Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism

Heterozygous mutations in the gene for the Kit transmembrane receptor have been identified recently in human piebaldism and mouse "dominant spotting." Interestingly, all of the 14 known missense mutations that cause depigmentation in these species map to the tyrosine kinase domain of the receptor, whereas none have involved the extracellular ligand-binding domain. In an attempt to detect these uncommon mutations, we screened the nine exons encoding the extracellular portion of Kit for single-strand conformation polymorphisms (SSCP) in eight piebald subjects previously reported to be negative for kinase mutations. Four of these eight kindreds proved to carry novel mutations. The first mutation, found in two apparently unrelated probands with mild piebaldism and English ancestry, substitutes an arginine for a highly conserved cysteine at codon 136. This substitution disrupts a putative disulfide bond required for formation of the second Ig-like (D2) loop of the Kit ligand-binding domain. The second mutation, detected in a piebald kindred characterized by unusually limited depigmentation, substitutes a threonine for an alanine at codon 178, a site just proximal to conserved cysteines at codons 183 and 186. The third mutation, occurring in a kindred with more extensive depigmentation, is a novel four-base insertion in exon 2 that results in a proximal frameshift and premature termination. The data strongly suggest that piebaldism can result from missense mutations in the Kit ligand-binding domain, although the resulting phenotype may be milder than that observed for null or kinase mutations. The apparent clustering of these uncommon mutations at or near the conserved cysteines for the D2 Ig-like loop further suggests a critical role for this region in Kit receptor function.     

Ambulatory urodynamics: extramural testing of the lower and upper urinary tract by Holter monitoring of cystometrogram, uroflowmetry, and renal pelvic pressures

This article elucidates the clinical applicability and state of the art of ambulatory urodynamics. Ambulatory urodynamics have evolved into practical investigations like EAC, HFM, and EAC combined with renal pelvimetry. EAC has been shown to be the method of preference if detrusor overactivity is involved. Conventional filling cystometry has proved to be an unreliable way to exclude detrusor instability. De novo instability after suspension surgery often indicates that an existing detrusor overactivity was not identified preoperatively. EAC including flowmetry has shown considerable variance in obstructive and contractility parameters in males with LUTS indicative for BPH. This raises doubt whether the clinical flow analysis is the suitable "gold standard" as advocated by the ICS. For a real break through of EAC, less complex automatic analysis is necessary. HFM is a newer method within the range of ambulatory urodynamic tests. It has not yet been completely evaluated. But, because the technique is analogous to the office flowmetry, noninvasive and very well accepted by the patients, it is expected to be widely used. This expectation is strengthened by the fact that HFM seems to show individual therapeutic efficacy of drugs, such as alpha-blockers. As a research tool to evaluate efficacy, it is far more powerful than conventional methods because of the reduction of within-patient standard deviation to about 10%. Finally, EAC combined with pelvimetry offers a promising method for the clinical evaluation of a combined dysfunction of upper and lower urinary tract.     

Frequency dependence of MR relaxation times. I. Paramagnetic ions

T1 and T2 of paramagnetic ions in free and chelated form were measured over the range of clinical magnetic resonance imaging field strengths (0.02-1.5 T). T1 values agreed with published data; however, to our knowledge, the field dependence of T2 has not been systematically studied before Mn2+, Cr3+, and Fe3+ all showed T2 reduction at high field strengths, although reduction due to Fe3+ was minimal. This is believed to be due to "contact" interactions, which have been previously noted for manganese. No such T2 reduction was seen in the chelates, except that dysprosium chelate (but not free ion) showed an anomalous decrease in T2 at high field strengths, which may possibly be explained by a dephasing effect caused by the large magnetic moment of Dy3+.     

A standardized interviewing technique for evaluating postgraduate training applicants

In an effort to streamline the personal interview and to reduce the influence of subjectivity inpreparation of ranking lists for postgraduate year-one applicants, a standardized interview was constructed for use in evaluating condidates for admission to a training program in internal medicine. The interview was conducted in a uniformly structured manner by 14 interviewers of 260 applicants. Each applicant received an interview score which correlated well with the final decision of the Intern Selection Committee. For each interviewer various measures of performance were obtained which allowed a classification into "hard" versus "easy" interviewer and indicated the comparability of each interview's evaluations with the final decisions. Thus, the standardized interview resulted in quantifiable data in the form of uniform evaluations of applicants and interviewers.     

