Rifaximin for maintenance therapy in antibiotic-dependent pouchitis

<p>Abstract</p> <p>Background</p> <p>Pouchitis is the most common long-term complication of in patients with restorative proctocolectomy and ileal pouch-anal anastomosis. Patients often develop antibiotic-dependent form of pouchitis requiring long-term antibiotic therapy for remission maintenance. Rifaximin, an oral, non-systemic, broad-spectrum antibiotic with a favorable safety profile, may be a promising candidate agent for maintenance therapy. This historical cohort open-label study investigated the efficacy and tolerability of rifaximin in maintaining symptomatic and endoscopic remission in patients with antibiotic-dependent pouchitis.</p> <p>Methods</p> <p>Adult patients with antibiotic-dependent pouchitis received a 2-week course of various antibiotics for induction of remission. Patients in remission then began maintenance therapy with rifaximin 200 mg/day (to 1800 mg/day) for up to 24 months. Pouchitis Disease Activity Index symptom scores were assessed every 1–3 months to evaluate efficacy.</p> <p>Results</p> <p>Fifty-one patients began maintenance therapy with rifaximin (median dose 200 mg/day); 33 (65%) maintained remission through 3 months (primary endpoint). Of these 33 patients, 26 (79%) successfully continued maintenance for 6 months after beginning maintenance, 19 (58%) successfully continued for 12 months, and two (6%) successfully continued for 24 months. Only one patient reported an adverse event (transient facial rash).</p> <p>Conclusion</p> <p>Patients' response to rifaximin as a maintenance therapy appears to be favorable in this open-labeled trial of antibiotic-dependent pouchitis. Randomized, placebo-controlled trials with a longer follow-up are warranted.</p

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic lowgrade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders

First insights into the genetic diversity of Mycobacterium tuberculosis isolates from HIV-infected Mexican patients and mutations causing multidrug resistance

<p>Abstract</p> <p>Background</p> <p>The prevalence of infections with <it>Mycobacterium tuberculosis </it>(MTb) and nontuberculous mycobacteria (NTM) species in HIV-infected patients in Mexico is unknown. The aims of this study were to determine the frequency of MTb and NTM species in HIV-infected patients from Mexico City, to evaluate the genotypic diversity of the <it>Mycobacterium tuberculosis </it>complex strains, to determine their drug resistance profiles by colorimetric microplate Alamar Blue assay (MABA), and finally, to detect mutations present in <it>kat</it>G, <it>rpo</it>B and <it>inh</it>A genes, resulting in isoniazid (INH) and rifampin (RIF) resistance.</p> <p>Results</p> <p>Of the 67 mycobacterial strains isolated, 48 were identified as MTb, 9 as <it>M. bovis</it>, 9 as <it>M. avium </it>and 1 as <it>M. intracellulare</it>. IS<it>6110</it>-RFLP of 48 MTb strains showed 27 profiles. Spoligotyping of the 48 MTb strains yielded 21 patterns, and 9 <it>M. bovis </it>strains produced 7 patterns. Eleven new spoligotypes patterns were found. A total of 40 patterns were produced from the 48 MTb strains when MIRU-VNTR was performed. Nineteen (39.6%) MTb strains were resistant to one or more drugs. One (2.1%) multidrug-resistant (MDR) strain was identified. A novel mutation was identified in a RIF-resistant strain, GAG → TCG (Glu → Ser) at codon 469 of <it>rpo</it>B gene.</p> <p>Conclusions</p> <p>This is the first molecular analysis of mycobacteria isolated from HIV-infected patients in Mexico, which describe the prevalence of different mycobacterial species in this population. A high genetic diversity of MTb strains was identified. New spoligotypes and MIRU-VNTR patterns as well as a novel mutation associated to RIF-resistance were found. This information will facilitate the tracking of different mycobacterial species in HIV-infected individuals, and monitoring the spread of these microorganisms, leading to more appropriate measures for tuberculosis control.</p

Gene Silencing of \u3ci\u3eArgonaute5\u3c/i\u3e Negatively Affects the Establishment of the Legume-Rhizobia Symbiosis

The establishment of the symbiosis between legumes and nitrogen-fixing rhizobia is finely regulated at the transcriptional, posttranscriptional and posttranslational levels. Argonaute5 (AGO5), a protein involved in RNA silencing, can bind both viral RNAs and microRNAs to control plant-microbe interactions and plant physiology. For instance, AGO5 regulates the systemic resistance of Arabidopsis against Potato Virus X as well as the pigmentation of soybean (Glycine max) seeds. Here, we show that AGO5 is also playing a central role in legume nodulation based on its preferential expression in common bean (Phaseolus vulgaris) and soybean roots and nodules. We also report that the expression of AGO5 is induced after 1 h of inoculation with rhizobia. Down-regulation of AGO5 gene in P. vulgaris and G. max causes diminished root hair curling, reduces nodule formation and interferes with the induction of three critical symbiotic genes: Nuclear Factor Y-B (NF-YB), Nodule Inception (NIN) and Flotillin2 (FLOT2). Our findings provide evidence that the common bean and soybean AGO5 genes play an essential role in the establishment of the symbiosis with rhizobia

