VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo

Three approximate free energy calculation methods are examined and applied to an example ligand design problem. The first of the methods uses a single simulation to estimate the relative binding free energies for related ligands that are not simulated. The second method is similar, except that it uses only first derivatives of free energy with respect to atomic parameters (most often charge, van der Waals equilibrium distance, and van der Waals well depth) to calculate free energy differences. The last method PROFEC (Pictorial Representation of Free Energy Components), generates contour maps that show how binding free energy changes when additional particles are added near the ligand. These three methods are applied to a benzamidine/trypsin complex. They each reproduce the general trends in the binding free energies, indicating that they might be useful for suggesting how ligands could be modified to improve binding and, consequently, useful in structure-based drug design.     

Functional results following the antegrade continence enema procedure

BACKGROUND: Forty children who underwent the antegrade continence enema (ACE) procedure for faecal soiling were studied to determine factors predictive of outcome. METHODS: There were four patient groups: (1) ambulant with spinal dysraphism (n = 13), (2) wheelchair bound with spinal dysraphism (n = 14), (3) ambulant with miscellaneous disorders (n = 11) and (4) wheelchair bound with miscellaneous disorders (n = 2). Effectiveness of the procedure was assessed using technical evaluation and quality-of-life improvement (QOLI) scores (0-5). Objective assessment included colonic transit time (CTT) and anorectal manometry. Median follow-up was 21 (range 5-37) months. RESULTS: Some 28 of 40 children achieved continence. The procedure was reversed in four of 40 children. Of the other 36 children with a functioning ACE stoma, all reported improvement in quality of life (mean QOLI score 3.5). There were no significant differences in technical evaluation score, QOLI score, CTT, manometry findings or continence between ambulant groups and the wheelchair-bound group with miscellaneous disorders. QOLI score, anorectal squeeze pressure and continence were significantly poorer in those who were wheelchair bound with spinal dysraphism. Absent squeeze pressure was associated with poor outcome. CONCLUSION: Wheelchair-bound children with spinal neuropathy have a poorer outcome following the ACE procedure. Although ACE is an effective method of promoting faecal continence, it is essential to determine the aetiology of incontinence and sphincter function before operation.     

Ambulatory health care use by patients in a public hospital emergency department

OBJECTIVE: To describe primary care clinic use and emergency department (ED) use for a cohort of public hospital patients seen in the ED, identify predictors of frequent ED use, and ascertain the clinical diagnoses of those with high rates of ED use. DESIGN: Cohort observational study. SETTING: A public hospital in Atlanta, Georgia. PATIENTS: Random sample of 351 adults initially surveyed in the ED in May 1992 and followed for 2 years. MEASUREMENTS AND MAIN RESULTS: Of the 351 patients from the initial survey, 319 (91%) had at least one ambulatory visit in the public hospital system during the following 2 years and one third of the cohort was hospitalized. The median number of subsequent ED visits was 2 (mean 6.4), while the median number of visits to a primary care appointment clinic was O (mean 1.1) with only 90 (26%) of the patients having any primary care clinic visits. The 58 patients (16.6%) who had more than 10 subsequent ED visits accounted for 65.6% of all subsequent ED visits. Overall, patients received 55% of their subsequent ambulatory care in the ED, with only 7.5% in a primary care clinic. In multivariate regression, only access to a telephone (odds ratio [OR] 0.48; 95% confidence interval [CI] 0.39, 0.60), hospital admission (OR 5.90; 95% CI 4.01, 8.76), and primary care visits (OR 1.68; 95% CI 1.34, 2.12) were associated with higher ED visit rates. Regular source of care, insurance coverage, and health status were not associated with ED use. From clinical record review, 74.1% of those with high rates of use had multiple chronic medical conditions, or a chronic medical condition complicated by a psychiatric diagnosis, or substance abuse. CONCLUSIONS: All subgroups of patients in this study relied heavily on the ED for ambulatory care, and high ED use was positively correlated with appointment clinic visits and inpatient hospitalization rates, suggesting that high resource utilization was related to a higher burden of illness among those patients. The prevalence of chronic medical conditions and substance abuse among these most frequent emergency department users points to a need for comprehensive primary care. Multidisciplinary case management strategies to identify frequent ED users and facilitate their use of alternative care sites will be particularly important as managed care strategies are applied to indigent populations who have traditionally received care in public hospital EDs.     

Myocardial infarction and percent arteriographic stenosis of culprit lesion: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH)

Domestic violence is a significant public health issue affecting women. Numerous medical organizations have recommended that routine screening of women be conducted to assist in the prevention, identification, and care for victims of violence. This article examines the scope of domestic violence in women, reviews ways to recognize abuse, examines the potential impact of abuse upon health and discusses the management of victims.     

