Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis

Hormone replacement therapy (HRT) increases the risk of venous thrombosis. We investigated whether this risk is affected by carriership of hereditary prothrombotic abnormalities. Therefore, we determined the two most common prothrombotic mutations, factor V Leiden and prothrombin 20210A in women who participated in a case-control study on venous thrombosis. Relative risks were expressed as odds ratios (OR) with 95% confidence intervals (CI95). Among 7 7 women aged 45-64 years with a first venous thrombosis, 51% were receiving HRT at the time of thrombosis, compared with 24% of control women (OR = 3.3, CI95 1.8-5.8). Among the patients, 23% had a prothrombotic defect, versus 7% among the control women (OR = 3.8, CI95 1.7- 8.5). Women who had factor V Leiden and used HRT had a 15-fold increased risk (OR = 15.5, CI95 3.1-77), which exceeded the expected joint odds ratio of 6.1 (under an additive model). We conclude that the thrombotic risk of HRT may particularly affect women with prothrombotic mutations. Efforts to avoid HRT in women with increased risk of thrombosis are advisable

Gene expression profiles of human endometrial cancer samples using a cDNA-expression array technique: assessment of an analysis method

The recently developed cDNA expression array technique can be used to generate gene-expression fingerprints of tumour specimens. To gain insight into molecular mechanisms involved in the development and progression of cancer, this cDNA expression array technique could be a useful tool, however, no established methods for interpreting the results are yet available. We used the Atlas cancer cDNA expression array (Clontech, USA) for analysing total RNA isolated from four human endometrial carcinoma samples (two cell-lines and two tissue samples), one benign endometrial tissue sample and a human breast cancer cell-line, in order to develop a method for analysing the array data. The obtained gene-expression profiles were highly reproducible. XY-scatterplots and regression analysis of the logarithmic transformed data provided a practical method to analyse the data without the need of preceding normalization. Three genes (Decorin, TIMP3 and Cyclin D1) were identified to be differentially expressed between the benign endometrial tissue sample and the endometrial carcinoma samples (tissue and cell-lines). These three genes may potentially be involved in cancer progression. A higher degree of similarity in gene-expression profile was found between the endometrial samples (tissue and cell-lines) than between the endometrial samples and the breast cancer cell-line, which is indicative for an endometrial tissue-specific gene-expression profile. © 2000 Cancer Research Campaig

Driving pressure during general anesthesia for open abdominal surgery (DESIGNATION) : study protocol of a randomized clinical trial

Background Intraoperative driving pressure (Delta P) is associated with development of postoperative pulmonary complications (PPC). When tidal volume (V-T) is kept constant, Delta P may change according to positive end-expiratory pressure (PEEP)-induced changes in lung aeration. Delta P may decrease if PEEP leads to a recruitment of collapsed lung tissue but will increase if PEEP mainly causes pulmonary overdistension. This study tests the hypothesis that individualized high PEEP, when compared to fixed low PEEP, protects against PPC in patients undergoing open abdominal surgery. Methods The "Driving prESsure durIng GeNeral AnesThesIa for Open abdomiNal surgery trial" (DESIGNATION) is an international, multicenter, two-group, double-blind randomized clinical superiority trial. A total of 1468 patients will be randomly assigned to one of the two intraoperative ventilation strategies. Investigators screen patients aged >= 18 years and with a body mass index <= 40 kg/m(2), scheduled for open abdominal surgery and at risk for PPC. Patients either receive an intraoperative ventilation strategy with individualized high PEEP with recruitment maneuvers (RM) ("individualized high PEEP") or one in which PEEP of 5 cm H2O without RM is used ("low PEEP"). In the "individualized high PEEP" group, PEEP is set at the level at which Delta P is lowest. In both groups of the trial, V-T is kept at 8 mL/kg predicted body weight. The primary endpoint is the occurrence of PPC, recorded as a collapsed composite of adverse pulmonary events. Discussion DESIGNATION will be the first randomized clinical trial that is adequately powered to compare the effects of individualized high PEEP with RM versus fixed low PEEP without RM on the occurrence of PPC after open abdominal surgery. The results of DESIGNATION will support anesthesiologists in their decisions regarding PEEP settings during open abdominal surgery

Association Between an Increase in Serum Sodium and In-Hospital Mortality in Critically Ill Patients*

OBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival. DESIGN: Retrospective cohort study. SETTING: Ten Dutch ICUs between January 2011 and April 2017. PATIENTS: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25]). CONCLUSIONS: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia

Identification of Rothia Bacteria as Gluten-Degrading Natural Colonizers of the Upper Gastro-Intestinal Tract

Gluten proteins, prominent constituents of barley, wheat and rye, cause celiac disease in genetically predisposed subjects. Gluten is notoriously difficult to digest by mammalian proteolytic enzymes and the protease-resistant domains contain multiple immunogenic epitopes. The aim of this study was to identify novel sources of gluten-digesting microbial enzymes from the upper gastro-intestinal tract with the potential to neutralize gluten epitopes.Oral microorganisms with gluten-degrading capacity were obtained by a selective plating strategy using gluten agar. Microbial speciations were carried out by 16S rDNA gene sequencing. Enzyme activities were assessed using gliadin-derived enzymatic substrates, gliadins in solution, gliadin zymography, and 33-mer α-gliadin and 26-mer γ-gliadin immunogenic peptides. Fragments of the gliadin peptides were separated by RP-HPLC and structurally characterized by mass spectrometry. Strains with high activity towards gluten were typed as Rothia mucilaginosa and Rothia aeria. Gliadins (250 µg/ml) added to Rothia cell suspensions (OD(620) 1.2) were degraded by 50% after ∼30 min of incubation. Importantly, the 33-mer and 26-mer immunogenic peptides were also cleaved, primarily C-terminal to Xaa-Pro-Gln (XPQ) and Xaa-Pro-Tyr (XPY). The major gliadin-degrading enzymes produced by the Rothia strains were ∼70-75 kDa in size, and the enzyme expressed by Rothia aeria was active over a wide pH range (pH 3-10).While the human digestive enzyme system lacks the capacity to cleave immunogenic gluten, such activities are naturally present in the oral microbial enzyme repertoire. The identified bacteria may be exploited for physiologic degradation of harmful gluten peptides