Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease.

Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.

Performance measurement of a Canadian provincial tuberculosis programme: Manitoba, 2008-2012.

BACKGROUND: Performance measurement assists tuberculosis (TB) programmes in understanding areas of strength and weakness, and planning for improvements. Canada currently does not have a national comprehensive system for the measurement and analysis of TB programme performance. OBJECTIVE: To analyse the performance of a Canadian provincial TB programme using measures and targets based on those published by the US Centers for Disease Prevention and Control for 2015. DESIGN: Using provincial surveillance data from the Canadian province of Manitoba, we analysed key programme performance outcome measures (treatment completion, early detection, human immunodeficiency virus [HIV] testing, paediatric TB, retreatment, and contact elicitation and assessment) for people diagnosed with TB between 2008 and 2010. RESULTS: Significant outcome variation was found between Indigenous and non-Indigenous populations as well as within populations. The reporting rate of HIV testing was low. High rates of paediatric TB among Indigenous populations, particularly in rural areas, were found. Significantly better performance in HIV testing and reporting as well as in contact investigation was found for rural compared with urban Indigenous populations. Foreign-born persons had the lowest contact assessment rate. CONCLUSION: This study of TB programme performance in Manitoba demonstrates the viability of the approach in the Canadian context, and could help to identify key areas for TB programme improvement.

Short communication: Muscle protein synthetic response to microparticulated whey protein in middle-aged men.

Whey protein concentrate (WPC) is a high-quality dairy ingredient that is often included in formulated food products designed to stimulate muscle anabolism. Whey protein concentrate can be affected by UHT processing, and its sensory properties are not compatible with some formulated food products. Microparticulated WPC (mWPC) is a novel ingredient that is resistant to heat treatment and has enhanced sensory properties. When 16 healthy middle-aged men consumed 20 g of either WPC or mWPC, both proteins increased plasma essential AA and leucine concentrations with no detectable difference in curve kinetics. Myofibrillar protein synthesis was increased in both groups for 90 min after ingestion with no difference between groups. Ingestion of mWPC resulted in a muscle anabolic response that was equivalent to that of WPC over the full 210-min measurement period. Formulated products incorporating mWPC or standard WPC would provoke equivalent anabolic responses.

Differential expression of key regulators of Toll-like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator-activated receptor gamma?

The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll-like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a co-ordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD. Of the six TLRs (TLRs 1, 2, 4, 5, 6 and 9) examined, only TLR-4 was increased significantly in IBD, specifically in active UC. In contrast, differential alterations in expression of TLR inhibitory proteins were observed. A20 and suppressor of cytokine signalling 1 (SOCS1) were increased only in active UC while interleukin-1 receptor-associated kinase 1 (IRAK-m) and B cell lymphoma 3 protein (Bcl-3) were increased in both active UC and CD. In contrast, expression of both peroxisome proliferator-activated receptor gamma (PPARγ) and Toll interacting protein (Tollip) was decreased in both active and inactive UC and CD and at both mRNA and protein levels. In addition, expression of both PPARγ and A20 expression was increased by stimulation of a colonic epithelial cell line Caco-2 with both TLR ligands and commensal bacterial strains. These data suggest that IBD may be associated with distinctive changes in TLR-4 and TLR inhibitory proteins, implying that alterations in these may contribute to the pathogenesis of IBD.

Tuberculosis among nomads in Adamawa, Nigeria: outcomes from two years of active case finding.

BACKGROUND: Nomadic populations are often isolated and have difficulty accessing health care, leading to increased morbidity and mortality. Although Nigeria has one of the highest tuberculosis (TB) burdens in Africa, case detection rates remain relatively low. METHODS: Active case finding for TB among nomadic populations was implemented over a 2-year period in Adamawa State. A total of 378 community screening days were organised with local leaders; community volunteers provided treatment support. Xpert(®) MTB/RIF was available for nomads with negative smear results. RESULTS: Through active case finding, 96 376 nomads were verbally screened, yielding 1310 bacteriologically positive patients. The number of patients submitting sputum for smear microscopy statewide increased by 112% compared with the 2 years before the intervention. New smear-positive notifications increased by 49.5%, while notifications of all forms of TB increased by 24.5% compared with expected notifications based on historical trends. Nomads accounted for respectively 31.4% and 26.0% of all smear-positive and all forms TB notifications. Pre-treatment loss to follow-up and treatment outcomes were similar among nomads and non-nomads. DISCUSSION: Nomads in Nigeria have high TB rates, and active case-finding approaches may be useful in identifying and successfully treating them. Large-scale interventions in vulnerable populations can improve TB case detection.

