Systems genetics uncover new loci containing functional gene candidates in Mycobacterium tuberculosis-infected Diversity Outbred mice.

Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB), infects 2 billion people across the globe, and results in 8-9 million new TB cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. We investigated the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected with M. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using clinical indicators of disease, granuloma histopathological features, and immune response traits identified five new loci on mouse chromosomes 1, 2, 4, 16 and three previously identified loci on chromosomes 3 and 17. Quantitative trait loci (QTLs) on chromosomes 1, 16, and 17, associated with multiple correlated traits and had similar patterns of allele effects, suggesting these QTLs contain important genetic regulators of responses to M. tuberculosis. To narrow the list of candidate genes in QTLs, we used a machine learning strategy that integrated gene expression signatures from lungs of M. tuberculosis-infected Diversity Outbred mice with gene interaction networks, generating functional scores. The scores were then used to rank candidates for each mapped trait in each locus, resulting in 11 candidates: Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa, and Zfp318. Importantly, all 11 candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling. Further, all candidates contain single nucleotide polymorphisms (SNPs), and some but not all SNPs were predicted to have deleterious consequences on protein functions. Multiple methods were used for validation including (i) a statistical method that showed Diversity Outbred mice carrying PWH/PhJ alleles on chromosome 17 QTL have shorter survival; (ii) quantification of S100A8 protein levels, confirming predicted allele effects; and (iii) infection of C57BL/6 mice deficient for the S100a8 gene. Overall, this work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and new functionally relevant gene candidates that may be major regulators of granuloma necrosis and acute inflammation in pulmonary TB.

Enoxaparin venous thromboembolism prophylaxis in bariatric surgery: A best evidence topic.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was: which is the best regimen of enoxaparin thromboprophylaxis for patients undergoing bariatric surgery? One hundred and twenty-five papers were identified using the reported literature search, of which four represented the best evidence to answer the clinical question. The authors, country and date of publication, patient groups, relevant outcomes and results of these papers were tabulated. All four studies are non-randomized cohort studies examining venous thromboembolism rates and major postoperative bleeding following varying regimens of Enoxaparin thromboprophylaxis. There is no level 1 evidence which significantly favors any particular thromboprophylaxis regimen. There is some evidence that extended duration of treatment of ten days after discharge significantly reduces the incidence of VTE compared to in-hospital treatment only, and that a higher incidence of post-operative bleeding occurs with a regimen that includes a pre-operative dose of Enoxaparin. With regard to dosage, for in-hospital treatment the higher dosage of 40 mg twice daily as opposed to 30 mg seems to significantly reduce the incidence of VTE without significantly affecting bleeding rate.

Outcomes following major emergency gastric surgery: the importance of specialist surgeons.

BACKGROUND: The increasing subspecialisation of general surgeons in their elective work may result in problems for the provision of expert care for emergency cases. There is very little evidence of the impact of subspecialism on outcomes following emergency major upper gastrointestinal surgery. This prospective study investigated whether elective subspecialism of general surgeon is associated with a difference in outcome following major emergency gastric surgery. METHODS: Between February 1994 and June 2010, the data from all emergency major gastric procedures (defined as patients who underwent laparotomy within 12 hours of referral to the surgical service for bleeding gastroduodenal ulcer and/or undergoing major gastric resection) was prospectively recorded. The sub-specialty interest of operating surgeon was noted and related to post-operative outcomes. RESULTS: Over the study period, a total of 63 major gastric procedures were performed of which 23 (37%) were performed by specialist upper gastrointestinal (UGI) consultants. Surgery performed by a specialist UGI surgeon was associated with a significantly lower surgical complication (4% vs. 28% of cases; p=0.04) and in-patient mortality rate (22% vs. 50%; p=0.03). CONCLUSIONS: Major emergency gastric surgery has significantly better clinical outcomes when performed by a specialist UGI surgeon. These results have important implications for provision of an emergency general surgical service.

Laparoscopic common bile duct exploration versus pre or post-operative ERCP for common bile duct stones in patients undergoing cholecystectomy: is there any difference?

