The MPO Study: just a European HEMO Study or something very different?

Although results from observational and epidemiological studies suggested a survival benefit associated with high-flux hemodialysis, conclusive evidence from prospective randomized clinical trials has been lacking. Both the HEMO Study in the USA and the Membrane Permeability Outcome Study (MPO Study) in Europe are randomized studies investigating the effect of high- and low-flux hemodialysis on patient outcomes, even though there were some significant differences in the design of the two studies. An earlier randomized clinical trial could not show differences on patient survival between patient groups being treated with membranes of different material and permeability, but this trial was not designed specifically to examine this particular endpoint. Based on these previous experiences, the MPO Study addressed a hemodialysis patient population which was considered to be more susceptible to the intervention with high-flux dialysis. To identify these patients with an elevated risk, low serum albumin levels were chosen as an indicator; low serum albumin is associated with malnutrition, inflammation, atherosclerosis, and with increased risk of morbidity and mortality. Together with low serum albumin, patients had to be new to dialysis to be selected for the MPO Study. These particular considerations on patient selection, together with additional methodological refinements in the study design allow the conclusion that the MPO Study is valid on its own rather than being a European version of the HEMO Study.     

Minireview: RET: normal and abnormal functions

The RET gene encodes a single-pass transmembrane receptor tyrosine kinase. RET is the oncogene that causes papillary thyroid carcinoma and medullary thyroid carcinoma. The latter may arise as a component of multiple endocrine neoplasia type 2 syndromes; germline mutations in RET are responsible for multiple endocrine neoplasia type 2 inheritance. In this report we review data on the mechanisms leading to RET oncogenic conversion and on RET targeting as a strategy in thyroid cancer treatment.     

Comprehensive health status assessment of centenarians: results from the 1999 large health survey of veteran enrollees

BACKGROUND: Information on the health status of centenarians provides a means for understanding the health care needs of this growing population. Therefore, we examined the health status of a national cohort of centenarian veteran enrollees. METHODS: Ninety-three centenarian veteran enrollees returned a complete health history questionnaire, which included questions about sociodemographic information, age-associated conditions, health behaviors, health-related quality of life as measured by the Veterans SF-36, and change in health status. RESULTS: Centenarian veteran enrollees are a group with major impairment across multiple dimensions of health-related quality of life despite having a relatively low prevalence of diseases. They had considerable physical limitations as reflected by their physical health summary scores (26.2 +/- 8.3). However, their mental health was comparatively good (mental health summary score 44.1 +/- 12.5). Compared to younger elderly veterans (ages 85-99), centenarians had a lower prevalence of hypertension, angina or myocardial infarction, diabetes, and chronic low back pain (p <.05). Centenarians had significantly worse physical functioning, role physical, vitality, and social functioning scores than did younger elderly veterans. The two groups did not differ in their general health, bodily pain, role emotional, and mental health scores. Centenarians did not perceive much decline in their physical or mental health during the preceding year. CONCLUSIONS: Centenarian veteran enrollees are a group with a low number of age-associated diseases and good mental health despite substantial physical limitations. These results support future studies of services directed toward improvement of function as opposed to those focused solely on the treatment of diseases.     

Interface connections of a transmembrane voltage sensor

Voltage-sensitive ion channels open and close in response to changes in transmembrane (TM) potential caused by the motion of the S4 voltage sensors. These sensors are alpha-helices that include four or more positively charged amino acids, most commonly arginine. The so-called paddle model, based on the high-resolution structure of the KvAP K+ channel [Jiang, et al. (2003) Nature 423, 33-41], posits that the S4 sensors move within the membrane bilayer in response to TM voltage changes. Direct exposure of S4 sensors to lipid is contrary to the classical expectation that the dielectric contrast between the membrane hydrocarbon core and water presents an insurmountable energetic penalty to burial of electric charges. Nevertheless, recent experiments have shown that a helix with the sequence of KvAP S4 can be inserted across the endoplasmic reticulum membrane. To reconcile this result with the classical energetics argument, we have carried out a molecular dynamics simulation of an isolated TM S4 helix in a lipid bilayer. The simulation reveals a stabilizing hydrogen-bonded network of water and lipid phosphates around the arginines that reduces the effective thickness of the bilayer hydrocarbon core to approximately 10 A in the vicinity of the helix. It suggests that bilayer phospholipids can adapt locally to strongly perturbing protein elements, causing the phospholipids to become a structural extension of the protein.     

Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease

OBJECTIVES: Increased homocysteine contributes to the pathophysiology of several chronic inflammatory diseases. Whether homocysteine could participate in mucosal inflammation in inflammatory bowel disease (IBD) has not been explored yet. Our aims were to study the levels of plasma and mucosal homocysteine in IBD patients and to assess whether homocysteine can trigger an inflammatory reaction on human intestinal microvascular endothelial cells (HIMECs). METHODS: Homocysteine was measured in the plasma, mucosal biopsy, and lamina propria mononuclear cell (LPMC) supernatants from normal and IBD subjects. HIMEC were cultured in presence of homocysteine, TNF-alpha, or folic acid, alone or in combination. Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule 1 was measured by flow cytometry and monocyte chemoattractant protein-1 (MCP-1) production by ELISA. Phosphorylation of p38 and p42/44 was assessed by immunoblot in HIMEC extracts. T-cell- and monocyte-HIMEC adhesion assays were used to evaluate the impact of homocysteine on leukocyte adhesion to intestinal endothelial cells. RESULTS: Patients with IBD displayed significantly higher homocysteine plasma and mucosal levels than control subjects. IBD-derived LPMC released higher homocysteine than control-derived LPMC. Treatment of HIMEC with homocysteine, and synergistically with the combination of TNF-alpha and homocysteine, triggered HIMEC inflammation, resulting in VCAM-1 up-regulation, MCP-1 production, and p38 phosphorylation. These events lead to an increased capacity of HIMEC to adhere T- and monocyte cells and were blocked by folic acid treatment. CONCLUSIONS: Homocysteine is increased in both the mucosa and plasma of patients with Crohn's disease and ulcerative colitis and contributes to the inflammatory state of the mucosal IBD endothelium. Therefore, homocysteine could play a proinflammatory role in IBD, which can be efficiently targeted by folic acid supplementation.     

Doppler reference values of the fetal vertebral and middle cerebral arteries,at 19–41 weeks gestation

Objectives: Blood flow to the fetal brain is supplied by two vascular systems: the vertebral artery (VA) and the internal carotid artery with its anatomical continuation, the middle cerebral artery (ICA/MCA). In this work, our aim was to establish consistent reference values for the comparative study of both arterial systems.

Methods: The study group consisted of 2323 Doppler examinations of the VA, MCA and UA performed on 2323 single pregnancies between 19 and 41 weeks. These values were afterwards used to calculate the pulsatility index (PI), peak systolic velocity (PSV) and cerebro-placental ratio (CPR) percentiles.

Results: The VA and MCA PI reached maximum values at the end of the second trimester and decreased afterwards due to an increase in the diastolic flow. Conversely, the VA and MCA PSV increased progressively until the end of pregnancy. Regarding the VA and MCA CPR values, they were higher in the middle of the third trimester and decreased afterwards.

Conclusions: In both arterial systems, Doppler reference values have been calculated for the PI, PSV and CPR, being available for future comparative studies.