Esophageal/pyloric ligation enhances development of the murine fetal stomach in organ culture

The polyphasic approach to taxonomic problems has led to the creation of complex datasets that lend themselves to numerical analysis. The numerical study, however, has to deal with mathematical problems linked with the presence of mixed-type data originating from the investigations. Correspondence analysis (CA) is an ordination technique widely used in ecology and social sciences but only rarely applied to taxonomic problems. In CA corresponding variables and taxa ordination are obtained simultaneously, thus allowing to explore the taxonomic interrelationships between taxa and variables in a single analysis. CA can be used on large and small datasets, and can be applied to mixed-type data after appropriate coding. It is not sensitive to variation of class number and size and is useful to screen large unstructured datasets, to suggest which variables should be retained to discriminate samples, to detect outliers or erroneous data and to perform identification of unknown samples. It also has the advantage of handling missing data particularly well. On the other hand, CA is sensitive to outliers, which can cause a distortion of the geometric map of the points in the graphical display. Nevertheless, the sensitivity of correspondence analysis to outliers can be effectively used to verify data. Finally, based on symmetry of row and column analyses correspondence analysis can be applied to find out which characters can be used to construct identification keys and to selectively group variables by their importance for the discrimination of samples.     

Role of E4 in eliciting CD4 T-cell and B-cell responses to adenovirus vectors delivered to murine and nonhuman primate lungs

Adenovirus vectors delivered to lung are being considered in the treatment of cystic fibrosis (CF). Vectors from which E1 has been deleted elicit T- and B-cell responses which confound their use in the treatment of chronic diseases such as CF. In this study, we directly compare the biology of an adenovirus vector from which E1 has been deleted to that of one from which E1 and E4 have been deleted, following intratracheal instillation into mouse and nonhuman primate lung. Evaluation of the E1 deletion vector in C57BL/6 mice demonstrated dose-dependent activation of both CD4 T cells (i.e., TH1 and TH2 subsets) and neutralizing antibodies to viral capsid proteins. Deletion of E4 and E1 had little impact on the CD4 T-cell proliferative response and cytolytic activity of CD8 T cells against target cells expressing viral antigens. Analysis of T-cell subsets from mice exposed to the vector from which E1 and E4 had been deleted demonstrated preservation of TH1 responses with markedly diminished TH2 responses compared to the vector with the deletion of E1. This effect was associated with reduced TH2-dependent immunoglobulin isotypes and markedly diminished neutralizing antibodies. Similar results were obtained in nonhuman primates. These studies indicate that the vector genotype can modify B-cell responses by differential activation of TH1 subsets. Diminished humoral immunity, as was observed with the E1 and E4 deletion vectors in lung, is indeed desired in applications of gene therapy where readministration of the vector is necessary.     

等离子喷涂-激光重熔制备AlCuFe准晶涂层的研究

报道了在氩气气氛下，利用固体YAG激光对等离子喷涂AlCuFe准晶涂层进行激光重熔制备包含二十面体准晶I相及β类似相涂层的研究。结果表明，在激光功率固定为300W的情况下，随着激光扫描速度的增加，低碳钢基体中Fe元素对涂层的稀释度减小，从而使不同扫描速度下所得离子喷涂-激光重熔涂层中I相和β相的含量比I/β依次增加。同时随着激光扫描速度的增加，激光熔化涂层的熔池深度变浅。当激光扫描速度大于某一定值时，涂层熔化深度达不到涂层与基体的结合界面从而无法使涂层与基体之间实现冶金结合，不利于涂层结合力的提高。     

Irreversible inactivation of protein kinase C by glutathione

The tripeptide glutathione (GSH) is the predominant low molecular weight thiol reductant in mammalian cells. In this report, we show that at concentrations at which GSH is typically present in the intracellular milieu, GSH and the oxidized GSH derivatives GSH disulfide (GSSG) and glutathione sulfonate each irreversibly inactivate up to 100% of the activity of purified Ca2+- and phosphatidylserine (PS)-dependent protein kinase C (PKC) isozymes in a concentration-dependent manner by a novel nonredox mechanism that requires neither glutathiolation of PKC nor the reduction, formation, or isomerization of disulfide bridges within PKC. Our evidence for a nonredox mechanism of PKC inactivation can be summarized as follows. GSSG antagonized the Ca2+- and PS-dependent activity of purified rat brain PKC with the same efficacy (IC50 = 3 mM) whether or not the reductant dithiothreitol was present. Glutathione sulfonate, which is distinguished from GSSG and GSH by its inability to undergo disulfide/thiol exchange reactions, was as effective as GSSG in antagonizing Ca2+- and PS-dependent PKC catalysis. The irreversibility of the inactivation mechanism was indicated by the stability of the inactivated form of PKC to dilution and extensive dialysis. The inactivation mechanism did not involve the nonspecific phenomena of denaturation and aggregation of PKC because it obeyed pseudo-first order kinetics and because the hinge region of PKC-alpha remained a preferential target of tryptic attack following GSH inactivation. The selectivity of GSH in the inactivation of PKC was also indicated by the lack of effect of the tripeptides Tyr-Gly-Gly and Gly-Ala-Gly on the activity of PKC. Furthermore, GSH antagonism of the Ser/Thr kinase casein kinase 2 was by comparison weak (<25%). Inactivation of PKC-alpha was not accompanied by covalent modification of the isozyme by GSH or other irreversible binding interactions between PKC-alpha and the tripeptide, but it was associated with an increase in the susceptibility of PKC-alpha to trypsinolysis. Treatment of cultured rat fibroblast and human breast cancer cell lines with N-acetylcysteine resulted in a substantial loss of Ca2+- and PS- dependent PKC activity in the cells within 30 min. These results suggest that GSH exerts negative regulation over cellular PKC isozymes that may be lost when oxidative stress depletes the cellular GSH pool.