Analyses of chondrogenic induction of adipose mesenchymal stem cells by combined co-stimulation mediated by adenoviral gene transfer

INTRODUCTION: Adipose-derived stem cells (ASCs) have the potential to differentiate into cartilage under stimulation with some reported growth and transcriptional factors, which may constitute an alternative for cartilage replacement approaches. In this study, we analyzed the in vitro chondrogenesis of ASCs transduced with adenoviral vectors encoding insulin-like growth factor-1 (IGF-1), transforming growth factor beta-1 (TGF-β1), fibroblast growth factor-2 (FGF-2), and sex-determining region Y-box 9 (SOX9) either alone or in combinations. METHODS: Aggregate cultures of characterized ovine ASCs were transduced with 100 multiplicity of infections of Ad.IGF-1, Ad.TGF-β1, Ad.FGF-2, and Ad.SOX9 alone or in combination. These were harvested at various time points for detection of cartilage-specific genes expression by quantitative real-time PCR or after 14 and 28 days for histologic and biochemical analyses detecting proteoglycans, collagens (II, I and X), and total sulfated glycosaminoglycan and collagen content, respectively. RESULTS: Expression analyses showed that co-expression of IGF-1 and FGF-2 resulted in higher significant expression levels of aggrecan, biglycan, cartilage matrix, proteoglycan, and collagen II (all P ≤0.001 at 28 days). Aggregates co-transduced with Ad.IGF-1/Ad.FGF-2 showed a selective expression of proteoglycans and collagen II, with limited expression of collagens I and × demonstrated by histological analyses, and had significantly greater glycosaminoglycan and collagen production than the positive control (P ≤0.001). Western blot analyses for this combination also demonstrated increased expression of collagen II, while expression of collagens I and × was undetectable and limited, respectively. CONCLUSION: Combined overexpression of IGF-1/FGF-2 within ASCs enhances their chondrogenic differentiation inducing the expression of chondrogenic markers, suggesting that this combination is more beneficial than the other factors tested for the development of cell-based therapies for cartilage repair

Urolithins Are the Main Urinary Microbial-Derived Phenolic Metabolites Discriminating a Moderate Consumption of Nuts in FreeLiving Subjects with Diagnosed Metabolic Syndrome

Walnuts (Juglans regia L.), hazelnuts (Corylus avellana L.), and almonds (Prunus dulcis Mill.) are rich sources of ellagitannins and proanthocyanidins. Gut microbiota plays a crucial role in modulating the bioavailability of these high molecular weight polyphenols. However, to date there are no studies evaluating the capacity to produce nut phenolic metabolites in subjects with metabolic syndrome (MetS), a pathology associated with an altered gut bacterial diversity. This study applied a LC-MS targeted approach to analyze the urinary excretion of nut phenolic metabolites in MetS subjects following 12 weeks of nut consumption, compared to sex- and age-matched individuals given a nut-free control diet. Metabolites were targeted in both hydrolyzed and nonhydrolyzed urine by LC-PDA-QqQ-MS/MS analysis, and identification of metabolites lacking available standards was confirmed by LC-ESI-ITD-FT-MS. Ellagitannin-derived urolithins A and B significantly increased after the nutenriched-diet, urolithins C and D were also detected, and a complex combination of urolithin-conjugated forms was observed in nonhydrolyzed urine, confirming an extensive phase II metabolism after absorption. In contrast, no significant increases in proanthocyanidin microbial metabolites were observed in urine following nut consumption. Because the intestinal microbiota of the subjects in this study could catabolize ellagitannins into a wide range of urolithins, further research is strongly warranted on the in vivo potential of these microbial metabolites in reducing cardiometabolic risk

Genomic diversity of human papillomavirus-16, 18, 31, and 35 isolates in a Mexican population and relationship to European, African, and Native American variants