Burden of tuberculosis in indigenous peoples globally: a systematic review.

BACKGROUND: The burden of tuberculosis (TB) in the estimated 370 million indigenous peoples worldwide is unknown. OBJECTIVE: To conduct a literature review to summarize the TB burden in indigenous peoples, identify gaps in current knowledge, and provide the foundation for a research agenda prioritizing indigenous health within TB control. METHODS: A systematic literature review identified articles published between January 1990 and November 2011 quantifying TB disease burden in indigenous populations worldwide. RESULTS: Among the 91 articles from 19 countries included in the review, only 56 were from outside Australia, Canada, New Zealand and the United States. The majority of the studies showed higher TB rates among indigenous groups than non-indigenous groups. Studies from the Amazon generally reported the highest TB prevalence and incidence, but select populations from South-East Asia and Africa were found to have similarly high rates of TB. In North America, the Inuit had the highest reported TB incidence (156/100000), whereas the Metis of Canada and American Indians/Alaska Natives experienced rates of <10/100000. New Zealand's Maori and Pacific Islanders had higher TB incidence rates than Australian Aborigines, but all were at greater risk of developing TB than non-indigenous groups. CONCLUSION: Where data exist, indigenous peoples were generally found to have higher rates of TB disease than non-indigenous peoples; however, this burden varied greatly. The paucity of published information on TB burden among indigenous peoples highlights the need to implement and improve TB surveillance to better measure and understand global disparities in TB rates.

Myosin 1e is a component of the glomerular slit diaphragm complex that regulates actin reorganization during cell-cell contact formation in podocytes.

Glomerular visceral epithelial cells, also known as podocytes, are critical to both normal kidney function and the development of kidney disease. Podocyte actin cytoskeleton and their highly specialized cell-cell junctions (also called slit diaphragm complexes) play key roles in controlling glomerular filtration. Myosin 1e (myo1e) is an actin-based molecular motor that is expressed in renal glomeruli. Disruption of the Myo1e gene in mice and humans promotes podocyte injury and results in the loss of the integrity of the glomerular filtration barrier. Here, we have used biochemical and microscopic approaches to determine whether myo1e is associated with the slit diaphragm complexes in glomerular podocytes. Myo1e was consistently enriched in the slit diaphragm fraction during subcellular fractionation of renal glomeruli and colocalized with the slit diaphragm markers in mouse kidney. Live cell imaging studies showed that myo1e was recruited to the newly formed cell-cell junctions in cultured podocytes, where it colocalized with the actin filament cables aligned with the nascent contacts. Myo1e-null podocytes expressing FSGS-associated myo1e mutant (A159P) did not efficiently assemble actin cables along new cell-cell junctions. We have mapped domains in myo1e that were critical for its localization to cell-cell junctions and determined that the SH3 domain of myo1e tail interacts with ZO-1, a component of the slit diaphragm complex and tight junctions. These findings suggest that myo1e represents a component of the slit diaphragm complex and may contribute to regulating junctional integrity in kidney podocytes.

TL1A/TNFSF15 directly induces proinflammatory cytokines, including TNFα, from CD3+CD161+ T cells to exacerbate gut inflammation.

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A)/TNF superfamily member 15 (TNFSF15) is a proinflammatory cytokine and TNFα superfamily member that is linked preclinically and clinically to inflammatory bowel disease (IBD). By homology and function, TNFα is its closest family member. In this study, we investigated the mechanism of TL1A-induced inflammation in CD4+ T cells and compared it with the TNFα pathway. We found that TL1A induces proinflammatory cytokines, including TNFα, from isolated human CD4+CD161+ T cells, whereas these cells were resistant to TNFα treatment. Anti-TNFα failed to block TL1A-induced cytokine production, indicating that the effects of TL1A are direct. Lastly, CD161 and TL1A expression were significantly and selectively increased in gut tissue biopsies, but not in the peripheral blood, from IBD patients. Thus, TLIA not only functions upstream of TNFα, driving its expression from CD161+ T cells, but is also independent of TNFα. These findings may have therapeutic IBD implications.

Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease.

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-α, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38α inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38α and p38α expression was evaluated by immunoblotting on intestinal biopsies from inflamed areas of patients affected by Crohn's disease and ulcerative colitis, and from normal mucosa of sex- and age-matched control subjects. Both mucosal biopsies and isolated LPMCs were incubated with four different p38α selective inhibitory drugs. TNF-α, interleukin (IL)-1ß and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phospho-p38α in the inflamed mucosa of IBD patients in comparison to controls. All the p38α inhibitory drugs inhibited p38α phosphorylation and secretion of TNF-α, IL-1ß and IL-6 from IBD LPMCs and biopsies. Activated p38α MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38α selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.

Fluoroquinolone resistance in renal isolates of Mycobacterium tuberculosis.

SETTING: Alberta, Canada, 1990-2003. OBJECTIVE: Monotherapy of active tuberculosis (TB) promotes drug resistance. Given the common practice of empiric fluoroquinolone (FQ) therapy for urinary tract infections (UTI) and frequent delayed diagnosis of renal TB, we assessed urine Mycobacterium tuberculosis isolates for FQ resistance. DESIGN: Retrospective study. Urine M. tuberculosis isolates underwent FQ susceptibility testing. Records were reviewed for evidence of FQ exposure and diagnostic delay. RESULTS: Among 78 culture-positive renal TB patients between 1990 and 2003, initial isolates of M. tuberculosis were available from 74 (94.9%). Three (4.1%) were FQ-resistant. Previous FQ use was confirmed in nine cases (12.2%). FQ-exposed isolates were more likely than non-exposed isolates to be FQ-resistant (2/9, 22.2% vs. 1/65, 1.5%, P = 0.037). Among 41 cases (55.4%) with signs or symptoms of UTI, eight (19.5%) had previous FQ exposure, of which seven (87.5%) had delayed diagnosis. Only 15/33 (45.5%) UTI symptomatic cases without prior FQ exposure had delayed diagnosis (P = 0.050). In 2/8 (25%) UTI symptomatic cases with prior FQ exposure, the M. tuberculosis isolate was FQ-resistant. CONCLUSION: FQ monotherapy of unsuspected renal TB may delay diagnosis and lead to FQ resistance.

Tobacco and tuberculosis: a qualitative systematic review and meta-analysis.

OBJECTIVES: To assess the strength of evidence in published articles for an association between smoking and passive exposure to tobacco smoke and various manifestations and outcomes of tuberculosis (TB). Clinicians and public health workers working to fight TB may not see a role for themselves in tobacco control because the association between tobacco and TB has not been widely accepted. A qualitative review and meta-analysis was therefore undertaken. METHODS: Reference lists, PubMed, the database of the International Union Against Tuberculosis and Lung Disease and Google Scholar were searched for a final inclusion of 42 articles in English containing 53 outcomes for data extraction. A quality score was attributed to each study to classify the strength of evidence according to each TB outcome. A meta-analysis was then performed on results from included studies. RESULTS: Despite the limitations in the data available, the evidence was rated as strong for an association between smoking and TB disease, moderate for the association between second-hand smoke exposure and TB disease and between smoking and retreatment TB disease, and limited for the association between smoking and tuberculous infection and between smoking and TB mortality. There was insufficient evidence to support an association of smoking and delay, default, slower smear conversion, greater severity of disease or drug-resistant TB or of second-hand tobacco smoke exposure and infection. CONCLUSIONS: The association between smoking and TB disease appears to be causal. Smoking can have an important impact on many aspects of TB. Clinicians can confidently advise patients that quitting smoking and avoiding exposure to others' tobacco smoke are important measures in TB control.

Transmission characteristics of tuberculosis in the foreign-born and the Canadian-born populations of Alberta, Canada.