A best evidence topic in surgery was written according to a structured protocol. The question addressed was: in patients with symptomatic gallstones and concomitant common bile duct (CBD) stones, is a single-stage surgical strategy (laparoscopic cholecystectomy (LC) with common bile duct exploration) preferable, or a two-stage procedure involving LC with pre or post-operative endoscopic retrograde cholangiography (ERCP)? Two hundred and six papers were found using the reported search, of which four presented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. A recent large meta-analysis concluded no significant difference in the clinical effectiveness or complication rate of either strategy. Three recent smaller studies concurred with this conclusion; however each noted improved cost-effectiveness of the single-stage approach advocating its use as the superior strategy when local resources and expertise are available. We conclude that for patients with symptomatic gallstones and concomitant choledocholithiasis, a single-stage surgical procedure is equivalent to two-stage LC and ERCP in terms of clinical outcomes, is associated with a shorter overall hospital stay and may be more cost-effective. On this basis a single-stage procedure is recommended for management of symptomatic gallstones and choledocholithiasis where local resources and expertise permit.

Circumferential resection margins of rectal tumours post-radiotherapy: how can MRI aid surgical planning?

BACKGROUND: Magnetic resonance imaging (MRI) is known to have high predictive accuracy for circumferential resection margin (CRM) involvement of pre-treatment rectal tumours. This study aims to assess predictive accuracy of MRI for CRM involvement in rectal cancers post-long-course chemoradiotherapy (CRT) and in particular to understand how this information can influence surgical planning. METHODS: Forty-seven rectal cancers treated with CRT followed by bowel resection in one hospital since 2005 were reviewed for clinical, radiological and pathological characteristics. Using a validated pro forma, a radiologist blinded to final histology and original MRI report predicted CRM status from post-CRT MRI images. Results were compared to histological CRM status of final specimen, and differential analysis by type of surgical operation was performed. RESULTS: Overall accuracy of MRI for CRM involvement post-CRT was 72 % with a negative predictive value of 92 %. Abdominoperineal excision (APE) post-CRT was associated with non-significantly higher rates of histologically involved CRM than anterior resection (AR; 41 vs. 21 %) as were mucinous adenocarcinomas when compared to non-mucinous (56 vs. 21 %). Overall accuracy and positive predictive value were non-significantly higher for cancer treated with a standard APE than AR, and negative predictive value was high for both groups. CONCLUSIONS: MRI post-CRT has high negative predictive value for CRM status. Such information is of particular clinical relevance in low rectal cancers treated with APE as it can indicate when a standard surgical approach is likely to be sufficient.

[Bone tumors. Their prevalence]. / Tumores óseos. Prevalencia.

1,200 cases of bone tumors were reviewed from the Orthopedic Hospital "Magdalena de las Salinas" between 1982 and 1989. 66.7% of them were benign tumors, 14.3% pseudotumoral lesions, 10.1% metastatic tumors, 8.6% primary malignant tumors, and 0.3% were malignant invasive tumors to bone. The most frequently found benign tumors were: osteochondroma, enchondroma and giant cell tumor; the most frequent pseudotumoral lesions were metaphyseal fibrous defects, solitary bone cysts and fibrous dysplasia; the most frequent primary malignant tumor was osteosarcoma. Prevalence, frequency, distribution, sex, most frequent ages, affected bones, multicentricity, and aggregated fractures, as well as the site of the primary lesion in metastatic and invading tumors, were similar to those reported in the classical series.

Social response to acoustic and visual characteristics of oral cleft.

This study was concerned with societal preference among speech, visual, and speech-visual characteristics of persons with repaired cleft lip and palate. A 16 mm motion film with sound was professionally made of 17 male, adult, cleft lip and palate speakers reading the first paragraph from "The Rainbow Passage." A heterogeneous group of 30 adults rated their preference for each of the conditions-auditory, visual and auditory-visual-on a seven-point equal-appearing intervals scale. A four-factor design analysis of variance with repeated measures was performed to determine whether the thirty judges preferred at least one variable of the three variables tested. Results indicated that this heterogenous population had no preference among auditory, visual, or auditory-visual characteristics of adult males with repaired cleft lip and palate. These variables appear to be considered of equal importance by persons who are representative of the lay public.