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Mycobacterium africanum consists of Lineages L5 and L6 of the Mycobacterium tuberculosis complex (MTBC) and causes human tuberculosis in specific regions of Western Africa, but is generally not transmitted in other parts of the world. Since M. africanum is evolutionarily closely placed between the globally dispersed Mycobacterium tuberculosis and animal-adapted MTBC-members, these lineages provide valuable insight into M. tuberculosis evolution. Here, we have collected 15 M. africanum L5 strains isolated in France over 4 decades. Illumina sequencing and phylogenomic analysis revealed a previously underappreciated diversity within L5, which consists of distinct sublineages. L5 strains caused relatively high levels of extrapulmonary tuberculosis and included multi- and extensively drug-resistant isolates, especially in the newly defined sublineage L5.2. The specific L5 sublineages also exhibit distinct phenotypic characteristics related to in vitro growth, protein secretion and in vivo immunogenicity. In particular, we identified a PE_PGRS and PPE-MPTR secretion defect specific for sublineage L5.2, which was independent of PPE38. Furthermore, L5 isolates were able to efficiently secrete and induce immune responses against ESX-1 substrates contrary to previous predictions. These phenotypes of Type VII protein secretion and immunogenicity provide valuable information to better link genome sequences to phenotypic traits and thereby understand the evolution of the MTBC. [ABSTRACT FROM AUTHOR]

In France, human botulism ismainly food-borne intoxication, whereas infant botulism is rare. A total of 99 group I and II Clostridium botulinumstrains including 59 typeA(12 historical isolates [1947-1961], 43 from France [1986-2013], 3 from other countries, and 1 collection strain), 31 type B (3 historical, 23 recent isolates, 4 from other countries, and 1 collection strain), and 9 type E (5 historical, 3 isolates, and 1 collection strain) were investigated by botulinum locus gene sequencing and multilocus sequence typing analysis. Historical C. botulinum A strains mainly belonged to subtype A1 and sequence type (ST) 1, whereas recent strains exhibited a wide genetic diversity: subtype A1 in orfX or ha locus, A1(B), A1(F), A2, A2b2, A5(B2') A5(B3'), as well as the recently identified A7 andA8 subtypes, and were distributed into 25 STs. Clostridium botulinum A1(B) was themost frequent subtype from food-borne botulism and food. Group I C. botulinum type B in France weremainly subtype B2 (14 out of 20 historical and recent strains) and were divided into19STs. Food-bornebotulism resulting fromhamconsumptionduring the recent periodwasdue to groupII C.botulinum B4. Type E botulismis rare in France, 5 historical and 1 recent strains were subtype E3. A subtype E12 was recently identified froman unusual ham contamination. Clostridium botulinum strains from human botulism in France showed a wide genetic diversity and seems to result not from a single evolutionary lineage but from multiple and independent genetic rearrangements. [ABSTRACT FROM AUTHOR]

Summary: We designed a PyQt graphical user interface--Sequanix--aimed at democratizing the use of Snakemake pipelines in the NGS space and beyond. By default, Sequanix includes Sequana NGS pipelines (Snakemake format) (http://sequana.readthedocs.io), and is also capable of loading any external Snakemake pipeline. New users can easily, visually, edit configuration files of expert-validated pipelines and can interactively execute these production-ready workflows. Sequanix will be useful to both Snakemake developers in exposing their pipelines and to a wide audience of users. [ABSTRACT FROM AUTHOR]

Objectives: The objective was to study a new vanG-type locus in Clostridium argentinense vanGCar and to determine its impact on glycopeptide susceptibility of the host. Methods: The whole genome of C. argentinense NCIB 10714 was sequenced using Illumina single-reads sequencing technology. The presence of vanGCar in seven C. argentinense strains was tested by PCR and its expression was tested by quantitative RT-PCR (qRT-PCR). Glycopeptide susceptibility was determined by the Etest procedure. Results: The vanGCar locus contained four genes encoding a carboxypeptidase, a D-alanine:D-serine ligase, a serine transporter and a serine racemase, and was present in the seven C. argentinense studied. An AraC-type transcriptional regulator was found upstream from the genes. C. argentinense NCIB 10714 was susceptible to vancomycin and to teicoplanin. qRT-PCR experiments revealed that vanGCar was not expressed without or with induction by a subinhibitory concentration of vancomycin. Conclusions: The new vanGCar locus was cryptic in C. argentinense and intrinsic to this species. Emergence of vancomycin resistance in C. argentinense due to decryptification of the vanGCar gene cluster could occur. [ABSTRACT FROM AUTHOR]

