New Mixed Li/Mg and Li/Mg/Zn Amides for the Chemoselective Metallation of Arenes and Heteroarenes

New mixed Li/Mg and Li/Mg/Zn amides have been synthesized starting from readily prepared secondary amines. They allow a highly chemoselective directed magnesiation or zincation of various polyfunctional aromatics and heteroaromatics. The kinetic basicity, solubility and stability of these new bases have been compared with those of the corresponding 2,2,6,6-tetramethylpiperamide-derived bases. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Relaxation evoked by extracellular Ca(2+) in rat aorta is nerve-independent and involves sarcoplasmic reticulum and L-type Ca(2+) channell

The perivascular nerve network expresses a Ca(2+) receptor that is activated by high extracellular Ca(2+) concentrations and causes vasorelaxation in resistance arteries. We have verified the influence of perivascular nerve fibers on the Ca(2+)-induced relaxation in aortic rings. To test our hypothesis, either pre-contracted aortas isolated from rats after sensory denervation with capsaicin or aortic rings acutely denervated with phenol were stimulated to relax with increasing extracellular Ca(2+) concentration. We also studied the role of the endothelium on the Ca(2+)-induced relaxation, and we verified the participation of endothelial/nonendothelial nitric oxide and cyclooxygenise-arachidonic acid metabolites. Additionally, the role of the sarcoplasmic reticulum, K(+) channels and L-type Ca(2+) channels on the Ca(2+)-induced relaxation were evaluated. We have observed that the Ca(2+)-induced relaxation is completely nerve independent, and it is potentiated by endothelial nitric oxide (NO). In endothelium-denuded aortic rings, indomethacin and AH6809 (PGF(2 alpha) receptor antagonist) enhance the relaxing response to Ca(2+). This relaxation is inhibited by thapsigargin and verapamil, while was not altered by tetraethylammonium. In conclusion, we have shown that perivascular nervous fibers do not participate in the Ca(2+)-induced relaxation, which is potentiated by endothelial NO. In endothelium-denuded preparations, indomethacin and AH6809 enhance the relaxation induced by Ca(2+). The relaxing response to Call was impaired by verapamil and thapsigargin, revealing the importance of L-type Ca(2+) channels and sarcoplasmic reticulum in this response. (c) 2008 Elsevier Inc. All rights reserved.

Effect of process variables on fluiddynamics and adhesion efficiency during spouted bed coating of hard gelatine capsules

This article presents an evaluation of the effects of the spouted bed design and operating conditions on system fluiddynamics and process performance during enteric coating of hard gelatine capsules. The design parameters studied were the column diameter (150 mm and 200 mm), the included angle of the conical base, gamma (60 degrees or 40 degrees) and the presence or absence of a Venturi inserted before the inlet air orifice. The process variables studied were the ratio between the feed flow rate of the coating suspension to the spouting gas flow rate (W(s)/W(g)), the mass of capsules loaded to the equipment (M(0)), and the ratio between the Spouting gas flow rate to the gas flow rate at minimum spouting condition (Q/Q(ms)). The response variables were the rate of increase of the capsules mass (K(1)), and the adhesion efficiency (eta). The linear regression equation for the dependent variable K, in terms of the independent variables adequately described the process with an r(2) value of 0.872. Analysis of variance (ANOVA) revealed that increasing of W(s)/W(g), Q/Q(ms) and gamma significantly increased the adhesion efficiency. Adhesion efficiencies higher than 90% were achieved by selecting precise coating conditions, indicating the feasibility of the process for coating of hard gelatine capsules. (C) 2008 Elsevier B.V. All rights reserved.

The Pharmaceutical care of patients with type 2 diabetes mellitus

Objective To evaluate the efficiency of pharmaceutical care on the control of clinical parameters, such as fasting glycaemia and glycosylated haemoglobin in patients with Type 2 Diabetes mellitus. Setting This study was conducted at the Training and Community Health Centre of the College of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil. Methods A prospective and experimental study was conducted with 71 participants divided in two groups: (i) pharmaceutical care group (n=40), and (ii) the control group (n=31). The distribution of patients within these groups was made casually, and the patients were monitored for 12 months. Main outcome measure: Values for fasting glycaemia and glycosylated haemoglobin were collected. Results Mean values of fasting glycaemia in the pharmaceutical care group were significantly reduced whilst a small reduction was detected in the control group at the same time. A significant reduction in the levels of glycosylated haemoglobin was detected in patients in the pharmaceutical care group, and an average increase was observed in the control group. Furthermore, the follow-up of the intervention group by a pharmacist contributed to the resolution of 62.7% of 142 drug therapy problems identified. Conclusion In Brazil, the information provided by a pharmacist to patients with Type 2 Diabetes mellitus increases compliance to treatment, solving or reducing the Drug Therapy Problem and, consequently, improving glycaemic control.