AbstractCervical cancer, mainly caused by infection with human papillomaviruses (HPVs), is a major public health problem in Mexico. During a study of the prevalence of HPV types in northeastern Mexico, we identified, as expected from worldwide comparisons, HPV-16, 18, 31, and 35 as highly prevalent. It is well known that the genomes of HPV types differ geographically because of evolution linked to ethnic groups separated in prehistoric times. As HPV intra-type variation results in pathogenic differences, we analyzed genomic sequences of Mexican variants of these four HPV types. Among 112 HPV-16 samples, 14 contained European and 98 American Indian (AA) variants. This ratio is unexpected as people of European ethnicity predominate in this part of Mexico. Among 15 HPV-18 samples, 13 contained European and 2 African variants, the latter possibly due to migration of Africans to the Caribbean coast of Mexico. We constructed phylogenetic trees of HPV-31 and 35 variants, which have never been studied. Forty-six HPV-31 isolates from Mexico, Europe, Africa, and the United States (US) contained a total of 35 nucleotide exchanges in a 428-bp segment, with maximal distances between any two variants of 16 bp (3.7%), similar to those between HPV-16 variants. The HPV-31 variants formed two branches, one apparently the European, the other one an African branch. The European branch contained 13 of 29 Mexican isolates, the African branch 16 Mexican isolates. These may represent the HPV-31 variants of American Indians, as a 55% prevalence of African variants in Mexico seems incomprehensible. Twenty-seven HPV-35 samples from Mexico, Europe, Africa, and the US contained 11 mutations in a 893-bp segment with maximal distances between any two variants of only 5 mutations (0.6%), including a characteristic 16-bp insertion/deletion. These HPV-35 variants formed several phylogenetic clusters rather than two- or three-branched trees as HPV-16, 18, and 31. An HPV-35 variant typical for American Indians was not identifiable. Our research suggests type specific patterns of evolution and spread of HPV-16, 18, 31, and 35 both before and after the worldwide migrations of the last four centuries. The high prevalence of highly carcinogenic HPV-16 AA variants, and the extensive diversity of HPV-18, 31, and 35 variants with unknown pathogenic properties raise the possibility that HPV intra-type variation contributes to the high cervical cancer burden in Mexico

Phosphate Deficiency Negatively Affects Early Steps of the Symbiosis between Common Bean and Rhizobia

Phosphate (Pi) deficiency reduces nodule formation and development in different legume species including common bean. Despite significant progress in the understanding of the genetic responses underlying the adaptation of nodules to Pi deficiency, it is still unclear whether this nutritional deficiency interferes with the molecular dialogue between legumes and rhizobia. If so, what part of the molecular dialogue is impaired? In this study, we provide evidence demonstrating that Pi deficiency negatively affects critical early molecular and physiological responses that are required for a successful symbiosis between common bean and rhizobia. We demonstrated that the infection thread formation and the expression of PvNSP2, PvNIN, and PvFLOT2, which are genes controlling the nodulation process were significantly reduced in Pi-deficient common bean seedlings. In addition, whole-genome transcriptional analysis revealed that the expression of hormones-related genes is compromised in Pi-deficient seedlings inoculated with rhizobia. Moreover, we showed that regardless of the presence or absence of rhizobia, the expression of PvRIC1 and PvRIC2, two genes participating in the autoregulation of nodule numbers, was higher in Pi-deficient seedlings compared to control seedlings. The data presented in this study provides a mechanistic model to better understand how Pi deficiency impacts the early steps of the symbiosis between common bean and rhizobia

Factors Contributing to the Utilization of Adult Mental Health Services in Children and Adolescents Diagnosed with Hyperkinetic Disorder

Objectives. To examine whether age of First diagnosis, gender, psychiatric comorbidity, and treatment modalities (pharmacotherapy or psychotherapy) at Child and Adolescent Mental Health Services (CAMHS) moderate the risk of Adult Mental Health Services (AMHS) utilization in patients diagnosed with hyperkinetic disorder at CAMHS. Methods. Data were derived from the Madrid Psychiatric Cumulative Register Study. The target population comprised 32,183 patients who had 3 or more visits at CAMHS. Kaplan-Meier curves were used to assess survival data. A series of logistic regression analyses were performed to study the role of age of diagnosis, gender, psychiatric comorbidity, and treatment modalities. Results. 7.1% of patients presented with hyperkinetic disorder at CAMHS. Compared to preschool children, children and adolescents first diagnosed with hyperkinetic disorder at CAMHS were more likely to use AMHS. Female gender and comorbidity with affective disorders, schizophrenia, schizotypal and delusional disorders increased the risk of use of AMHS. Pharmacological or combined treatment of hyperkinetic disorder diagnosed at CAMHS was associated with increased risk of use at AMHS. Conclusions. Older age of first diagnosis, female gender, psychiatric comorbidity, and pharmacological treatment at CAMHS are markers of risk for the transition from CAMHS to AMHS in patients with hyperkinetic disorder diagnosed at CAMHS