Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.

Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11sut/sut mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11sut/sut primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11sut/sut muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11sut/sut mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.

Outcomes following anastomotic leak from rectal resections, including bowel function and quality of life.

PURPOSE: Anastomotic leak (AL) is an uncommon but potentially devastating complication after rectal resection. We aim to provide an updated assessment of bowel function and quality of life after AL, as well as associated short- and long-term outcomes. METHODS: A retrospective audit of all rectal resections performed at a colorectal unit and associated private hospitals over the past 10 years was performed. Relevant demographic, operative, and histopathological data were collected. A prospective survey was performed regarding patients' quality of life and fecal continence. These patients were matched with nonAL patients who completed the same survey. RESULTS: One hundred patients (out of 1,394 resections) were included. AL was contained in 66.0%, not contained in 10.0%, and only anastomotic stricture in 24.0%. Management was antibiotics only in 39.0%, percutaneous drainage in 9.0%, operative abdominal drainage in 19.0%, transrectal drainage in 6.0%, combination of percutaneous drainage and transrectal drainage in 2.0%, and combination abdominal/transrectal drainage in 1.0%. The 1-year stoma rate was 15.0%. Overall, mean Fecal Incontinence Severity Instrument scores were higher for AL patients than their matched counterparts (8.06±10.5 vs. 2.92±4.92, P=0.002). Patients with an AL had a mean EuroQol visual analogue scale (EQ-VAS) of 76.23±19.85; this was lower than the matched mean EQ-VAS for non-AL patients of 81.64±18.07, although not statistically significant (P=0.180). CONCLUSION: The majority of AL patients in this study were managed with antibiotics only. AL was associated with higher fecal incontinence scores in the long-term; however, this did not equate to lower quality of life scores.

Circumferentially oversewn inverted stapled anastomosis.

BACKGROUND: Leak rates of over 5% following anastomoses between the ileum and colon continue to be reported in large series and are associated with substantial morbidity and with mortality rates of 10-20%. In 1994, we began performing circumferentially oversewn inverted stapled anastomoses in patients undergoing ileo-colic anastomoses or ileostomy closure. It has become increasingly apparent that this method is associated with a low risk of leakage, which we should report. METHODS: The anastomotic technique described was used in all patients undergoing ileo-colic anastomosis or closure of ileostomy by surgeon 1 (1994-2015) and in all ileo-colic anastomoses by surgeon 2 (2007-2015). All patients had a widely patent anastomosis constructed by two firings of a linear cutting stapler, as previously described. Additionally, the entire staple line was carefully oversewn with interrupted, inverting 4/0 polydioxanone sutures. Anastomotic leak was defined as a patient requiring re-operation or radiological drainage. RESULTS: One thousand and twelve patients underwent ileo-colic anastomosis and 685 patients underwent closure of ileostomy by surgeon 1, and 165 patients underwent ileo-colic anastomosis by surgeon 2. None of the 1862 patients required re-operation or radiological drainage for a leak (event rate 0%, 95% confidence interval 0-0.2%). However, there were three possible contained leaks treated successfully conservatively. The time taken to perform the actual anastomosis was measured in the last 30 ileo-colic resections. The median time was 42 min. CONCLUSION: While this method may well be too slow to gain widespread adoption, we hope this report encourages increased research into finding techniques with similar low leak rates.