The effect of solifenacin on postvoid dribbling in women: results of a randomized, double-blind placebo-controlled trial.

INTRODUCTION AND HYPOTHESIS: To determine the effectiveness of the muscarinic receptor antagonist solifenacin (VESIcare®) in the treatment of postvoid dribbling (PVD). METHODS: We carried out a multicenter, 12-week, double-blind, randomized, placebo-controlled, parallel design study. Between 2012 and 2015, a total of 118 women (age 18-89 years) with PVD at least twice/weekly, were randomized to receive solifenacin (5 mg; n = 58) or placebo (n = 60) once daily. The primary outcome was the percentage reduction in PVD episodes. Secondary outcomes included the percentage of patients with ≥50% reduction in PVD episodes and changes in quality of life. RESULTS: There were no differences in either the primary or secondary outcome variables. Subgroup analysis, based on those with more severe disease (>10 PVD episodes/week), showed a greater and significant percentage reduction in the frequency of PVD episodes per day (60.3% vs 32.1%; p = 0.035) and a higher percentage of patients showing ≥50% reduction in the frequency of PVD episodes with solifenacin (68.1% vs 45.8%; p = 0.0476). A significant solifenacin effect occurred at week 2 and continued through week 12 for the subgroup. For solifenacin, PVD reduction was the same for the entire cohort and subgroup, whereas for placebo, it was 10% lower in the subgroup, declining from 42% to 32%. CONCLUSION: There were no differences in PVD outcomes between the solifenacin and placebo groups. Solifenacin may play a role in treating women with the most severe symptoms. Because of the powerful placebo response seen in this study, behavior-based interventions may be useful for treating PVD.

Thromboembolic complications following a first isolated episode of superficial vein thrombosis: a cross-sectional retrospective study.

Superficial vein thrombosis (SVT) may be associated with complications such as venous thromboembolism (VTE) and recurrent SVT. The purpose of this study was to explore risk factors among patients with a first isolated episode of SVT (index SVT) involving upper and lower extremities and to estimate the prevalence of VTE complications within 1 year of index SVT. Retrospective chart review of electronic records at Marshfield Clinic in Wisconsin identified 381 subjects with a first isolated SVT diagnosis (male/female: 170/211; median age 59.4 years). Patients were stratified based on whether they did (n = 44; 11.5 %) or did not (n = 337; 88.5 %) experience VTE complications and whether they did (n = 25; 6.6 %) or did not (n = 356; 93.4 %) experience pulmonary embolism (PE) and/or deep vein thrombosis (DVT) within 1 year of index SVT. There were 49 complications among 44 patients; these included DVT (n = 18, 36.7 %), propagation of SVT (n = 18, 36.7 %), PE (n = 9, 18.4 %), new SVT at different location (n = 3, 6.1 %), and recurrent SVT (n = 1, 2.0 %). Univariate analysis of all VTE complications identified seven potential risk factors and similar analysis of PE/DVT complications identified eight potential risk factors, with six common risk factors identified in both analyses. Multivariate analysis identified indwelling venous catheter 30 days prior to SVT (p = 0.044), cancer history with treatment in the previous year (p = 0.001), and non-surgical trauma 7 days prior to SVT (p < 0.001) as independent risk factors for PE/DVT complications. Independent risk factors identified in the current study may convey greater risk for VTE complications, especially PE/DVT, following an initial isolated SVT episode.

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans.

RATIONALE: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism. OBJECTIVES: To examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers. METHODS: Serum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15-minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach. MEASUREMENTS AND MAIN RESULTS: Metabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together with increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial ß-oxidation-derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation of ß-oxidation by ozone in exercising humans. CONCLUSIONS: As in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517).

Metabolites in stored platelets associated with platelet recoveries and survivals.

