Ischaemic colitis: Practical challenges and evidence-based recommendations for management

Ischaemic colitis (IC) is a common condition with rising incidence, and in severe cases a high mortality rate. Its presentation, severity and disease behaviour can vary widely, and there exists significant heterogeneity in treatment strategies and resultant outcomes. In this article we explore practical challenges in the management of IC, and where available make evidence-based recommendations for its management based on a comprehensive review of available literature. An optimal approach to initial management requires early recognition of the diagnosis followed by prompt and appropriate investigation. Ideally, this should involve the input of both gastroenterology and surgery. CT with intravenous contrast is the imaging modality of choice. It can support clinical diagnosis, define the severity and distribution of ischaemia, and has prognostic value. In all but fulminant cases, this should be followed (within 48 hours) by lower gastrointestinal endoscopy to reach the distal-most extent of the disease, providing endoscopic (and histological) confirmation. The mainstay of medical management is conservative/supportive treatment, with bowel rest, fluid resuscitation and antibiotics. Specific laboratory, radiological and endoscopic features are recognised to correlate with more severe disease, higher rates of surgical intervention and ultimately worse outcomes. These factors should be carefully considered when deciding on the need for and timing of surgical intervention

Aberrant Motility in Unaffected Small Bowel is Linked to Inflammatory Burden and Patient Symptoms in Crohn's Disease.

BACKGROUND: Inflammation-related enteric dysmotility has been postulated as a cause for abdominal symptoms in Crohn's disease (CD). We investigated the relationship between magnetic resonance imaging-quantified small bowel (SB) motility, inflammatory activity, and patient symptom burden. METHODS: The Harvey-Bradshaw index (HBI) and fecal calprotectin were prospectively measured in 53 patients with CD (median age, 35; range, 18-78 years) the day before magnetic resonance enterography, which included a dynamic (cine), breath-hold motility sequence, repeated to encompass the whole SB volume. A validated registration-based motility quantitation technique produced motility maps, and regions of interest were drawn to include all morphologically normal SB (i.e., excluding diseased bowel). Global SB motility was correlated with calprotectin, HBI, and symptom components (well-being, pain, and diarrhea). Adjustment for age, sex, smoking, and surgical history was made using multivariate linear regression. RESULTS: Median calprotectin was 336 (range, 0-1280). Median HBI, motility mean, and motility variance were 3 (range, 0-16), 0.33 (0.18-0.51), and 0.01 (0.0014-0.034), respectively. Motility variance was significantly negatively correlated with calprotectin (rho = -0.33, P = 0.015), total HBI (rho = -0.45, P 0.05). CONCLUSIONS: Reduced motility variance in morphologically normal SB is associated with patient symptoms and fecal calprotectin levels, supporting the hypothesis that inflammation-related enteric dysmotility may explain refractory abdominal symptoms in CD

Evolution from a nodeless gap to d(x2-y2) form in underdoped La(2-x)SrxCuO4

Using angle-resolved photoemission (ARPES), it is revealed that the low-energy electronic excitation spectra of highly underdoped superconducting and non-superconducting La(2-x)SrxCuO4 cuprates are gapped along the entire underlying Fermi surface at low temperatures. We show how the gap function evolves to a d(x2-y2) form as increasing temperature or doping, consistent with the vast majority of ARPES studies of cuprates. Our results provide essential information for uncovering the symmetry of the order parameter(s) in strongly underdoped cuprates, which is a prerequisite for understanding the pairing mechanism and how superconductivity emerges from a Mott insulator.Comment: 5 pages, 4 figure

Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo

Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5′azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing