) from the interaction region of BRCA complex and studied in 100 breast cancer patients and 100 controls using tetra-ARMS-PCR. RESULTS: Here we show that BRCA1 and BRCA2 variants are significantly associated with high breast cancer risk (BRCA1 rs80356932; Genotype T/T OR 8.66, 95% CI 3.16-23.71, p < 0.0001; Allele-T, OR 2.48, 95% CI 1.62-3.81, p < 0.0001 and BRCA2 rs80359182; Genotype C/C OR 4.32, 95% CI 1.95-9.53, p = 0.0001; Allele-C, OR 2.19, 95% CI 1.43-3.34, p = 0.0002). Additionally, bioinformatics analysis showed that BRCA2-tryptophan > arginine substitutions result in altered interaction of BRCA1/PALB2/BRCA2/protein complex and impaired HDDR pathway. We also observed that breast cancer risk was significantly increased in over-weighted and obese women. CONCLUSIONS: Our results indicate that high risk of breast cancer is significantly associated with BRCA1 and BRCA2 variants, and mutations may alter the protein interactions of BRCA complex that results in tumor genesis.

A large inflammatory fibroid polyp of the rectum removed by transanal excision.

Inflammatory fibroid polyps (IFP) are rare benign lesions arising from the submucosa of the gastrointestinal tract, most commonly found in the stomach and small intestine. IFPs are very rarely found in the rectum, with only a few reported cases, and their presentation is quite varied. The patient is a 53 year old male who underwent routine screening colonoscopy, during which a lobular mass of the proximal rectum was discovered. The patient subsequently underwent an endoscopic ultrasound (EUS) with fine needle aspiration (FNA) biopsy. Pathology displayed scant spindle cells with benign glandular epithelium suspicious for a spindle cell neoplasm. The mass was excised transanally. The morphological and immunohistochemical findings supported the diagnosis of inflammatory fibroid polyp. Although this is not a malignant tumor, the treatment and surveillance guidelines have not been determined and there is no standard of care.

Breast cancer risk associated with genes encoding DNA repair MRN complex: a study from Punjab, Pakistan.

BACKGROUND: Variants of DNA repair genes are extensively reported to cause genetic instability and increase the risk of breast cancer. In combination with NBS1, MRE11 and RAD50 constitute an MRN (MRE11-RAD50-NBS1) complex that repairs DNA damage. However, certain genetic alterations in MRE11 and RAD50 produce abnormal protein that affects the repairing process and may result in malignancy. We aimed to investigate the association of MRE11 and RAD50 polymorphisms with breast risk in the female population of Punjab, Pakistan. METHODS: We collected blood samples of 100 breast cancer patients and 100 tumor-free females selected as controls. Extracted DNA was genotyped by tetra ARMS-PCR followed by gel electrophoresis. Results were analyzed by SPSS and SNPstats to analyze the association of different clinical factors and SNPs (single nucleotide polymorphisms) with the risk of breast cancer. RESULTS: We found that the increased risk of breast cancer is associated with MRE11 variant rs684507 (odds ratio-OR 3.71, 95% confidence interval-CI 1.68-8.18, p value < 0.0001), whereas, RAD50 variant rs28903089 appeared to have protective effect (OR 0.55, CI 0.29-1.02, p value = 0.003). Additionally, clinical factors such as positive family history, life style, and marital status also play significant roles in breast cancer development. CONCLUSION: In the present study, strong risk of breast cancer was associated with MRE11 gene. However, RAD50 showed protective effect. Additionally, clinical factors are also pivotal in risk assessment. We anticipate that targeting specific genetic variations confined to ethnic groups would be more effective in future therapeutic approaches for prevention and treatment of breast cancer.

Helicobacter pylori Infection: An Update for the Internist in the Age of Increasing Global Antibiotic Resistance.

Helicobacter pylori infects approximately half the world's population and is especially prevalent in the developing world. H. pylori is an important cause of global ill health due to its known etiological role in peptic ulcer disease, dyspepsia, gastric cancer, lymphoma, and more recently, recognized in iron deficiency anemia and idiopathic thrombocytopenic purpura. Increased antibiotic usage worldwide has led to antibiotic resistance among many bacteria, including H. pylori, resulting in falling success rates of first-line anti-H. pylori therapies. Eradication failures are principally due to resistance to clarithromycin, levofloxacin, and metronidazole. Several new treatment options or modifications of established regimens are now recommended by updated practice guidelines for primary or secondary therapy. Because these updated recommendations were published in the gastroenterological literature, internists and primary care physicians, who commonly manage H. pylori, may be unaware of these advances. In this review, we outline the changing epidemiology of H. pylori, advise on diagnostic test selection for patients not undergoing endoscopy, and highlight current management options in this era of growing antibacterial resistance.

Effects of infection on post-transplant outcomes: living versus deceased donor liver transplants.

INTRODUCTION: Post-transplant infections have been studied widely but data on comparisons of deceased donor liver transplants (DDLT) and living donor liver transplants (LDLT), type and timings of infections, and their relations to outcomes are not explored. MATERIAL AND METHODS: We analysed data from 612 participants of the Adult-to-Adult Living Donor Liver Transplantation Study (A2ALL), a retrospective data set of LDLT and DDLT. We compared the type and timing of the first post-transplant infection in relation to transplant outcomes between the two groups. RESULTS: Out of 611 patients, 24.5% experienced the first post-transplant infection, the majority of which were bacterial (35.3%), followed by fungal (11%) and viral infections (4.2%). There was no significant difference in the rate, type or timing of infection between LDLT and DDLT. Patients with late (> 1 year) first infection were 1.8 times more likely to die (95% CI: 1.12-2.98, p = 0.015) and 9 times more likely to have graft failures (95% CI: 3.26-24.8, p < 0.001). DDLT recipients who experienced bacterial infection had a significantly lower survival rate compared to LDLT recipients (p < 0.001). CONCLUSIONS: Late infection is associated with lower survival in both DDLT and LDLT. Bacterial infection might be more detrimental for DDLT than LDLT. Late infection should be managed aggressively to improve outcomes.

Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy.

Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6 months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied. RNA was isolated from a subset of cases, and gene expression analysis of 285 genes involved in inflammation was performed using NanoString technology. There was no difference in the presenting symptoms among groups. The number of eosinophils/high-power field among nonresponders was higher (66±15) than responders (39±8; P<.0001) and similar to patients who relapsed (62±11). Six genes were expressed by at least 4-fold compared with reflux at a false discovery rate < 0.05, including overexpression of ALOX15, CCL26, FCER2, RTNLB, and RNASE2, and underexpression of DSG1. EoE patients refractory to therapy or who relapsed showed a trend toward higher ALOX15 expression compared with patients with good response to therapy (364.4- and 425-fold change, P=.097 and P=.07). RTNLB was significantly overexpressed in patients who were refractory to therapy versus those who responded favorably (10-fold versus 3-fold; P<.01). In conclusion, the number of eosinophils/high-power field in the initial biopsy inversely correlates with therapy response. Overexpression of RTNLB in refractory-to-therapy patients and overexpression of ALOX15 and CCL26 suggest that they are critical in the EoE pathogenesis.