Ciprofloxacin-Resistant Neisseria meningitidis, Delhi, India

Decreased susceptibility of Neisseria meningitidis isolates to ciprofloxacin emerged from an outbreak in Delhi, India. Results of antimicrobial susceptibility testing of the meningococcal isolates to ciprofloxacin and further sequencing of DNA gyrase A quinolone-resistance–determining region confirmed the emergence of ciprofloxacin resistance in the outbreak

Efficacy of maternal B-12 supplementation in vegetarian women for improving infant neurodevelopment: protocol for the MATCOBIND multicentre, double-blind, randomised controlled trial

INTRODUCTION: Vitamin B12 deficiency is widely prevalent across many low- and middle-income countries, especially where the diet is low in animal sources. While many observational studies show associations between B12 deficiency in pregnancy and infant cognitive function (including memory, language and motor skills), evidence from clinical trials is sparse and inconclusive. METHODS AND ANALYSIS: This double-blind, multicentre, randomised controlled trial will enrol 720 vegetarian pregnant women in their first trimester from antenatal clinics at two hospitals (one in India and one in Nepal). Eligible mothers who give written consent will be randomised to receive either 250 mcg methylcobalamin or 50 mcg (quasi control), from enrolment to 6 months post-partum, given as an oral daily capsule. All mothers and their infants will continue to receive standard clinical care. The primary trial outcome is the offspring's neurodevelopment status at 9 months of age, assessed using the Development Assessment Scale of Indian Infants. Secondary outcomes include the infant's biochemical B12 status at age 9 months and maternal biochemical B12 status in the first and third trimesters. Maternal biochemical B12 status will also be assessed in the first trimester. Modification of association by a priori identified factors will also be explored. ETHICAL CONSIDERATIONS AND DISSEMINATION: The study protocol has been approved by ethical committees at each study site (India and Nepal) and at University College London, UK. The study results will be disseminated to healthcare professionals and academics globally via conferences, presentations and publications. Researchers at each study site will share results with participants during their follow-up visits.Trial registration numberCTRI/2018/07/015048 (Clinical Trial Registry of India); NCT04083560 (ClinicalTrials.gov)

Network Inference Algorithms Elucidate Nrf2 Regulation of Mouse Lung Oxidative Stress

A variety of cardiovascular, neurological, and neoplastic conditions have been associated with oxidative stress, i.e., conditions under which levels of reactive oxygen species (ROS) are elevated over significant periods. Nuclear factor erythroid 2-related factor (Nrf2) regulates the transcription of several gene products involved in the protective response to oxidative stress. The transcriptional regulatory and signaling relationships linking gene products involved in the response to oxidative stress are, currently, only partially resolved. Microarray data constitute RNA abundance measures representing gene expression patterns. In some cases, these patterns can identify the molecular interactions of gene products. They can be, in effect, proxies for protein–protein and protein–DNA interactions. Traditional techniques used for clustering coregulated genes on high-throughput gene arrays are rarely capable of distinguishing between direct transcriptional regulatory interactions and indirect ones. In this study, newly developed information-theoretic algorithms that employ the concept of mutual information were used: the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Context Likelihood of Relatedness (CLR). These algorithms captured dependencies in the gene expression profiles of the mouse lung, allowing the regulatory effect of Nrf2 in response to oxidative stress to be determined more precisely. In addition, a characterization of promoter sequences of Nrf2 regulatory targets was conducted using a Support Vector Machine classification algorithm to corroborate ARACNE and CLR predictions. Inferred networks were analyzed, compared, and integrated using the Collective Analysis of Biological Interaction Networks (CABIN) plug-in of Cytoscape. Using the two network inference algorithms and one machine learning algorithm, a number of both previously known and novel targets of Nrf2 transcriptional activation were identified. Genes predicted as novel Nrf2 targets include Atf1, Srxn1, Prnp, Sod2, Als2, Nfkbib, and Ppp1r15b. Furthermore, microarray and quantitative RT-PCR experiments following cigarette-smoke-induced oxidative stress in Nrf2+/+ and Nrf2−/− mouse lung affirmed many of the predictions made. Several new potential feed-forward regulatory loops involving Nrf2, Nqo1, Srxn1, Prdx1, Als2, Atf1, Sod1, and Park7 were predicted. This work shows the promise of network inference algorithms operating on high-throughput gene expression data in identifying transcriptional regulatory and other signaling relationships implicated in mammalian disease