The occurrence of several unusual disorders in a single patient prompted the question as to whether these may all have been part of a single syndrome, and the possible differential diagnosis is discussed in detail. The case was thought to be an instance of acquired T-lymphocyte depletion leading to the development of premature malignant disease. [ABSTRACT FROM PUBLISHER]

In industrialized countries Candida albicans is considered the predominant commensal yeast of the human intestine, with approximately 40% prevalence in healthy adults. We discovered a highly original colonization pattern that challenges this current perception by studying in a 4- year interval a cohort of 151 Amerindians living in a remote community (French Guiana), and animals from their environment. The prevalence of C. albicans was persistently low (3% and 7% of yeast carriers). By contrast, Candida krusei and Saccharomyces cerevisiae were detected in over 30% of carriers. We showed that C. krusei and S. cerevisiae carriage was of food or environmental origin, whereas C. albicans carriage was associated with specific risk factors (being female and living in a crowded household). We also showed using whole-genome sequence comparison that C. albicans strains can persist in the intestinal tract of a healthy individual over a 4-year period. [ABSTRACT FROM AUTHOR]

Here we report the sequence of three mitochondrial genomes from yeasts of the Nakaseomyces clade that includes the pathogenic yeast Candida glabrata, namely, that of Kluyveromyces delphensis, Candida castellii and Kluyveromyces bacillisporus. The gene content is equivalent to that of C. glabrata, but reveals the existence of new group I introns in COX1 and CYTB and new potential intronic endonucleases. Gene order is highly rearranged in these genomes, which contain numerous palindromic GC clusters. The more GC nucleotides these elements contain, the longer and more AT-rich are the intergenes containing them, leading to a direct relationship between the number of Gs and Cs within the elements and the size of the genomes. Thus, there is a fivefold difference in size between the smallest and the largest mitochondrial genome, with the largest being the most AT-rich overall. Sequences are available under EMBL accession numbers , , and . [ABSTRACT FROM AUTHOR]

Investigates the attenuation of endotoxin-mediated inflammatory responses to hydroxymethylglutaryl co-enzyme A reductase inhibition. Alteration of the expression of endothelial constitutive nitric oxide synthase; Utilization of intravital microscopy to determine leucocyte-endothelial cell interactions; Release of proinflammatory cytokines.

Interleukin (IL)-2 immunotherapy is used for the treatment of metastatic melanoma and renal cell carcinoma and mediates its effects through the clonal expansion of lymphocytes. Although IL-2 remains the most effective form of therapy for these cancers, response rates are poor and dose escalation is hampered by side effects, which include vascular leak and lymphopenia. The mechanism underlying T cell loss is currently unidentified but could be the induction of activation-induced cell death (AICD) mediated by FasL. Our previous studies have shown that the amino acid taurine can attenuate apoptosis induced by a number of factors in different cell types. Here, we induced T cell AICD via CD3 and IL-2 stimulation and investigated the effect of taurine on lymphocyte apoptosis. Anti-CD3-activated Jurkat T cells treated with IL-2 significantly increased FasL expression, which was associated with increased apoptosis. Treatment with taurine prior to stimulation down-regulated FasL protein expression and partially inhibited apoptosis. Inhibition of FasL-signalling resulted in an identical reduction in apoptosis. As the kinetics of AICD are completely different in circulating T cells, we repeated these experiments in such cells to confirm our finding. Stimulation of CD4+ circulating T cells induced apoptosis in sensitized, but not freshly isolated T cells, which was abrogated partially by taurine. In Jurkat cells it was determined that taurine-mediated down-regulation of FasL protein expression was associated with decreased FasL mRNA expression and reduced NFκB activation. These results reveal one possible mechanism underlying the lymphopenia observed with IL-2 immunotherapy, involving increased FasL expression leading to apoptosis. Taurine may be of use in reversing the lymphopenia associated with IL-2, thereby augmenting its immunotherapeutic potential. [ABSTRACT FROM AUTHOR]

Evaluates the tumor microvasculature and the role of tumor-associated macrophages in vascular endothelial growth factor (VEGF) production after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer. Increase in VEGF levels in the serum of patients with oesophageal carcinoma; Analysis of pertinent topics and relevant issues; Implications on studies of surgery.

