Elevated inosine monophosphate levels in resting muscle of patients with stable chronic obstructive pulmonary disease.

Department of Pulmonology, Maastricht University, The Netherlands. In order to investigate disturbances in energy metabolism in resting muscle of patients with stable chronic obstructive pulmonary disease (COPD), concentrations of adenine nucleotides and related compounds were examined comparing 34 COPD patients with eight age-matched healthy control subjects. Biopsies were taken from the anterior tibialis muscle. Special attention was paid to the muscle content of inosine monophosphate (IMP), a deamination product of adenosine monophosphate (AMP), because IMP formation is thought to reflect an imbalance between resynthesis and utilization of adenosine triphosphate (ATP). The absolute concentrations of high-energy phosphate compounds did not differ between patients and control subjects, but the ATP/ADP and the phosphocreatine/creatine ratio were significantly lower in the patients. IMP (detection level = 0.06 mmol/kg dry weight) was detected in 25 of 34 patients versus one of eight control subjects (p = 0.001). Mean (SD) IMP level in these patients was 0.18 (0.14) versus 0.06 mmol/kg dry weight in the one control subject. Based on the presence of detectable levels of muscle IMP, the patient group was divided into two subgroups. In IMP-positive patients, ATP/ADP and phosphocreatine/creatine ratios were significantly lower than in IMP-negative patients. IMP-positive patients were furthermore characterized by a significantly lower DL(CO). The results of this study indicate an imbalance between the utilization and resynthesis of ATP in resting muscle of patients with stable COPD

Favorable effect of endoscopic reassessment of clinically staged T2 esophageal adenocarcinoma: A multicenter prospective cohort study

Background Clinical tumor stage of esophageal adenocarcinoma (EAC) is determined by endoscopic ultrasound and/or computed tomography scan, which have low accuracy for stages T1 and T2, potentially leading to overtreatment. We aimed to assess the proportion of cT2 EACs downstaged to cT1 after endoscopic reassessment (ERA) by an experienced interventional endoscopist. Methods We performed a prospective multicenter cohort study. Patients with cT2N0M0 EAC were included and underwent ERA. The primary outcome was proportion of cT2 EACs downstaged to cT1 after ERA. Results 15/25 included patients (60%) were downstaged from cT2 to cT1 EAC after ERA and underwent attempted endoscopic resection. Endoscopic resection was aborted in 3/15 patients because of tumor invasion into the muscle layer; all three underwent successful surgical resection. Endoscopic resection was successful in 12/15 patients (80%), all of whom had pT1 tumors. Overall, 10/25 (40%) were treated with endoscopic resection alone. Conclusions ERA downstaged about half of the cT2 tumors to cT1, rendering them suitable for endoscopic resection. ERA had substantial clinical impact on therapeutic management, preventing overtreatment in 40% of patients

Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus

Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids. Design: A placebo-controlled randomized, proof-of-concept study. Methods: Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test. Results: Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change. Conclusion: Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin-glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.</p

Decontamination of the digestive tract and oropharynx in ICU patients.

Contains fulltext : 79996.pdf (publisher's version ) (Open Access)BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.

Analysis of metastases rates during follow-up after endoscopic resection of early "high-risk" esophageal adenocarcinoma

Background and Aims: After endoscopic resection (ER) of early esophageal adenocarcinoma (EAC), the optimal management of patients with high-risk histologic features for lymph node metastases (ie, submucosal invasion, poor differentiation grade, or lymphovascular invasion) remains unclear. We aimed to evaluate outcomes of endoscopic follow-up after ER for high-risk EAC. Methods: For this retrospective cohort study, data were collected from all Dutch patients managed with endoscopic follow-up (endoscopy, EUS) after ER for high-risk EAC between 2008 and 2019. We distinguished 3 groups: intramucosal cancers with high-risk features, submucosal cancers with low-risk features, and submucosal cancers with high-risk features. The primary outcome was the annual risk for metastases during follow-up, stratified for baseline histology. Results: One hundred twenty patients met the selection criteria. Median follow-up was 29 months (interquartile range, 15-48). Metastases were observed in 5 of 25 (annual risk, 6.9%; 95% confidence interval [CI], 3.0-15) high-risk intramucosal cancers, 1 of 55 (annual risk, .7%; 95% CI, 0-4.0) low-risk submucosal cancers, and 3 of 40 (annual risk, 3.0%; 95% CI, 0-7.0) high-risk submucosal cancers. Conclusions: Whereas the annual metastasis rate for high-risk submucosal EAC (3.0%) was somewhat lower than expected in comparison with previous reported percentages, the annual metastasis rate of 6.9% for high-risk intramucosal EAC is new and worrisome. This calls for further prospective studies and suggests that strict follow-up of this small subgroup is warranted until prospective data are available