The association between glycemia and endothelial function in nondiabetic individuals: the importance of body weight

The aim of this study was to examine the association between glycemia and markers of early atherosclerosis in healthy nondiabetic individuals. In 309 individuals without diabetes or symptomatic cardiovascular disease, we assessed long-term glycemia by glycosylated hemoglobin (HbA1c) and endothelial function by flow-mediated dilatation (FMD) in the brachial artery. HbA1c was negatively associated with FMD (r = -0.162, P = 0.004). Multivariate linear regression analysis after adjusting for common risk factors of cardiovascular disease showed that BMI was an effect modifier of the association between HbA1c and FMD (P = 0.034 for the HbA1c x BMI interaction). We stratified the FMD outcome data into two groups separated by the median BMI (group 1: BMI < or = 26.1 kg/m(2) and group 2: BMI > 26.1 kg/m(2)). In the lower BMI group, HbA1c was an independent predictor of FMD even when adjusted for confounding factors associated with impaired glucose metabolism (r = -0.215, P = 0.009), but in the higher BMI group HbA1c was not associated with FMD (r = -0.051, P = 0.5). In a nondiabetic population, long-term glycemia was associated with endothelial dysfunction only in lean individuals. In the overweight individuals, this association was not apparent, possibly because some of the mechanisms that mediate the effect of glycemia on vascular function are shared by obesity.     

The role of erythropoietin as an inhibitor of tissue ischemia

Erythropoietin is a hypoxia-induced cytokine that stimulates erythropoiesis through the promotion of erythroid precursor cell proliferation and differentiation. Recent evidence supports that erythropoietin has a broad spectrum of tissue protecting actions affecting other systems than hemopoietic. Lately, research has focused on the nonhemopoietic effects of erythropoietin against tissue ischemia due to the unexpected observations of erythropoietin receptor expression by various cells, such as endothelial cells, neuronal cells, cardiac myocytes, and vascular smooth muscle cells. It has been shown that erythropoietin exerts its cardioprotective action during cardiac ischemic injury through reducing the infract size and enhancing new vessel formation over a longer time frame. Erythropoietin plays a crucial role in neuroprotection in many types of ischemic injury in the central and the peripheral nervous system. It is also strongly believed that erythropoietin exhibits a critical role in many other disorders that are pathogenetically related to acute tissue ischemia. This article reviews the proposed implications of erythropoietin in tissue ischemia and discusses the possible mechanisms for this action along with its potential therapeutic applications.     

Application of the OECD 301F respirometric test for the biodegradability assessment of various potential endocrine disrupting chemicals

The biodegradability of several potential endocrine disrupting compounds, namely 4-n-nonylphenol (4-n-NP), nonylphenol monoethoxylate (NP1EO), nonylphenol diethoxylate (NP2EO), bisphenol A (BPA), triclosan (TCS), di-(2-ethylhexyl)-phthalate (DEHP), perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) was evaluated in this study, using OECD method 301F (manometric respirometry test) and activated sludge as inoculum. According to the results, 4-n-NP and BPA meet the strict definition of ready biodegradability and they are not expected to be persistent during the activated sludge process. Partial biodegradation was observed for DEHP (58.7+/-5.7%, n=3), TCS (52.1+/-8.5%, n=3) and NP1EO (25.9+/-8.1%, n=3), indicating their possible biodegradation in wastewater treatment systems, while no biodegradation was observed for NP2EO, PFOA and PFNA. Experiments in the co-presence of a readily biodegradable compound showed the absence of co-metabolic phenomena during 4-n-NP, BPA and TCS biodegradation. Using first order kinetics to describe biodegradation of the target compounds, half-lives of 4.3+/-0.6, 1.3+/-0.2, 1.8+/-0.5, 6.9+/-2.6 days were calculated for 4-n-NP, BPA, TCS and DEHP, respectively. Toxicity tests using marine bacterium Vibrio fischeri showed that biodegradation of 4-n-NP, NP1EO, BPA and TCS is a simultaneous detoxification process, while possible abiotic or biotic transformations of NP2EO, DEHP, PFOA and PFNA during respirometric test resulted to significant increase of their toxicities.     

Identification of novel cystinuria mutations and polymorphisms in SLC3A1 and SLC7A9 genes: absence of SLC7A10 gene mutations in cystinuric patients

Cystinuria represents 3% of nephrolithiasis in humans with an overall prevalence of 1 in 7,000 neonates. Two genes have been reported to account for the genetic basis of cystinuria, the SLC3A1 and the SLC7A9. Recently, the possible involvement of the SLC7A10 gene in the genetic basis of the disorder was also reported. In the present study, we found a total of 15 mutations in 20 Greek cystinuric patients. Eight mutations are novel, 4 in the SLC3A1: F266S, T351I, R456C, and N516D, and 4 in the SLC7A9: 479-1G>C, Y232C, D233E, and 1399+1G>T. Furthermore, 2 polymorphisms were identified in the SLC3A1 gene and 16 polymorphic variants were also found in the SLC7A9 gene of which the 235+18C>A, 604+10G>A, and 604+24T>C are novel. Finally, no mutation was found in the SLC7A10 gene in all patients. Only, the novel 634+8C>G and the previously reported 913-11C+T polymorphisms were identified in the SLC7A10 gene. In conclusion, a spectrum of SLC3A1 and SLC7A9 mutations are responsible for the genetic basis of cystinuria in Greek patients.     