Background: An increased plasma level of homocysteine has been proposed as an independent risk factor for atherosclerosis; this review examines the evidence. Methods: A Medline search was undertaken for English language articles on homocysteine and vascular disease. Further papers were identified by cross-referencing from the reference lists of relevant major articles. Results: Although much interest has been generated about homocysteine and atherosclerotic disease, contradictory data exist regarding its role in disease progression. There is insufficient current evidence to regard increased homocysteine level as a causative factor in atherosclerotic disease. Conclusion: It is not known whether lowering plasma homocysteine concentration will reduce cardiovascular risk in the long term. Until such data become available, there is no evidence for the widespread use of folic acid therapy to reduce cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

Background: Systemic ischaemia–reperfusion (IR) injury is in part an oxidant injury mediated by neutrophils. Diethylmaleate (DEM), an intracellular pro-oxidant agent, has been shown to alleviate neutrophil-mediated tissue injury. The aim of this study was to evaluate whether DEM could have a protective effect on neutrophil-mediated lung injury in an animal model of lower-torso IR. Methods: Sprague–Dawley rats (seven per group) were randomized into three groups. The control group underwent midline laparotomy only; the IR group underwent laparotomy and clamping of the infrarenal abdominal aorta for 30 min followed by 2 h of reperfusion; and the third group was pretreated with DEM 6 mmol/kg intraperitoneally 1 h before the IR insult. Results: IR resulted in a significant increase in both microvascular leakage and pulmonary neutrophil infiltration as measured by bronchoalveolar lavage protein concentration and pulmonary myeloperoxidase activity respectively. Pretreatment with DEM significantly attenuated both microvascular leakage and neutrophil infiltration. Conclusion: Preconditioning with DEM protected against IR-induced lung injury. This protective effect raises the possibility of using pro-oxidants to prevent inflammatory injury. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is critical for tumour growth and metastasis. The switch to the angiogenic phenotype depends on the net balance between positive and negative angiogenic factors released by the tumour. It was hypothesized that patients with oesophageal cancer would express raised serum levels of vascular endothelial growth factor (VEGF) which would return to normal values with neoadjuvant chemoradiotherapy. Methods: Forty-four patients with oesophageal cancer who were selected for treatment with neoadjuvant chemoradiotherapy had blood samples taken before treatment, during chemoradiotherapy, before operation, on days 1, 3 and 5 after surgery, and 3 months after resection. Serum levels of VEGF were measured. Values were correlated with response to treatment. Controls were patients who were undergoing surgery for non-malignant conditions. Results: Serum VEGF levels were raised in patients with oesophageal cancer compared with age-matched controls (mean 247 versus 1157 pg/ml; P < 0·01). VEGF levels were unaffected by neoadjuvant treatment but fell significantly on the first day after operation (652 versus 1057 pg/ml before operation; P < 0·05). No decrease occurred in control patients. VEGF levels had returned to preoperative levels by day 5. A similar postoperative rise in VEGF levels was seen in the control subjects (1194 pg/ml on day 5 versus 71 pg/ml before operation; P = 0·001). There was no correlation between VEGF level and response to treatment or tumour stage. VEGF levels had decreased significantly at 3 months following tumour resection (594 versus 1558 pg/ml on day 5; P = 0·03). Conclusion: VEGF levels are raised in patients with oesophageal cancer and are unaltered by neoadjuvant treatment, suggesting an additional source other than tumour cells for this proangiogenic agent. [ABSTRACT FROM AUTHOR]

Summary Background: Preconditioning describes the process whereby tissue exposure to a subcritical stress confers protection from subsequent injuries. This study assessed diaphragmatic muscle function after lower torso ischaemia–reperfusion (IR) and the role of thermal preconditioning in attenuation of this injury. Methods: Sprague–Dawley rats were randomized into three groups (24 per group): a control group, an IR group that had aortic cross-clamping for 1 h followed by reperfusion, and a third group that received thermal preconditioning 18 h before IR. Diaphragmatic function was assessed at 24 h, 48 h and 7 days. Results: IR resulted in significant diaphragmatic twitch and tetanic dysfunction compared with control muscle. Thermal preconditioning significantly attenuated this injury (P < 0·05). Mean(s.e.m.) muscle twitch and tetanic forces in the IR group were 204·9(17·2) and 282·7(19·2) g respectively at 24 h. Corresponding twitch and tetanic forces in preconditioned muscle were 270·4(25·1) and 552·0(35·2) g. Conclusion: This study demonstrated that systemic IR injury produced a respiratory muscle mechanical dysfunction that was attenuated by thermal preconditioning, at 24 h, 48 h and 7 days. Preconditioning may have a role in clinical practice, particularly before elective surgery. [ABSTRACT FROM AUTHOR]