BACKGROUND: Transfusion of platelets (PLTs) is a common therapy in a number of clinical settings. However, it is well understood that there is substantial donor-to-donor variation in how well PLTs store and thus the quality of the products that are transfused. The basis of such variation is poorly understood, and there are limited metrics by which units of PLTs can be assessed for their posttransfusion performance. It has repeatedly been demonstrated that myriad biologic changes take place during PLT storage; however, which of the changes correlate with quality of the stored PLTs and/or are mechanistically involved in PLT function remains undetermined. STUDY DESIGN AND METHODS: The current study tested stored PLTs from 21 normal subjects, combining high-resolution metabolomics of stored PLTs with in vivo PLT recoveries and survivals. Both individual analytes and metabolic pathways that correlate with posttransfusion PLT viability were identified. RESULTS: Caffeine metabolites were associated with poor PLT recovery; caffeine metabolism was not ongoing in the PLT bag and remained at prestorage levels. Acylcarnitines, particular fatty acid metabolites, and oxidized fatty acids were associated with poor PLT survivals. Of the myriad metabolic changes during PLT storage, these are the first reported metabolic findings to begin distinguishing which changes are of functional importance regarding posttransfusion PLT performance. CONCLUSIONS: Together, these findings provide novel mechanistic insights into the functional biology of the PLT storage lesion as well as identifying potential targets for modifying donor environment (e.g., caffeine consumption) and also metrics of quality assessment for stored human PLTs.

From metabolomics to fluxomics: a computational procedure to translate metabolite profiles into metabolic fluxes.

We describe a believed-novel procedure for translating metabolite profiles (metabolome) into the set of metabolic fluxes (fluxome) from which they originated. Methodologically, computational modeling is integrated with an analytical platform comprising linear optimization, continuation and dynamic analyses, and metabolic control. The procedure was tested with metabolite profiles obtained from ex vivo mice Langendorff-heart preparations perfused with glucose. The metabolic profiles were analyzed using a detailed kinetic model of the glucose catabolic pathways including glycolysis, pentose phosphate (PP), glycogenolysis, and polyols to translate the glucose metabolome of the heart into the fluxome. After optimization, the ability of the model to simulate the initial metabolite profile was confirmed, and metabolic fluxes as well as the structure of control and regulation of the glucose catabolic network could be calculated. We show that the step catalyzed by phosphofructokinase together with ATP demand and glycogenolysis exert the highest control on the glycolytic flux. The negative flux control exerted by phosphofructokinase on the PP and polyol pathways revealed that the extent of glycolytic flux directly affects flux redirection through these pathways, i.e., the higher the glycolytic flux the lower the PP and polyols. This believed-novel methodological approach represents a step forward that may help in designing therapeutic strategies targeted to diagnose, prevent, and treat metabolic diseases.

Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis.

BACKGROUND & AIMS: A greater understanding of cholestatic disease is necessary to advance diagnostic tools and therapeutic options for conditions such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The purpose of this study was to determine and compare the serum metabolomes of patients with PBC (n = 18) or PSC (n = 21) and healthy controls (n = 10) and to identify metabolites that may differentiate these two cholestatic diseases. METHODS AND RESULTS: Using a mass spectrometry-based, non-targeted biochemical profiling approach, we identified 420 serum metabolites, 101 that differed significantly (P ≤ 0.05) between PBC and control groups, 115 that differed significantly between PSC and control groups, and 56 that differed significantly between PSC and PBC groups. Random forest classification analysis was able to distinguish patients with PBC or PSC with 95% accuracy with selected biochemicals reflective of protein and amino acid metabolism identified as the major contributors. Metabolites related to bile acid metabolism, lipid metabolism, inflammation, and oxidative stress/lipid peroxidation were also identified as differing significantly when comparing the disease groups and controls, with some of these pathways differentially affected in the PBC and PSC groups. CONCLUSION: In this study, we identified novel metabolic changes associated with cholestatic disease that were both consistent and different between PBC and PSC. Validation studies in larger patient cohorts are required to determine the utility of these biochemical markers for diagnosis and therapeutic monitoring of patients with PBC and PSC.

Strain-specific red blood cell storage, metabolism, and eicosanoid generation in a mouse model.

