Selective NR1/2B N-methyl-D-aspartate receptor antagonists among indole-2-carboxamides and benzimidazole-2-carboxamides

(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.     

Molecular epidemiology of VIM-4 metallo-beta-lactamase-producing Pseudomonas sp. isolates in Hungary

VIM metallo-beta-lactamase-producing serotype O11 or O12 Pseudomonas aeruginosa isolates infecting or colonizing 19 patients from seven hospitals in Hungary were characterized between October 2003 and November 2005. Macrorestriction analysis revealed the involvement of hospitals from three different towns in northwest Hungary in an outbreak caused by VIM-4-producing P. aeruginosa.     

Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney

Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein-coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca2+, the production of NO and prostaglandin (PGE2), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.     

Orlistat increases serum paraoxonase activity in obese patients

Background and aimPrevious studies have demonstrated that oxidative stress is increased in obese patients. The high-density lipoprotein (HDL) associated human paraoxonase 1 (PON1) can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Our objective was to assess the effects of orlistat therapy combined with diet on body mass index (BMI), waist circumference, lipid parameters, blood pressure, serum glucose level and PON1 activity.Methods and resultsA longitudinal, multicenter, randomized study with and without orlistat treatment was performed. One hundred thirty nine otherwise healthy, obese subjects were divided in to two groups: 78 persons received orlistat (120 mg three times a day) combined with diet while 61 persons were kept on diet only. Anthropometrical parameters, serum lipid levels and PON1 activity were measured at baseline and after 6 months of treatment. BMI and waist circumference were reduced more pronouncedly in the orlistat group than in the control group. Patients receiving orlistat also had significantly greater improvements in fasting blood glucose levels and blood pressure. The orlistat-treated group showed a greater reduction in total cholesterol and triglyceride levels. In addition, the serum PON1 activity in these patients was significantly increased compared to the diet-only group.ConclusionsThe 6-month treatment with orlistat had a beneficial effect on the lipid profile and improved the antioxidant status by increasing serum PON1 activity. However, because of the limited therapeutic effectiveness, obese patients with hypercholesterolemia should receive additional lipid lowering medications.     

Projections of primary afferent fibers to last-order premotor interneurons in the lumbar spinal cord of rats

It is well established that last-order premotor interneurons in the spinal cord have crucial importance in the integration of activities generated by the spinal motor apparatus, sensory information and volleys arising from higher motor centers, indicating that they play a substantial role in spinal motor functions. Despite extensive studies, synaptic input systems of these neurons have not been investigated in detail up to now with morphological approaches. On this basis, the present experiments were aimed at the visualization of possible contacts between primary afferents and last-order premotor interneurons in the lumbar spinal cord of rats using double label neural tracing methods in light microscopy. The findings show that terminal puncta of primary afferents do establish indeed appositions on last-order premotor interneurons. From the quantitative point of view, these appositions occur, however, in limited numbers. The study also shows that last-order premotor interneurons contacted by primary afferents tend to be concentrated at the segmental level of the innervated motoneurons, and are evenly distributed along the mediolateral extent of laminae V-VI and in the dorsal portion of lamina VII.     

A 10-year follow-up of ischemic heart disease risk factors in military pilots

INTRODUCTION: Cardiovascular diseases (CVDs) represent the reason for approximately 10% of all groundings among military pilots. After their first screening examination, which decides their fitness for flight, pilots are required to appear for screening examinations yearly, which makes it possible to monitor the changes in the risk factors of ischemic heart disease (IHD) from their candidate days until their retirement or final grounding. SUBJECTS AND METHODS: During regular fitness screenings, we determined the individual and common occurrence and changes of recorded or measured IHD risk factors on the basis of 10- (baseline), 5-, and 0-year (current) data in the cases of 250 active male military pilots, broken down into 5-year age groups. In addition, by the help of complex risk calculation methods, we calculated the 5- and 10-year risk of coronary artery disease and CVDs, respectively. RESULTS: In the first year of the examinations, the following risk factors appeared: positive family history (25.0%), obesity (40.8%), smoking (31.7%), physical inactivity (23.9%), high blood pressure (14.7%), hypercholesterolemia (53.9%), pathological electrocardiogram deviations (1.3%). By aging, the occurrence of each risk factor remained unchanged or increased and their cumulative occurrence became more frequent, except for those above 45 to 50 yrs, who seldom had four or more risk factors at the same time. The cardiovascular risk calculated by the Futrex program was elevated in 40% of the study population (levels 3 and 4). By aging, the indices received by complex risk calculation methods deteriorated in the age group 25 to 45 years, while they improved in the age group of >45 years. The 5-year risk of CVDs was below 2.5% in half of the study population and it did not exceed 15 to 20% even in the age group with the highest risk. DISCUSSION: Based on reference data, pilots usually represent a healthier population in those countries where coronary artery diseases are leading health problems. In Hungary, many young pilots leave the army due to its currently ongoing transformation, while the elder are less motivated to change careers. It is probably the role of the stricter physical fitness test and screening examinations, and the effect of military propaganda targeting health conservation, that is in the background of the elder pilots' value improvements. It is also an influencing factor that by administering antilipid and antihypertensive medication based on NATO recommendations in the cases of those with increased risk, the probability of the development of IHD decreases and the affected pilots can be kept longer in service.     

Dynamic control of a central pattern generator circuit: a computational model of the snail feeding network

Central pattern generators (CPGs) are networks underlying rhythmic motor behaviours and they are dynamically regulated by neuronal elements that are extrinsic or intrinsic to the rhythmogenic circuit. In the feeding system of the pond snail, Lymnaea stagnalis, the extrinsic slow oscillator (SO) interneuron controls the frequency of the feeding rhythm and the N3t (tonic) has a dual role; it is an intrinsic CPG interneuron, but it also suppresses CPG activity in the absence of food, acting as a decision-making element in the feeding circuit. The firing patterns of the SO and N3t neurons and their synaptic connections with the rest of the CPG are known, but how these regulate network function is not well understood. This was investigated by building a computer model of the feeding network based on a minimum number of cells (N1M, N2v and N3t) required to generate the three-phase motor rhythm together with the SO that was used to activate the system. The intrinsic properties of individual neurons were represented using two-compartment models containing currents of the Hodgkin-Huxley type. Manipulations of neuronal activity in the N3t and SO neurons in the model produced similar quantitative effects to food and electrical stimulation in the biological network indicating that the model is a useful tool for studying the dynamic properties of the feeding circuit. The model also predicted novel effects of electrical stimulation of two CPG interneurons (N1M and N2v). When tested experimentally, similar effects were found in the biological system providing further validation of our model.