Predominance of CTX-M-type extended-spectrum beta-lactamase genes among enterobacterial isolates from outpatients in Brazil

Two hundred fifty-seven nalidixic acid-resistant enterobacterial isolates were collected in a Brazilian community from January 2000 to May 2005 to determine the prevalence of plasmid-encoded extended-spectrum beta-lactamases. The bla(CTX-M) genetic environment was determined by polymerase chain reaction and sequencing. Eleven isolates (4.2%) harbored a bla(CTX-M-2) gene, 3 isolates bla(CTX-M-9), 2 isolates bla(CTX-M-8), and 6 isolates bla(SHV-5). Two novel bla(CTX-M-2) variants, namely, bla(CTX-M-74) and bla(CTX-M-75), were identified. (C) 2009 Elsevier Inc. All rights reserved.

Nosocomial outbreak by imipenem-resistant metallo-beta-lactamase-producing Pseudomonas aeruginosa in an adult intensive care unit in a Brazilian teaching hospital

Objective: To describe an outbreak of imipenem-resistant metallo-beta-lactamase-producing Pseudomonas aeruginosa, enzyme type bla, by horizontal transmission in patients admitted to a mixed adult ICU. Methods: A case-control study was carried out, including 47 patients (cases) and 122 patients (control) admitted to the mixed ICU of a university hospital in Minas Gerais. Brazil from November 2003 to July 2005. The infection site, risk factors, mortality, antibiotic susceptibility, metallo-beta-lactamase (MBL) production, enzyme type, and clonal diversity were analyzed, Results: A temporal/spatial relationship was detected in most patients (94%), overall mortality was 55.3%, and pneumonia was the predominant infection (85%). The majority of isolates (95%) were resistant to imipenem and other antibiotics, except for polymyxin, and showed MBL production (76.7%). Only bla SPM-1 (33%) was identified in the 15 specimens analyzed. In addition, 4 clones were identified, with a predominance of clone A (61.5%) and B (23.1%). On multivariate analysis, advanced age, mechanical ventilation, tracheostomy, and previous imipenem use were significant risk factors for imipenem-resistant P. aeruginosa infection. Conclusions: Clonal dissemination of MBL-producing P. aeruginosa strains with a spatial/temporal relationship disclosed problems in the practice of hospital infection control, low adherence to hand hygiene, and empirical antibiotic use. (C) 2008 Elsevier Espana, S.L. All rights reserved.

An alpha-type phospholipase A(2) inhibitor from Bothrops jararacussu snake plasma: Structural and functional characterization

An inhibitory protein that neutralizes the enzymatic, toxic and pharmacological activities of several phospholipases A(2) from Bothrops venoms was isolated from B. jararacussu snake plasma by affinity chromatography using the immobilized myotoxin BthTX-I on Sepharose gel. Biochemical characterization of this inhibitory protein, denominated alpha BjussuMIP, showed it to be an oligomeric glycoprotein with M-r of 24,000 for the monomeric subunit. Secondary structural analysis by circular dichroism revealed 44% alpha-helix, 18% beta-sheet, 10% beta-turn and 28% random coil structures. Circular dichroism spectroscopy indicated that no significant alterations in the secondary structure of either alpha BjussuMIP or the target protein occur following their interaction. The product from the reaction with reverse transcriptase produced a cDNA fragment of 432 bp that codifies for a mature protein of 144 amino acid residues. The first 21 amino acid residues from the N-terminal and five tryptic peptides were characterized by mass spectrometry of the mature protein and confirmed by the nucleotide sequence. Alignment of alpha BjussuMIP with other snake inhibitors showed a sequence similarity of 73-92% with these alpha PLIs. alpha BjussuMIP was relatively stable within the pH range of 6-12 and temperatures from 0 degrees C to 80 degrees C, even after deglycosylation. The results showed effects against Bothrops phospholipase A(2) activities (enzymatic, edema inducing, myotoxic, cytotoxic and bactericidal), suggesting that alpha BjussuMIP may prove useful in the treatment of snakebite envenomations. (C) 2008 Elsevier Masson SAS. All rights reserved.

Association Among Microalbuminuria and Oxidative Stress Biomarkers in Patients With Type 2 Diabetes

Aim: Hyperglycemia in diabetes mellitus (DM) may be one of the most important factors responsible for the development of oxidative stress, which promotes the main complications in DM patients. Therefore, this study evaluated if the hyperglycemia could be related to oxidative stress biomarkers, lipid profile, and renal function in type 2 diabetes patients without clinic complications. Methods: Plasmatic malondialdehyde (MDA), serum protein carbonyl (PCO), serum creatinine levels, microalbuminuria, glycated hemoglobin, and lipid profile were analyzed in 37 type 2 diabetic patients and 25 subjects with no diabetes. Results: Serum creatinine levels were within the reference values, but microalbuminuria presented increased levels in all the patients compared with controls (P G 0.05) and above of the reference values. The MDA, PCO, low- density lipoprotein, and triglyceride levels showed positive correlation with microalbuminuria levels. Moreover, glycated hemoglobin presented positive correlation with MDA, PCO, and microalbuminuria levels. Conclusions: The hyperglycemia could be responsible for the increase of the microalbuminuria levels and for the oxidation process in lipids and proteins in DM patients. Therefore, we suggested that the microvascular lesion is a direct consequence from hyperglycemia and an indirect one from the increased oxidative stress. Malondialdehyde and protein carbonyl levels could be suggested as additional biochemical evaluation to verify tissue damage in type 2 DM patients.