BACKGROUND: Red blood cell (RBC) transfusion is a lifesaving therapy, the logistic implementation of which requires RBC storage. However, stored RBCs exhibit substantial donor variability in multiple characteristics, including hemolysis in vitro and RBC recovery in vivo. The basis of donor variability is poorly understood. STUDY DESIGN AND METHODS: We applied a murine model of RBC storage and transfusion to test the hypothesis that genetically distinct inbred strains of mice would demonstrate strain-specific differences in RBC storage. In vivo recoveries were determined by monitoring transfused RBCs over 24 hours. Timed aliquots of stored RBCs were subjected to tandem chromatography/mass spectrometry analysis to elucidate metabolic changes in the RBCs during storage. RESULTS: Using independent inbred mouse strains as donors, we found substantial strain-specific differences in posttransfusion RBC recovery in vivo after standardized refrigerated storage in vitro. Poor posttransfusion RBC recovery correlated with reproducible metabolic variations in the stored RBC units, including increased lipid peroxidation, decreased levels of multiple natural antioxidants, and accumulation of cytidine. Strain-dependent differences were also observed in eicosanoid generation (i.e., prostaglandins and leukotrienes). CONCLUSION: These findings provide the first evidence of strain-specific metabolomic differences after refrigerated storage of murine RBCs. They also provide the first definitive biochemical evidence for strain-specific variation of eicosanoid generation during RBC storage. The molecules described that correlate with RBC storage quality, and their associated biochemical pathways, suggest multiple causal hypotheses that can be tested regarding predicting the quality of RBC units before transfusion and developing methods of improved RBC storage.

Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study.

UNLABELLED: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). CONCLUSION: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.

A bloodspot-based diagnostic test for fibromyalgia syndrome and related disorders.

The aim of this study was to investigate the ability of a rapid biomarker-based method for diagnosis of fibromyalgia syndrome (FM) using mid-infrared microspectroscopy (IRMS) to differentiate patients with FM from those with osteoarthritis (OA) and rheumatoid arthritis (RA), and to identify molecular species associated with the spectral patterns. Under IRB approval, blood samples were collected from patients diagnosed with FM (n = 14), RA (n = 15), or OA (n = 12). Samples were prepared, placed onto a highly reflective slide, and spectra were collected using IRMS. Spectra were analyzed using multivariate statistical modeling to differentiate groups. Aliquots of samples also were subjected to metabolomic analysis. IRMS separated subjects into classes based on spectral information with no misclassifications among FM and RA or OA patients. Interclass distances of 15.4 (FM vs. RA), 14.7 (FM vs. OA) and 2.5 (RA vs. OA) among subjects, demonstrating the ability of IRMS to achieve reliable resolution of unique spectral patterns specific to FM. Metabolomic analysis revealed that RA and OA groups were metabolically similar, whereas biochemical differences were identified in the FM that were quite distinctive from those found in the other two groups. Both IRMS and metabolomic analysis identified changes in tryptophan catabolism pathway that differentiated patients with FM from those with RA or OA.

Household Composition, Income, and Fast-Food Consumption among Black Women and Men.

Black adults are more likely to consume meals from fast-food restaurants than other racial/ethnic groups with implications for disparities in dietary quality and obesity outcomes. Family and economic characteristics are associated with fast-food consumption. The aim of this study was to determine the association between household composition, income, and fast-food consumption among Black women and men. A cross-sectional, secondary analysis of nationally representative data from the 2011-2018 National Health and Nutrition Examination Survey using multiplicative interaction terms and negative binomial regressions were used to assess whether household income moderated associations between number of children or older adults in the household and number of weekly fast-food meals consumed. Household composition was not associated with fast-food consumption among Black women overall. Yet, demonstrated by a significant interaction (incidence rate ratio (IRR) = 3.41, 95% confidence interval (CI) = 1.59-7.32), Black women with higher household income (≥ $75,000) and multiple young children consumed more fast-food compared to women with no children in the household. In contrast, Black men with one school-aged child in the home consumed fewer weekly fast-food meals than men with no school-aged children in the home (IRR = 0.69, 95% CI = 0.51-0.93). A significant interaction between number of older adults in the household and household income ≥ $75,000 (IRR = 3.56, 95% CI = 1.59-8.01) indicated that Black men with lower incomes and at least one older adult in the household consumed fewer weekly fast-food meals. These findings demonstrate that household composition and household income interact on fast-food consumption among Black women and men. Future studies should interrogate these differences, while programs and policies can be informed by the results of this study.

Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD), ranging from relatively benign simple steatosis to progressive nonalcoholic steatohepatitis (NASH) and fibrosis, is an increasingly common chronic liver disease. Liver biopsy is currently the only reliable tool for staging the subtypes of NAFLD; therefore, noninvasive serum biomarkers for evaluation of liver disease and fibrosis are urgently needed. We performed this study to describe changes in the serum proteome and identify biomarker candidates in serum samples from 69 patients with varying stages of NAFLD (simple steatosis, NASH, and NASH with advanced bridging [F3/F4] fibrosis) and 16 obese controls. Using a label-free mass spectrometry-based approach we identified over 1,700 serum proteins with a peptide identification (ID) confidence level of >75%, 605 of which changed significantly between any two patient groups (false discovery rate <5%). Importantly, expression levels of 55 and 15 proteins changed significantly between the simple steatosis and NASH F3/F4 group and the NASH and NASH F3/F4 group, respectively. Classification of proteins with significant changes showed involvement in immune system regulation and inflammation, coagulation, cellular and extracellular matrix structure and function, and roles as carrier proteins in the blood. Further, many of these proteins are synthesized exclusively by the liver and could potentially serve as diagnostic biomarkers for identifying and staging NAFLD. CONCLUSION: This proteomic analysis reveals important information regarding the pathogenesis/progression of NAFLD and NASH and demonstrates key changes in serum protein expression levels between control subjects and patients with different stages of fatty liver. Future validation of these potential biomarkers is needed such that these proteins may be used in place of liver biopsy to facilitate diagnosis and treatment of patients with NAFLD.

Hepatic lipid peroxidation and cytochrome P-450 2E1 in pediatric nonalcoholic fatty liver disease and its subtypes.

GOAL: To compare hepatic lipid peroxidation and cytochrome P-450 2E1 (CYP2E1) protein content in liver biopsies from children with nonalcoholic fatty liver disease (NAFLD) and 2 control groups. BACKGROUND: Elevated hepatic lipid peroxidation resulting from increased hepatic CYP2E1 enzyme activity is involved in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) in adults, but studies in children are lacking. STUDY: Liver biopsies from 59 children with NAFLD (49 with NASH), 10 children with normal liver histology, and 9 children with mild chronic hepatitis C (HCV) infection were examined. Hepatic malondialdehyde (a measure of lipid peroxidation) levels and CYP2E1 protein content were quantitated, as a percentage of the total area, by immunohistochemical staining of liver biopsy material followed by digital image quantitation. RESULTS: Lipid peroxidation was significantly greater in NAFLD liver biopsies (46.7 ± 20.8%) compared with biopsies from children with normal liver histology (7.6 ± 9.4%; P<0.001) or HCV infection (7.7 ± 7.6%; P<0.001). However, hepatic CYP2E1 expression was not different across the NAFLD, normal liver histology, and HCV groups (60.7 ± 8.7%, 53.5 ± 10.7%, and 60.0 ± 11.9%, respectively; P=0.116). Among children with NAFLD, lipid peroxidation and CYP2E1 protein content did not differ between biopsies with and without NASH. Body mass index was independently associated with hepatic lipid peroxidation levels (r=0.549; P<0.001). CONCLUSIONS: Hepatic lipid peroxidation is increased in children with NAFLD but this is not related to hepatic CYP2E1 expression. No difference in lipid peroxidation in pediatric NAFLD versus NASH argues against a role in disease progression.

Serum proteomic analysis of diet-induced steatohepatitis and metabolic syndrome in the Ossabaw miniature swine.

We recently developed a nutritional model of steatohepatitis and metabolic syndrome in Ossabaw pigs. Here we describe changes in the serum proteome of pigs fed standard chow (control group; n = 7), atherogenic diet (n = 5), or modified atherogenic diet (M-ath diet group; n = 6). Pigs fed atherogenic diet developed metabolic syndrome and mildly abnormal liver histology, whereas pigs fed M-ath diet exhibited severe metabolic syndrome and liver injury closely resembling human nonalcoholic steatohepatitis (NASH). Using a label-free mass spectrometry-based proteomics approach, we identified 1,096 serum proteins, 162 of which changed significantly between any two diet groups (false discovery rate <5%). Biological classification of proteins with significant changes revealed functions previously implicated in development of NASH in humans, including immune system regulation and inflammation (orosomucoid 1, serum amyloid P component, paraoxonase 1, protein similar to alpha-2-macroglobulin precursor, beta-2-microglobulin, p101 protein, and complement components 2 and C8G), lipid metabolism (apolipoproteins C-III, E, E precursor, B, and N), structural and extracellular matrix proteins (transthyretin and endopeptidase 24.16 type M2), and coagulation [carboxypeptidase B2 (plasma)]. Several proteins with significant differential expression in pigs were also identified in our recent human proteomics study as changing significantly in serum from patients across the spectrum of nonalcoholic fatty liver disease, including apolipoproteins C-III and B, orosomucoid 1, serum amyloid P component, transthyretin, paraoxonase 1, and a protein similar to alpha-2-macroglobulin precursor. This serum proteomic analysis provides additional information about the pathogenesis of NASH and further characterizes our large animal model of diet-induced steatohepatitis and metabolic syndrome in Ossabaw pigs.