Lycopene from two food sources does not affect antioxidant or cholesterol status of middle-aged adults

Background

Epidemiological studies have reported associations between reduced cardiovascular disease and diets rich in tomato and/or lycopene. Intervention studies have shown that lycopene-containing foods may reduce cholesterol levels and lipid peroxidation, factors implicated in the initiation of cardiovascular disease. The objective of this study was to determine whether consumption of lycopene rich foods conferred cardiovascular protection to middle-aged adults as indicated by plasma lipid concentrations and measures of ex vivo antioxidants.

Methods

Ten healthy men and women consumed a low lycopene diet with no added lycopene (control treatment) or supplemented with watermelon or tomato juice each containing 20 mg lycopene. Subjects consumed each treatment for three weeks in a crossover design. Plasma, collected weekly was analyzed for total cholesterol, high density lipoprotein cholesterol (HDL-C) and triglyceride concentrations and for the antioxidant biomarkers of malondialdehyde formation products (MDA), plasma glutathione peroxidase (GPX) and ferric reducing ability of plasma (FRAP). Data were analyzed using Proc Mixed Procedure and associations between antioxidant and lipid measures were identified by Pearson's product moment correlation analysis.

Results

Compared to the control diet, the lycopene-containing foods did not affect plasma lipid concentrations or antioxidant biomarkers. Women had higher total cholesterol, HDL-C and triglyceride concentrations than did the men. Total cholesterol was positively correlated to MDA and FRAP while HDL-C was positively correlated to MDA and GPX. GPX was negatively correlated to triglyceride concentration.

Conclusions

The inclusion of watermelon or tomato juice containing 20 mg lycopene did not affect plasma lipid concentrations or antioxidant status of healthy subjects. However, plasma cholesterol levels impacted the results of MDA and FRAP antioxidant tests.     

Entwicklung rechtssicherer Web-Anwendungen

A broad variety of juridical requirements has to be considered during the development of Web-applications. Disregard of these requirements holds severe financial dangers. A complete compilation of juridical requirements is complicated due to the multitude of juridical areas and the variety of Web-applications. Therefore, a development-driven juridical framework is suggested. From a software engineering point of view it is crucial to capture requirements at an early stage of development in order to avoid much higher costs at a later time. Thus, specialized conceptual modelling methods are examined with regard to their capability to model juridical requirements. A lack of methodical support is identified which is addressed by a systematic adaption and extension of the eW3DT method.     

火灾烟气特征的实验研究

烟气是火灾过程的重要物理现象 .烟气中悬浮的烟气颗粒目、尺寸分布、团聚效应和烟气的湍流效应是火灾探测的重要影响因素 .本文分析了火灾烟气的特征 ,为多参数特征的火灾探测提供了理论依据     

Fusion-competent vaccines: broad neutralization of primary isolates of HIV

Current recombinant human immunodeficiency virus (HIV) gp120 protein vaccine candidates are unable to elicit antibodies capable of neutralizing infectivity of primary isolates from patients. Here, "fusion-competent" HIV vaccine immunogens were generated that capture the transient envelope-CD4-coreceptor structures that arise during HIV binding and fusion. In a transgenic mouse immunization model, these formaldehyde-fixed whole-cell vaccines elicited antibodies capable of neutralizing infectivity of 23 of 24 primary HIV isolates from diverse geographic locations and genetic clades A to E. Development of these fusion-dependent immunogens may lead to a broadly effective HIV vaccine.     

Potential mechanisms of metabolic imprinting that lead to chronic disease

This review synthesizes a subset of human epidemiologic and experimental animal studies that suggest that early nutrition affects susceptibility to chronic diseases in adulthood. These studies provide evidence that biological mechanisms may exist to "memorize" the metabolic effects of early nutritional environments. However, hypothesis-driven investigations of potential mechanisms have been scant. Thus, our understanding of the biology underlying metabolic imprinting is incomplete. A working definition of metabolic imprinting is proposed, emphasizing the adaptive nature and limited ontogenic window of the mechanisms putatively responsible for these relations. Five specific candidate mechanisms of metabolic imprinting are elaborated: 1) induced variations in organ structure, 2) alterations in cell number, 3) clonal selection, 4) metabolic differentiation, and 5) hepatocyte polyploidization. Last, experimental approaches for probing potential mechanisms with animal models are discussed.