Aims Although dilated cardiomyopathy is the most frequent form of cardiomyopathy, its aetiology is still poorly understood. In about 20–30% of cases the disease is familial with a large predominance of autosomal dominant transmission. Ten different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy. Only two genes have been associated with pure forms (without myopathy and/or conduction disorders) of the disease, the cardiac actin and the desmin genes. Our aim was to determine the proportion of dilated cardiomyopathy affected individuals carrying a mutation in one of these two genes.Methods and Results We performed (1) a systematic polymerase chain reaction-SSCP-sequencing screening of the coding sequences of cardiac actin on DNA samples from 43 probands of dilated cardiomyopathy families and 43 sporadic cases; (2) a systematic polymerase chain reaction-SSCP-sequencing screening of the coding sequences of desmin combined with a search for the described missense mutation (Ile451Met) by restriction fragment length polymorphism analysis on DNA samples from 41 probands of dilated cardiomyopathy families and 22 sporadic cases.Conclusion None of the patients presents a mutation in any of these two genes. Consequently, the proportion of European dilated cardiomyopathy affected individuals bearing a mutation in (1) the cardiac actin gene is less than 1·2%, (2) the desmin gene is less than 1·6%. [ABSTRACT FROM PUBLISHER]

Evaluates a short questionnaire developed for the purpose of school doctors examining psychological problems of Dutch children. Aim of child health care in the Netherlands; Reasons for failing to detect psychological or psychiatric complaints of children; Analysis of isolated studies on specific aspects of psychosocial behavior symptoms.

Background Surgery depresses host tumoricidal activity and may increase tumour growth. This study compared the effects of laparoscopy with laparotomy on extraperitoneal tumour growth and immune function in a murine model. Methods C57BL/6 female mice aged 8–10 weeks had tumours induced in the right flank (n=45) and were randomized to undergo halothane anaesthesia only, laparoscopy or laparotomy. Flank tumour volume was assessed over 10 days. A second group of animals (n=540) were randomized to undergo the same procedures and killed at 24, 48 and 96 h. Splenocytes were harvested for natural killer (NK) cell and lymphokine activated killer (LAK) cell cytotoxicity studies. Results There was a significant increase in flank tumour growth in the first 48 h after laparotomy and laparoscopy compared with controls (P<0·01). By 96 h the difference was only significant in the laparotomy group (P<0·01). Both NK and LAK cell cytotoxicities were suppressed significantly (P≤0·03) from 24 h up to 96 h following laparotomy compared with control and laparoscopy groups. There was also a significant suppression in the laparoscopy group compared with controls in the first 48 h after operation (P≤0·02). Conclusion Extraperitoneal tumour growth was significantly accelerated after laparotomy and correlated with significantly suppressed NK and LAK cytotoxicity for at least 4 days after operation. Laparoscopy had a shorter, less profound effect on tumour growth and immune function. [ABSTRACT FROM AUTHOR]

Background For most solid tumours, surgery remains the most effective primary treatment. Despite apparently curative resection, significant numbers of patients develop secondary disease due to growth of undetected micrometastases. The ability of a tumour to metastasize is related to the degree of angiogenesis it induces. In addition, micrometastases rely on new vessel formation to provide the nutrients necessary for growth. A better understanding of how tumours acquire their blood supply may lead to more effective adjuvant therapies and improve survival following surgery. Methods A systematic review of the literature on angiogenesis between 1971 and 1997 was performed using the Medline database to ascertain current thinking on angiogenesis and its relevance in oncological surgery. Results Angiogenesis is a physiological process subject to autocrine and paracrine regulation which has the potential to become abnormal and play a part in a number of pathological states, including cancer. Increased angiogenic stimuli in the perioperative period, associated with concomitant reduction in tumour-derived antiangiogenic factors following resection of a primary tumour, result in a permissive environment which allows micrometastases to grow. Conclusion Recognition of the role of angiogenesis in metastatic tumour growth represents a significant development in our understanding of tumour biology. The development of antiangiogenic agents offers new promise in the treatment of malignancy. Such agents may prevent or control the development and growth of primary and metastatic tumours. [ABSTRACT FROM AUTHOR]