Adjuvant chemotherapy for small intestine adenocarcinoma

BACKGROUND: Although the small intestine represents 75% of the length and over 90% of the mucosal surface of the alimentary tract, it is the site of only about 2% of malignant gastrointestinal tumours. Adenocarcinoma is the most common histological subtype, accounting for about 40% of all malignant small intestinal tumours. The infrequent occurrence when compared with malignancies of the stomach and colon is accompanied by non‐specific clinical symptoms. The consequences are a significant delay in diagnosis and the finding of advanced, incurable disease at operation. Wide surgical resection of early lesions is the only potentially curative treatment, but it is possible only in a minority of patients. The rare nature of adenocarcinomas of the small intestine has led to a paucity of information about the benefits of adjuvant chemotherapy but there are reports of overall better survival for those patients that receive combination treatment. Most chemotherapy regimens consist of 5‐fluorouracil (5‐FU), alone or in combination with a variety of other agents like doxorubicin, cisplatin, mitomycin C, cyclophosphamide and oxaliplatin. OBJECTIVES: To determine the role of adjuvant chemotherapy in the management of adenocarcinoma of the small intestine compared to another adjuvant treatment, a placebo or no other adjuvant treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to 2009), EMBASE (1974 to 2009), PubMed and CINHAL using the Cochrane highly sensitive search strategy for randomised controlled trials. Additional hand searching was done by going through abstracts of major conferences like American society of clinical oncology and World GI cancer conference. SELECTION CRITERIA: Phase III randomised controlled trials comparing post‐operative adjuvant chemotherapy for adenocarcinoma of the small intestine with other adjuvant therapies, placebo or no adjuvant treatment. DATA COLLECTION AND ANALYSIS: No suitable trials were identified. MAIN RESULTS: No studies fulfilled the inclusion criteria. AUTHORS' CONCLUSIONS: There is a need for high quality randomised controlled trials to evaluate the effectiveness of adjuvant chemotherapy in the management of adenocarcinoma of the small intestine

Bacterial & fungal biofilms in chronic rhinosinusitis.

Chronic Rhinosinusitis (CRS) is a recalcitrant disease, characterized by headache, nasal discharge / blockage, which substantially impairs daily functioning and negatively affect quality of life. Endoscopic Sinus Surgery (ESS) is an important treatment option for CRS, but has variable success rates. Biofilms are well organised heterogeneous communities of microbes embedded in a mosaic of extracellular matrix, adherent to biotic / abiotic surfaces. As they are resistant to host defences and medical treatments, they have been touted as possible pathogenic factors in CRS, which may perpetuate the recurrent and recalcitrant character of the disease and negatively affect treatment outcomes. This thesis encompasses research undertaken to enhance our understanding about the effect that presence and types of biofilms have on the clinical profile and treatment outcomes of patients suffering with chronic rhinosinusitis. An in-vitro model of fungal biofilms and a potential tool to assay in-vivo mucosal biofilms on sinonasal tissues has also been described. Chapter 1 of the thesis comprehensively reviews the scientific literature pertaining to biofilms and CRS, and exhaustively evaluates the evidence present in relation to bacterial and fungal biofilms in CRS. Chapter 2 describes a study to investigate the effect of biofilms on outcomes following ESS in CRS patients using internationally accepted standardised symptom scores, quality of life measures and endoscopy scores to assess the disease. It showed that patients with biofilms presented with more severe disease before surgery, and after surgery had persistent symptoms, ongoing mucosal inflammation and infections necessitating extra post-operative visits and multiple antibiotic treatments. This study thus strengthened the evidence for the role that biofilms may play in recalcitrant CRS. Chapter 3 describes a further subgroup analysis of the above patients in whom the specific organisms forming the biofilms were identified and how patients with specific biofilm types progressed after surgery was studied. Patients with polymicrobial biofilms suffered more severe disease and had worse post-surgery mucosal outcomes requiring more post–operative visits. S.aureus biofilms played a dominant role in negatively affecting outcomes of ESS with persisting post-operative symptoms, ongoing mucosal inflammation and infections. Chapter 4 describes an in-vitro model characterizing A. fumigatus biofilm formation on primary human sinonasal epithelium cultures under different growth conditions. 3-dimensional biofilm structures with parallel-packed and cross-linked hyphae, channels/passages, extracellular matrix (ECM) encasing the hyphae, were formed. Biofilms formed under flow conditions displayed more robust and faster growth kinetics as compared to those under static conditions, with extensive ECM production. Chapter 5 investigates application of an analysis program ‘COMSTAT 2’ for assaying & quantitatively describing the 3-dimensional in-vivo biofilm structures observed via confocal scanning microscopy on sino-nasal mucosal samples. This can be used for temporal analysis of biofilm development, comparison of different types of biofilms formed under controlled conditions, analysis of influence of varying environmental factors on biofilms and the efficacy of different antibiofilm treatments. Chapter 6 summarises and discusses the salient features of the studies included in this thesis which has attempted to characterize fungal and bacterial biofilms and the impact they may have in CRS patients.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201