Language disorders in dementia of the Alzheimer type

The language profile of a group of 18 Alzheimer patients is documented and their performance on a standard aphasia test battery compared to a group of institutionalized, nonneurologically impaired control subjects matched for age, sex, and educational level. The Alzheimer patients scored significantly lower than the controls in the areas of verbal expression, auditory comprehension, repetition, reading, and writing. Articulation abilities were the same in each group. A language deficit was evident in all Alzheimer patients. The language disorder exhibited resembled a transcortical sensory aphasia. Syntax and phonology remained relatively intact but semantic abilities were impaired. The results support the inclusion of a language deficit as a diagnostic criterion of Alzheimer's disease.

The Scientific Basis for High-Intensity Interval Training: Optimising Training Programmes and Maximising Performance in Highly Trained Endurance Athletes

While the physiological adaptations that occur following endurance training in previously sedentary and recreationally active individuals are relatively well understood, the adaptations to training in already highly trained endurance athletes remain unclear. While significant improvements in endurance performance and corresponding physiological markers are evident following submaximal endurance training in sedentary and recreationally active groups, an additional increase in submaximal training (i.e. volume) in highly trained individuals does not appear to further enhance either endurance performance or associated physiological variables [e.g. peak oxygen uptake (V-dot O2peak), oxidative enzyme activity]. It seems that, for athletes who are already trained, improvements in endurance performance can be achieved only through high-intensity interval training (HIT). The limited research which has examined changes in muscle enzyme activity in highly trained athletes, following HIT, has revealed no change in oxidative or glycolytic enzyme activity, despite significant improvements in endurance performance (p < 0.05). Instead, an increase in skeletal muscle buffering capacity may be one mechanism responsible for an improvement in endurance performance. Changes in plasma volume, stroke volume, as well as muscle cation pumps, myoglobin, capillary density and fibre type characteristics have yet to be investigated in response to HIT with the highly trained athlete. Information relating to HIT programme optimisation in endurance athletes is also very sparse. Preliminary work using the velocity at which V-dot O2max is achieved (Vmax) as the interval intensity, and fractions (50 to 75%) of the time to exhaustion at Vmax (Tmax) as the interval duration has been successful in eliciting improvements in performance in long-distance runners. However, Vmax and Tmax have not been used with cyclists. Instead, HIT programme optimisation research in cyclists has revealed that repeated supramaximal sprinting may be equally effective as more traditional HIT programmes for eliciting improvements in endurance performance. Further examination of the biochemical and physiological adaptations which accompany different HIT programmes, as well as investigation into the optimal HIT programme for eliciting performance enhancements in highly trained athletes is required.

Selection bias in gene extraction on the basis of microarray gene-expression data

In the context of cancer diagnosis and treatment, we consider the problem of constructing an accurate prediction rule on the basis of a relatively small number of tumor tissue samples of known type containing the expression data on very many (possibly thousands) genes. Recently, results have been presented in the literature suggesting that it is possible to construct a prediction rule from only a few genes such that it has a negligible prediction error rate. However, in these results the test error or the leave-one-out cross-validated error is calculated without allowance for the selection bias. There is no allowance because the rule is either tested on tissue samples that were used in the first instance to select the genes being used in the rule or because the cross-validation of the rule is not external to the selection process; that is, gene selection is not performed in training the rule at each stage of the cross-validation process. We describe how in practice the selection bias can be assessed and corrected for by either performing a cross-validation or applying the bootstrap external to the selection process. We recommend using 10-fold rather than leave-one-out cross-validation, and concerning the bootstrap, we suggest using the so-called. 632+ bootstrap error estimate designed to handle overfitted prediction rules. Using two published data sets, we demonstrate that when correction is made for the selection bias, the cross-validated error is no longer zero for a subset of only a few genes.

Clustering Process Analysis in a Large-Size Dropshaft and in a Hydraulic Jump

Recent efforts in the characterization of air-water flows properties have included some clustering process analysis. A cluster of bubbles is defined as a group of two or more bubbles, with a distinct separation from other bubbles before and after the cluster. The present paper compares the results of clustering processes two hydraulic structures. That is, a large-size dropshaft and a hydraulic jump in a rectangular horizontal channel. The comparison highlighted some significant differences in clustering production and structures. Both dropshaft and hydraulic jump flows are complex turbulent shear flows, and some clustering index may provide some measure of the bubble-turbulence interactions and associated energy dissipation.