Th1/Th2 cytokine pattern in bronchoalveolar lavage fluid and induced sputum in pulmonary sarcoidosis

Background

Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of ACE inhibitors on mortality for patients hospitalized with community-acquired pneumonia.

Methods

A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation.

Results

Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk. In the multivariable conditional logistic regression analysis, after adjusting for potential confounders, the use of ACE inhibitors at presentation (odds ratio 0.44, 95% confidence interval 0.22–0.89) was significantly associated with 30-day mortality.

Conclusion

Prior outpatient use of an ACE inhibitor was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect.     

A prototype manipulator for magnetic resonance-guided interventions inside standard cylindrical magnetic resonance imaging scanners

The aim of this work is to develop a remotely controlled manipulator to perform minimally invasive diagnostic and therapeutic interventions in the abdominal and thoracic cavities, with real-time magnetic resonance imaging (MRI) guidance inside clinical cylindrical MR scanners. The manipulator is composed of a three degree of freedom Cartesian motion system, which resides outside the gantry of the scanner, and serves as the holder and global positioner of a three degree of freedom arm which extends inside the gantry of the scanner At its distal end, the arm's end-effector can carry an interventional tool such as a biopsy needle, which can be advanced to a desired depth by means of a seventh degree of freedom. These seven degrees of freedom, provided by the entire assembly, offer extended manipulability to the device and a wide envelope of operation to the user, who can select a trajectory suitable for the procedure. The device is constructed of nonmagnetic and nonconductive fiberglass, and carbon fiber composite materials, to minimize artifacts and distortion on the MR images as well as eliminate effects on its operation from the high magnetic field and the fast switching magnetic field gradients used in MR imaging. A user interface was developed for man-in-the-loop control of the device using real-time MR images. The user interface fuses all sensor signals (MR and manipulator information) in a visualization, planning, and control command environment. Path planning is performed with graphical tools for setting the trajectory of insertion of the interventional tool using multislice and/or three dimensional MR images which are refreshed in real time. The device control is performed with an embedded computer which runs real-time control software. The manipulator compatibility with the MR environment and image-guided operation was tested on a 1.5 T MR scanner.     

Morphometric study of the human muscle spindle

OBJECTIVE: To study the morphometric characteristics of the human muscle spindle in normal muscle and to investigate the influence of aging. STUDY DESIGN: The following variables were studied in 72 spindles: area and diameter of the spindle; thickness of the capsule; number, area and diameter of fibers; and number and area of nuclei. RESULTS: In deltoid and extensor digitorum brevis muscles, a reduction in the diameter of the spindle as a function of age was found, while no statistically significant change in the variables as a function of age was observed in the quadriceps femoris and biceps muscles. In the deltoid, a reduction in the number of fibers and an increase in their diameter were also observed. CONCLUSION: These findings could prove useful in the study of the spindle in relation to disease.     

Kinetic analysis of maize glutathione <Emphasis Type="Italic">S</Emphasis>-transferase I catalysing the detoxification from chloroacetanilide herbicides

Glutathione S-transferases (GSTs, EC 2.5.1.18) are a family of multi-functional enzymes involved in biodegradation of several herbicide classes. The ability of the maize isoenzyme GST I to detoxify from the acetanilide herbicide alachlor was investigated by steady-state kinetics and site-directed mutagenesis studies. Steady-state kinetics fit well to a rapid equilibrium random sequential bi-bi mechanism with intrasubunit modulation between GSH binding site (G-site) and electrophile binding site (H-site). The rate-limiting step of the reaction is viscosity-dependent and thermodynamic data suggest that product release is rate-limiting. Three residues of GST I (Trp12, Phe35 and Ile118), which build up the xenobiotic binding site, were mutated and their functional and structural roles during alachlor conjugation were investigated. These residues are not conserved, hence may affect substrate specificity and/or product dissociation. The work showed that the key amino acid residue Phe35 modulates xenobiotic substrate binding and specificity, and participates in k_cat regulation by affecting the rate-limiting step of the catalytic reaction. Trp12 and Ile118 do not seem to carry out such functions but instead, regulate the K_m for alachlor by contributing to its productive orientation in the H-site. The results of the present work have practical significance since this may provide the basis for the rational design of new engineered GSTs with altered substrate specificity towards herbicides and may facilitate the design of new, more selective herbicides.     

Cadherins mediate both the association between PS1 and beta-catenin and the effects of PS1 on beta-catenin stability

Presenilin1 (PS1), a protein involved in cellular development, forms functional complexes with beta-catenin, a regulator of Wnt signaling and cell-cell adhesion. In addition, both proteins have been shown to play important roles in disease including cancer and Alzheimer disease. Although PS1 and beta-catenin are found in the same complexes, it is not clear whether they bind directly to each other or a third complex component, like cadherin, may mediate their interactions. Here we show that PS1 and beta-catenin form no detectable complexes in cells that express no cadherin. In contrast, these complexes are readily found in E-cadherin containing cells. Furthermore, binding of both PS1 and beta-catenin to E-cadherin is necessary for the formation of PS1/beta-catenin complexes. Importantly, our data show that binding of PS1 to cadherin mediates the effects of PS1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of PS1 and beta-catenin and the effects of PS1 on the cellular levels of beta-catenin.