Azimilide dihydrochloride

Azimilide dihydrochloride is an antiarrhythmic drug with Vaughn Williams class III properties, which blocks both fast (IKr) and slow (IKs) components of the delayed rectifier cardiac potassium channel. The drug slows the heart rate slightly and, like other class III antiarrhythmic drugs, prolongs ventricular repolarization and thus, the QT interval. Unlike sotalol, another class III antiarrhythmic drug, azimilide does not exhibit reverse-use dependence, that is, its binding characteristics and effectiveness are not related to the heart rate. Azimilide is 85% bioavailable, reaches peak blood concentrations in 6-8 h and has a long elimination half-life of 114 h. Clinical trials have utilized once-daily dosing. These trials have tested the use of the drug for patients with supraventricular and ventricular arrhythmias.     

Gene expression profiling allows distinction between primary and metastatic squamous cell carcinomas in the lung

Lung neoplasms commonly develop in patients previously treated for head and neck carcinomas. The derivation of these tumors, either as new primary lung cancers or as metastatic head and neck cancers, is difficult to establish based on clinical or histopathologic criteria since both are squamous cell carcinomas and have identical features under light microscopy. However, this distinction has significant treatment and prognostic implications. Gene expression profiling was performed on a panel of 52 sequentially collected patients with either primary lung (n = 21) or primary head and neck (n = 31) carcinomas using the Affymetrix HG_U95Av2 high-density oligonucleotide microarray. Unsupervised hierarchical clustering with Ward linkage and the Pearson correlation metric was performed. To assess robustness, bootstrap resampling was performed with 1,000 iterations. A t test of the normalized values for each gene was used to determine the genes responsible for segregating head and neck from lung primary carcinomas, and those with the most differential expression were used for later analyses. In the absence of a large "test" set of tumors, we used a supervised leave-one-out cross-validation to test how well we could predict the tumor origin. Once a gene expression profile was established, 12 lung lesions taken from patients with previously treated head and neck cancers were similarly analyzed by gene expression profiling to determine their sites of origin. Unsupervised clustering analysis separated the study cohort into two distinct groups which reliably remained segregated with bootstrap resampling. Group 1 consisted of 30 tongue carcinomas. Group 2 consisted of 21 lung cancers and 1 tongue carcinoma. The clustering was not changed even when normal lung or tongue profiles were subtracted from the corresponding carcinomatous lesions, and a leave-one-out cross-validation showed a 98% correct prediction (see Supplementary Data 1). A minimum set of 500 genes required to distinguish these groups was established. Given the ability to segregate these lesions using molecular profiling, we analyzed the lung tumors of undetermined origin. All cases clearly clustered with either lung or tongue tumor subsets, strongly supporting our hypothesis that this technique could elucidate the tissue of origin of metastatic lesions. Although histologically similar, squamous cell carcinomas have distinct gene expression profiles based on their anatomic sites of origin. Accordingly, the application of gene expression profiling may be useful in identifying the derivation of lung nodules and consequently enhances treatment planning.     

What is important in evaluating health care quality? An international comparison of user views

Background  

Quality of care from the perspective of users is increasingly used in evaluating health care performance. Going beyond satisfaction studies, quality of care from the users' perspective is conceptualised in two dimensions: the importance users attach to aspects of care and their actual experience with these aspects. It is well established that health care systems differ in performance. The question in this article is whether there are also differences in what people in different health care systems view as important aspects of health care quality. The aim is to describe and explain international differences in the importance that health care users attach to different aspects of health care.     

An x-ray diffraction study of corneal structure in mimecan-deficient mice

PURPOSE: Keratan sulfate proteoglycans (KSPGs) in the corneal stroma are believed to influence collagen fibrillar arrangement. This study was performed to investigate the fibrillar architecture of the corneal stroma in mice homozygous for a null mutation in the corneal KSPG, mimecan. METHODS: Wild-type (n = 9) and mimecan-deficient (n = 10) mouse corneas were investigated by low-angle synchrotron x-ray diffraction to establish the average collagen fibrillar spacing, average collagen fibril diameter, and level of fibrillar organization in the stromal array. RESULTS: The mean collagen fibril diameter in the corneas of mimecan-null mice, as an average throughout the whole thickness of the tissue, was not appreciably different from normal (35.6 +/- 1.1 nm vs. 35.9 +/- 1.0 nm). Average center-to-center collagen fibrillar spacing in the mutant corneas measured 52.6 +/- 2.6 nm, similar to the 53.3 +/- 4.0 nm found in wild-type mice. The degree of local order in the collagen fibrillar array, as indicated by the height-width (H:W) ratio of the background-subtracted interfibrillar x-ray reflection, was also not significantly changed in mimecan-null corneas (23.4 +/- 5.6), when compared with the corneas of wild-types (28.2 +/- 4.8). CONCLUSIONS: On average, throughout the whole depth of the corneal stroma, collagen fibrils in mimecan-null mice, unlike collagen fibrils in lumican-null mice and keratocan-null mice, are of a normal diameter and are normally spaced and arranged. This indicates that, compared with lumican and keratocan, mimecan has a lesser role in the control of stromal architecture in mouse cornea.     

Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone

Dexamethasone (DEX) administration to the pregnant woman has become the treatment of choice for the prevention of genital masculinization in female fetuses affected with congenital adrenal hyperplasia (CAH). Although no somatic teratological side effects have been found to date, recent animal research has shown adverse effects of glucocorticoids on brain structures such as the hippocampus, raising concerns about possible functional side effects of DEX on human development. The current survey of 487 children, 1 month to 12 yr of age, focused on cognitive and motor development. The mothers of 174 prenatally DEX-exposed children (including 48 with CAH) and 313 unexposed children (including 195 with CAH) completed four standardized developmental questionnaires about their children. None of the comparisons of prenatally DEX-exposed children and unexposed controls was significant. Among the DEX-exposed children, increased duration of DEX exposure was correlated with significantly fewer developmental delays on three variables of one of the questionnaires, but none of the correlations reached significance, when Bonferroni corrections for multiple correlations were used. With the methods used, we were unable to document any adverse effects of early-prenatal DEX treatment in the doses recommended for the treatment of pregnancies at risk for CAH on motor and cognitive development.