Background Ischaemia–reperfusion injury is mediated by neutrophil–endothelial interaction. Induction of heat shock proteins attenuates neutrophil–endothelial interactions. The aim of this study was to determine whether thermal preconditioning could have a protective effect on neutrophil-mediated lung injury in an animal model of lower torso ischaemia–reperfusion. Methods Sprague-Dawley rats were randomized into: control, ischaemia–reperfusion, and ischaemia–reperfusion preconditioned with hyperthermia groups. Ischaemia–reperfusion injury was induced by infrarenal aortic clamping for 30 min and reperfusion for 120 min. Thermotolerance was induced by raising the core body temperature to 40·5–41·5°C for 15 min, 18 h before ischaemia–reperfusion. Wet:dry lung (W:D) weight ratio, bronchoalveolar lavage protein (BALprot) concentration, tissue myeloperoxidase (MPO) activity and bronchoalveolar lavage polymorphonuclear neutrophil (BAL PMN) count were measured. Heat shock protein 72 (hsp72) expression in lung, intestine and mesentery was measured using Western immunoblotting. Results Ischaemia–reperfusion resulted in a significant increase in tissue oedema (W:D weight ratio) and BALprot concentration. In addition there was a marked increase in tissue neutrophil infiltration (MPO activity, BAL PMN concentration). Preconditioning with hyperthemia resulted in increased expression of hsp72 and significantly reduced tissue oedema and neutrophil infiltration. Conclusion Thermal preconditioning protects against neutrophil-mediated ischaemia–reperfusion-induced lung injury, possibly by increasing the expression of heat shock proteins. [ABSTRACT FROM AUTHOR]

Oral cholecystography is a well established method for studying the human gallbladder and radiological non-visualization of the gallbladder has been shown to correlate highly with the presence of disease. The exact mechanism by which diseased gallbladders fail to visualize is unclear, but may be due to a failure of the gallbladder to concentrate the luminal contents. Concentration of gallbladder contents is achieved by the reabsorption of water, the driving force for which is active sodium (Na+) absorption. Therefore Na+ transport was studied by measuring the flux of Na22 across isolated human gallbladder mucosa (obtained at cholecystectomy) and compared with the results of oral cholecystography and histological grading. In 27 gallbladders studied, 59% absorbed Na+, whilst the remainder secreted Na+. Comparison with histological grading showed that as gallbladders became more diseased they absorbed less Na+ and were more likely to secrete Na+. In addition, gallbladders that absorbed Na+ were significantly more likely to visualize on cholecystography than those that secreted Na+. These results indicate that some diseased human gallbladders secrete, rather than absorb, Na+ and suggest that the mechanism for radiological non-visualization is failure of fluid absorption and the development of active fluid secretion. [ABSTRACT FROM PUBLISHER]

A series of 29 patients with primary biliary cirrhosis has been studied in the last seven years. An unusual feature of this group was that 38% wee over the age of 65, and 24% over the age of 70 at presentation. Detailed analysis of the seven patients presenting over the age of 70 is provided. All of these patients had symptomatic primary biliary cirrhosis rather than representing prolonged survival of the asymptomatic state. It is important that primary biliary cirrhosis be included in the differential diagnosis of liver disease presenting in the elderly. [ABSTRACT FROM AUTHOR]

Investigates the effects of pravastatin on ischemia-reperfusion induced vasomotor dysfunction in the microvasculature of the diabetic. Preservation of endothelial function; Reduction of the cholesterol; Effectiveness of pravastatin.

Examines the therapeutic role of pravastatin on ischemia-reperfusion induced (IR) diaphragmatic dysfunction. Reduction of tetanus in IR treated with prevastatin patients; Determination of the percentage of fatigability; Advantages of the agent in patients undergoing elective vascular reconstruction.

Examines the effects of provastatin on ischemia-reperfusion induced renal injury. Protection of hypoxia by upregulation of constitutive endothelial nitric oxide synthase (ceNOS); Use of western blotting in determining the expression of ceNOS; Effectiveness of the agent.

Examines the effects of vitamin C on ischemia-reperfusion (IR) acute muscle injury. Role of vitamin C in the prevention of IR; Reduction in muscle twitch and tetanic contraction; Promotion of neutrophil infiltration and tissue edema.