SETTING: All notified cases of tuberculosis in the province of Alberta, Canada, 1994-1998. OBJECTIVE: To compare the transmission characteristics of tuberculosis among foreign-born and Canadian-born cases. DESIGN: Retrospective analysis using DNA fingerprinting (IS6110 restriction fragment length polymorphism and spoligotyping) and patient information from the Alberta Tuberculosis Registry. Transmission indexes were determined by calculating the average number of culture-positive pulmonary cases generated by a single source case. RESULTS: Of the 750 cases of active tuberculosis, 437 (58.3%) were in the foreign-born. DNA fingerprinting of Mycobacterium tuberculosis isolates from all 573 culture-positive cases over the 5 years from 1994 to 1998 showed that there was significantly less clustering among foreign-born isolates (9.8%) compared to Canadian-born non-Aboriginal (28.8%) and Aboriginal (44.7%) isolates. The transmission index was significantly higher for males, lower for those > or =65 years of age, and higher for Aboriginals. CONCLUSION: Although cases of tuberculosis in the foreign-born constitute the majority in Alberta, there is little transmission to other foreign-born or to Canadian-born individuals. Transmission of tuberculosis among the Aboriginal population remains a significant problem in Alberta.

Stop TB-Halte à la Tuberculose-Canada: engaging industrialised nations in the challenge to meet global targets.

The Stop TB Partnership has engaged the 22 high-burden countries in a drive toward the goal of finding 70% of cases and curing 85% by 2005. Traditional partners, aid agencies and governments of industrialised nations have joined the Partnership, but the broader range of civil society remains outside the discourse, risking disinterest on the part of the donor community. Stop TB-Halte à la Tuberculose-Canada was organised to engage new partners to support the Canadian government's commitment to the goal of reducing poverty and diseases of poverty, including tuberculosis, by 50% by 2010. The successes and challenges are explored, and the possibility raised that having a Stop TB movement in every country will ensure that support is sustained and goals of global tuberculosis control reached.

Anterior gastropexy may reduce the recurrence rate after laparoscopic paraesophageal hernia repair.

BACKGROUND: Although laparoscopic repair of type 3 paraesophageal hernias is safe and results in symptomatic relief, recent data have questioned the anatomic integrity of the laparoscopic approach. The reports document an asymptomatic recurrence rate as high as 42% with radiologic follow-up evaluation for type 3 paraesophageal hernias repaired laparoscopically. This disturbingly high recurrence rate has prompted the addition of an anterior gastropexy to our standard laparoscopic paraesophageal hernia repair. METHODS: A prospective series of 28 patients underwent laparoscopic repair of large type 3 hiatal hernias between July 2000 and January 2002 at the Cleveland Clinic Foundation by one surgeon. All the patients underwent reduction of the hernia, sac excision, crural repair, antireflux procedure, and anterior gastropexy. They all had a video esophagram 24 h after surgery, then at 3-, 6-, and 12-month follow-up visits and annually thereafter. Symptomatic outcomes were assessed with a standard questionnaire at each follow-up visit. RESULTS: In this study, 21 women and 7 men with a mean age of 67 years (range, 35-82 years) underwent successful laparoscopic paraesophageal hernia repair. The mean operative time was 146 min (range, 101-186 min), and the average blood loss was 71 ml (range, 10-200 ml). One intraoperative complication occurred: A small esophageal mucosal tear occurred during esophageal dissection and was repaired laparoscopically. At 24 h, upper gastrointestinal examination identified no leaks. At this writing, all the patients have undergone video esophagram at a 3-month follow-up visit. All were asymptomatic and all examinations were normal. Of the 28 patients, 27 have undergone follow-up assessment at 6 months. At this writing, all the patients have undergone video esophagram at 3, 6, and 12 months follow up visits. All were asymptomatic and all examinations were normal. Ten patients have completed 2 year follow up barium swallows with no recurrences. CONCLUSIONS: With up to 2 years of follow-up evaluation, the addition of an anterior gastropexy to the laparoscopic repair of type 3 hiatal hernias resulted in no recurrences. These encouraging results necessitate further follow-up evaluation to document the long-term effects of anterior gastropexy in reducing postoperative recurrence after laparoscopic repair of paraesophageal hernias.

The molecular epidemiology of tuberculosis in western Canada.