Bariatric surgery-induced weight loss reduces hepatic lipid peroxidation levels and affects hepatic cytochrome P-450 protein content.

OBJECTIVE: To evaluate the effects of surgical weight loss on hepatic lipid peroxidation levels and cytochrome P-450 protein expression in patients with nonalcoholic fatty liver disease (NAFLD). SUMMARY BACKGROUND DATA: NAFLD and nonalcoholic steatohepatitis (NASH) affect hepatic cytochrome P-450 (CYP) protein expression and activity, and CYP2E1 may play a role in the pathogenesis of NAFLD and NASH through induction of oxidative stress and lipid peroxidation. NAFLD and NASH are associated with increased systemic lipid peroxidation levels and elevated hepatic CYP2E1 activity, but hepatic CYP3A4/5 activity is decreased. METHODS: Liver biopsies from 20 patients with NAFLD who underwent bariatric surgery were obtained intraoperatively and at 15 +/- 7 months following surgery. Hepatic malondialdehyde (MDA) levels (a marker of lipid peroxidation), CYP2E1 and CYP3A4/5 protein expression, and steatosis, as a percent of total area, were measured by immunohistochemistry followed by digital image quantitation. RESULTS: Following weight loss, as reflected by reduced BMI (54 +/- 9 vs. 37 +/- 9 kg/m2; P < 0.001), features of the metabolic syndrome, grade and stage of liver disease, and liver histology were all significantly improved (P < 0.01). Hepatic MDA staining (35 +/- 18% vs. 23 +/- 14%; P = 0.02), CYP2E1 protein content (68 +/- 9% vs. 56 +/- 11%; P < 0.001), and steatosis (17 +/- 7% vs. 2 +/- 3%; P < 0.001) were significantly reduced following weight loss. CYP3A4/5 protein content was unchanged (57 +/- 13% vs. 55 +/- 13%; P = 0.433). The reduction in lipid peroxidation was independently associated with changes in CYP2E1 protein expression after bariatric surgery (r = 0.477; P = 0.033). CONCLUSION: Elevations in hepatic lipid peroxidation and CYP2E1 expression that are seen in NAFLD improve significantly with weight loss induced by bariatric surgery.

Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase(SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

Epidemiology of idiosyncratic drug-induced liver injury.

Idiosyncratic drug-induced liver injury (DILI) is a significant health problem because of its unpredictable nature, poorly understood pathogenesis, and potential to cause fatal outcomes. It is also a significant hurdle for drug development and marketing of safe prescription medications. Idiosyncratic DILI is generally rare, but its occurrence is likely underappreciated due to the lack of active reporting or surveillance systems and substantial challenges involved in its recognition and diagnosis. Nonetheless, DILI is a common cause of potentially serious and fatal acute liver failure in both children and adults. Population-based studies that accurately estimate the incidence and full spectrum of DILI are limited. However, using a prospective, population-based French study with an annual estimated incidence of 13.9 +/- 2.4 DILI cases per 100,000 inhabitants, it has been extrapolated that nearly 44,000 individuals in the United States will suffer from DILI each year. Although increasing numbers of patients are also being seen with DILI due to herbal and dietary supplements, the epidemiology of this entity requires further investigation. In this article, the epidemiology of DILI, both in the general population and in potentially high-risk subgroups, is reviewed.

Ozone-induced changes in the serum metabolome: Role of the microbiome.

