Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumors, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mitochondrial DNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting that they may confer a metabolic advantage. To test this, we deleted the tumor suppressor Apc in OXPHOS-deficient intestinal stem cells in mice. The resulting tumors were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumors undergo metabolic remodeling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway. Moreover, normal human colonic crypts upregulate the serine synthesis pathway in response to OXPHOS deficiency before tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodeling that can functionally contribute to accelerated intestinal cancer development.
The Malone antegrade enema (MACE) and the caecostomy button (CB) are two methods of achieving colonic lavage in constipated children with faecal soiling. We reviewed our experience with the MACE and CB, aiming to compare results, complications, and outcomes. Between June 1998 and August 2002, 37 children (15 boys) underwent MACE and 12 children (9 boys) underwent CB for idiopathic constipation that had failed conventional treatment. Rectal biopsy was ganglionic in all cases. Mean age at surgery was 9.9 years for the MACE patients and 9.8 years for the CB patients. All children are under continuous review, and mean follow-up is 18 months. Statistical analysis of proportions used Fisher's exact test. Soiling stopped completely in 30 children with MACE and in 9 with CB. Occasional soiling is still present in two children with a CB and in one with MACE. One child with a CB had resumed regular bowel activity, and the CB was removed. MACE failed in 5 (14%) patients because of ineffective colonic lavage, and in one patient (3%) the appendix was replaced by a CB because of perforation of the appendicostomy. CB failed in one patient (8%) because of faecal leak around the button; the child was subsequently converted to MACE (P = >0.5). Complications requiring operative intervention were seen in 9 (24%) of the 37 patients who underwent MACE and none of the 12 patients who underwent CB (P = 0.09). The main complication requiring surgical intervention was stoma stenosis (11%). Complications not requiring operative intervention were seen in 7 (19%) patients after MACE and 11 (92%) of the 12 patients who underwent CB (P < 0.001). The MACE and CB procedures are reliable and effective with high success rates. The MACE has a higher incidence of complications requiring operative intervention. Conversely, complications not requiring operative intervention are more frequent with CB. CB is a safe and effective alternative to MACE in children with faecal soiling.
Purpose of review Some older people living with HIV (PLWH) exhibit features of unsuccessful ageing, such as frailty. Mitochondrial dysfunction is one of the best characterized ageing mechanisms. There has been recent interest in whether some people ageing with HIV may have an excess of mitochondrial dysfunction. This review aims to address this question through: analogy with ageing and chronic disease; discussion of the key unknowns; suggested ways that measures of mitochondrial dysfunction might be incorporated into HIV research studies. Recent findings Recent data suggest that mitochondrial dysfunction in PLWH may not be wholly a legacy effect of historical nucleoside analog reverse transcriptase inhibitor exposures. Research in the non-HIV setting has altered our understanding of the important mediators of mitochondrial dysfunction in ageing. Summary Mitochondrial dysfunction is a very plausible driver of adverse ageing phenotypes in some older PLWH. As such it may be a target for therapeutic interventions. Currently, however, there remain considerable uncertainties around the extent of this phenomenon, and its relative importance. Current studies are likely to clarify these questions over the next few years.
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