OBJECTIVE: To define the molecular epidemiology of TB in western Canada, and in particular the risk factors for clustering. MEASUREMENTS: We prospectively identified all positive cultures from newly diagnosed cases of TB diagnosed between February 1995 and January 1997 and carried out restriction fragment length polymorphism (RFLP) testing on all isolates. RESULTS: Of 956 cases identified, 944 fulfilled the entry criteria. The mean age was 49.65 years (+/- 22.33), and 508 (53.6%) were males. Three hundred and three (32.1%) subjects were clustered; this varied from 20.2% of the foreign born, 48.4% of Canadian non-Aboriginal and 61.1% of all Aboriginal persons. Younger persons (P = 0.0001), males (P = 0.015), those with pulmonary disease (P < 0.001), living in a shelter in the past year (P < 0.001), drug-susceptible disease (P < 0.036), predisposing factors (P < 0.001), prior contact (P < 0.001), and prior skin test (P < 0.002) were more likely to cluster. Among specific risk factors, HIV infection, injection drug use, alcohol excess, and weight loss were all significant. CONCLUSIONS: In this description of the molecular epidemiology of TB in Western Canada, previous results have been confirmed and extended. These results highlight the importance of identifying specific high risk groups, especially in the context of renewed efforts to target persons for treatment of latent TB infection.

Recurrence after laparoscopic ventral hernia repair.

BACKGROUND: Although the early results of laparoscopic ventral hernia repair have shown a low recurrence rate, there is a paucity of long-term data. This study reviews a single institution's experience with laparoscopic ventral hernia repair (LVHR). METHODS: We carried out a retrospective analysis of all LVHR performed at the Cleveland Clinic Foundation from January 1996 to March 2001. Recurrence rates were determined by physical exam or telephone follow-up. Factors predictive of recurrence were determined using Cox regression. RESULTS: Of 100 ventral hernias completed laparoscopically, 96 were available for long-term follow-up (average, 30 months; range 4-65). There were no deaths and major morbidity occurred in seven patients. Recurrences were identified in 17 patients. Nine recurrences occurred in the 1st postoperative year; however, hernia recurrence continued throughout the period of follow-up. Multivariate analysis showed that a prior failed hernia repair was associated with a more likely chance of another recurrence (65% vs 35%, odds ratio (OR) 3.6; p = 0.05) and that an increased estimated blood loss (106 cc vs 51 cc, OR 1.03; p = 0.005) predicted recurrence. Other variables, including body mass index (BMI) (32 vs 31 kg/m2, p = 0.38), defect size (115 cm2 vs 91 cm2; p = 0.23), size of mesh (468 cm2 vs 334 cm2, p = 0.19), type of mesh (p = 0.62), and mesh fixation (p = 0.99), did not predict recurrence. An additional 14 cases required conversion to an open operation, and seven of these cases (50%) had recurrence on long-term follow-up. CONCLUSION: Although LVHR remains the preferred method of hernia repair at our institution, this study documents a higher recurrence rate than many other short-term series. There results underscore the importance of long-term follow-up in assessing hernia surgery outcome.

The economic impact of flexible endoscopy in a large academic surgical department.

BACKGROUND: There has been considerable controversy concerning the value added to a general surgery practice when flexible gastrointestinal endoscopy is incorporated. The purpose of this study was to assess the economic impact of flexible endoscopy performed by general surgeons in a large academic practice. METHODS: A retrospective review of gross billing charges for a group practice of 11 surgeons over the fiscal year 1999 was performed at the Cleveland Clinic Foundation. The total billing for clinic visits and outpatient and inpatient surgical procedures was compiled, and the percentage attributable to flexible endoscopy was determined. Of the 11 surgeons, three had incorporated flexible endoscopy into their practice. RESULTS: The three endosurgeons generated 33% of the total gross billing for the Department of General Surgery. Flexible endoscopy alone accounted for 12.2% of the total percentage of gross billings for the department. Meanwhile, this revenue was generated from only 8% of the workweek when performing flexible endoscopic procedures were performed. CONCLUSION: Flexible endoscopy can contribute significantly to the financial productivity of the general surgeon.

Medical versus surgical treatment of a primary tuberculous pleural peel.

The role and timing of surgical decortication in the management of a primary tuberculous pleural peel remains controversial. The present report describes the case of a young man with an extensive primary tuberculous pleural peel that responded dramatically to medical therapy. A serious attempt at surgical decortication three weeks into antituberculous drug therapy may have removed some compressive aspects of the peel, facilitating lung expansion. However, it had almost no measurable impact on the size of peel and was technically very difficult. Response to treatment was measured anatomically (computed tomography scans) and physiologically (pulmonary function tests).