Ozone is an asthma trigger. In mice, the gut microbiome contributes to ozone-induced airway hyperresponsiveness, a defining feature of asthma, but the mechanistic basis for the role of the gut microbiome has not been established. Gut bacteria can affect the function of distal organs by generating metabolites that enter the blood and circulate systemically. We hypothesized that global metabolomic profiling of serum collected from ozone exposed mice could be used to identify metabolites contributing to the role of the microbiome in ozone-induced airway hyperresponsiveness. Mice were treated for two weeks with a cocktail of antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) in the drinking water or with control water and then exposed to air or ozone (2 ppm for 3 hours). Twenty four hours later, blood was harvested and serum analyzed via liquid-chromatography or gas-chromatography coupled to mass spectrometry. Antibiotic treatment significantly affected 228 of the 562 biochemicals identified, including reductions in the known bacterially-derived metabolites, equol, indole propionate, 3-indoxyl sulfate, and 3-(4-hydroxyphenyl)propionate, confirming the efficacy of the antibiotic treatment. Ozone exposure caused significant changes in 334 metabolites. Importantly, ozone-induced changes in many of these metabolites were different in control and antibiotic-treated mice. For example, most medium and long chain fatty acids declined by 20-50% with ozone exposure in antibiotic-treated but not control mice. Most taurine-conjugated bile acids increased with ozone exposure in antibiotic-treated but not control mice. Ozone also caused marked (9-fold and 5-fold) increases in the polyamines, spermine and spermidine, respectively, in control but not antibiotic-treated mice. Each of these metabolites has the capacity to alter airway responsiveness and may account for the role of the microbiome in pulmonary responses to ozone.

Variation in Definitions of Immobility in Pharmacological Thromboprophylaxis Clinical Trials in Medical Inpatients: A Systematic Review.

BACKGROUND: Although immobility is a common risk factor for venous thromboembolism (VTE) in medical inpatients, lack of a consistent definition of this term may limit accurate assessment of VTE risk for thromboprophylaxis. OBJECTIVE: To examine various definitions of immobility used in recent pharmacological thromboprophylaxis clinical trials. DATA SOURCES: PubMed and relevant references from articles/reviews from 2008 to 2016 were searched. Randomized controlled trials (RCTs) and other clinical studies involving adult hospitalized medical patients in acute care hospital settings that used the term immobility were selected. Two investigators independently abstracted data in duplicate, and accuracy was checked by a third investigator. RESULTS: Twenty-one clinical studies were included. There was heterogeneity among individual VTE risk factors, with respect to the definition of immobility in medical inpatients in these trials. Thirteen studies utilized objective criteria to define "immobility" including duration (12 studies) and distance or time walked (6 studies). In contrast, 7 studies focused principally on subjective definitions (ie, describing the nature of immobility rather than specifying its quantitative measurement). Three RCTs vaguely defined the level of patient's immobility after hospitalization. CONCLUSION: Despite the well-known effectiveness of pharmacological thromboprophylaxis for the prevention of VTE in acutely ill medical patients, there is no current consensus on how to define immobility. The heterogeneous nature of definitions of immobility has led to uncertainty about the importance of immobility in VTE risk assessment models. Although clinical studies have incorporated varying definitions of immobility into their inclusion criteria, immobility as a specific VTE risk factor has not been clearly defined.

Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma.

An altered metabolism is involved in the development of clear cell - renal cell carcinoma (ccRCC), and in this tumor many altered genes play a fundamental role in controlling cell metabolic activities. We delineated a large-scale metabolomic profile of human ccRCC, and integrated it with transcriptomic data to connect the variations in cancer metabolism with gene expression changes. Moreover, to better analyze the specific contribution of metabolic gene alterations potentially associated with tumorigenesis and tumor progression, we evaluated the transcription profile of primary renal tumor cells. Untargeted metabolomic analysis revealed a signature of an increased glucose uptake and utilization in ccRCC. In addition, metabolites related to pentose phosphate pathway were also altered in the tumor samples in association with changes in Krebs cycle intermediates and related metabolites. We identified NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) as the most highly expressed gene in renal cancer cells and evaluated its role in sustaining angiogenesis, chemoresistance, and mitochondrial dysfunction. Finally, we showed that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.

Colorectal Cancer Screening.

Colorectal cancer (CRC) continues to be one of the most commonly diagnosed cancers and contributes significantly to many cancer-related deaths despite sustained progress in diagnostic and treatment options. Many forms of CRC can be prevented through early and routine screening, when precancerous lesions may be detected and removed before they undergo malignant transformation or metastasis. Despite widespread efforts to improve CRC screening rates, at least 40% of age-eligible adults do not adhere to screening guidelines. A new generation of noninvasive, molecular-based diagnostic tests with high sensitivities and specificities has the potential to improve screening rates through optimal risk stratification of patients who may benefit from more invasive screening techniques. This review presents various guidelines and methods that are currently available for CRC screening, summarizes the rationale behind utilization of novel molecular-based diagnostic tests for CRC screening and prevention, and discusses appropriate screening techniques and intervals in populations of varying risk.