Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations.

Pharmacologic studies of itraconazole (IZ), a triazole antifungal, indicated unexplained differences between bioassay and chromatographic determinations and large variations in steady-state blood concentrations. We show that concentrations of a hydroxylated metabolite, hydroxyitraconazole (HIZ), are approximately twofold higher than IZ over a range of concentrations. Though HIZ and IZ appear equipotent against selected pathogens, HIZ is two to three times more active against a commonly used bioassay fungus but minimally affects IZ activity. Hence, HIZ probably contributes importantly to the therapeutic activity attributed to IZ and contributes approximately four to six times the activity of IZ in bioassays, explaining discrepancies observed between assay methods.     

Heterotopic microvascular epiphyseal plate transplantation: A new model using the rabbit metatarsal

The purpose of this study is to develop a new vascularized epiphyseal plate model in the New Zealand White rabbit using a metatarsal epiphyseal plate having limited longitudinal growth potential. Such a model could be utilized in various experiments aimed at manipulating epiphyseal plate growth. The viability of the harvested live subject grafts was demonstrated with continued epiphyseal uptake during Tc99-MDP radionuclide bone scanning. The currently described models used in epiphyseal transplant research all involve long bone epiphyseal plates with significantly greater growth potential than the new metatarsal model. This new model therefore fills a void in the field by allowing investigators to transplant a growth plate with limited growth potential into any heterotopic site and study the effects of various hormonal and physical influences upon epiphyseal plate growth performance. © 1995 Wiley-Liss, Inc.     

多索茶碱及其片剂的高效液相色谱分析

多索茶碱及其片剂的高效液相色谱分析刘春胜，何秀峰，王云萍，谷士杰，周同惠（中国医学科学院、中国协和医科大学药物研究所，北京１０００５０）多索茶碱（ｄｏｘｏｆｙｌｌｉｎｅ）是用于治疗支气管哮喘合并支气管痉挛的慢性阻塞性肺部疾病的新一代黄嘌吟衍生物，其药...     

HLA-DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland

Celiac disease (CD) has one of the strongest class II HLA associations of any human illness. We used DNA-RFLP typing to study the class II HLA genotypes of celiac disease patients from the West of Ireland, the geographic area with the highest rate of celiac disease in the world. We confirmed the high frequency of HLA-DR3 in this population, and we were also able to demonstrate the additional risk of developing celiac disease imparted by HLA-DR7. This was done by clearly distinguishing DR7, DQ2 haplotypes from DR7, DQ9 haplotypes, and by "subtraction analysis" of haplotype frequencies. As reported in other populations, most of the patients without DR3 were heterozygous for DR7 and DR11 or 12 (DR5), or had DR4. We used PCR-RFLP and direct sequencing of amplified DNA to examine HLA-DR4 subtypes. The frequency of HLA-DR4 was markedly decreased in patients compared with controls (p=0.000001) and there was a significant alteration of DR4 subtypes of the patients compared with controls (p=0.0227). Moreover, all of the CD patients (5 of 5) with DR4 had a haplotype associated with the DQB1*0302 allele compared with only 11 of 23 control subjects with DR4. Our results in this population with exceptionally high risk of CD strongly support the DQ heterodimer hypothesis and suggest that the recently described sequence difference between the DQB1*02 alleles of DR3 and DR7 may contribute to a synergistic increased risk when these haplotypes are inherited together. In addition, our findings suggest a role for HLA-DQ in DR4-associated CD.     

Abnormal Digital Pressure Measurements in Diabetic Neuropathic Foot Ulceration

The diabetic neuropathic ulcer is typically slow to heal and recurrent. Macrovascular insufficiency is usually excluded as foot pulses are present and ankle:brachial pressure ratios are not decreased. These assessments cannot however exclude more distal vascular disease. Digital pressure measurements enable a reliable assessment of the distal peripheral vascular status to be made. The aim of this study was therefore to use toe pressures to assess the contribution of distal ischaemia in the pathogenesis of the neuropathic ulcer. Sixteen diabetic patients with recurrent neuropathic foot ulceration had their toe pressures compared to 10 neuropathic patients without a history of foot ulceration, 10 diabetic control subjects, and 11 normal subjects. Four non-diabetic patients with neuropathy and foot ulceration were also assessed. All subjects had ankle:brachial pressure indices ≧ 1. Toe pressure was assessed using laser Doppler flowmetry to record the return of skin blood flow. The toe:brachial pressure index (TBI) was then calculated. The diabetic patients with a history of recurrent neuropathic ulceration, had the lowest mean TBI, 0.63 ± 0.14 (SD), compared to the non-ulcerated diabetic neuropathy patients, the diabetic control subjects, and the normal subjects. 0.84 ± 0.11, 0.82 ± 0.1, and 0.81 ± 0.07, p < 0.01, respectively. Three of the four non-diabetic patients with neuropathic foot ulceration also had an abnormally low TBI. Reduced toe pressure measurements are thus found to be associated with neuropathic foot ulceration. The contribution of distal ischaemia in the pathogenesis of the diabetic neuropathic foot ulcer needs to be evaluated. One hundred and eight non-insulin-dependent diabetic patients who had been tested for autonomic dysfunction in 1984/85 were re-evaluated 5 years later. Autonomic function was assessed by means of four cardiovascular tests (heart rate variation during deep breathing and standing, and blood pressure variation after standing and sustained handgrip). Eighteen subjects were lost to follow-up; in the 90 patients who completed the study, both the deep breathing and the handgrip test significantly worsened (respectively from 13.7 ± 7.8 to 11.6 ± 6.3 beats min^?1 p < 0.01, and from 16.9 ± 8.2 to 12.7 ± 7.1 mmHg, p < 0.001), whereas both the 30:15 ratio and the variation of blood pressure on standing did not change. The impairment of a comprehensive evaluation score (from 2.5 ± 1.7 to 3.0 ± 1.5; p < 0.05) also confirmed the gradual deterioration of autonomic function over the study period.     

Feasibility analysis for medical services.

Feasibility analysis is an important aspect of business planning. A feasibility study is a study of the impacts of revenues, cost, and returns on a decision. It helps answer the questions of "What share of total sales can be attained?" "What revenues will be generated?" "What costs will be incurred?" "What will be the return on investment?" The discipline of going through a systematic approach to analyze market demand, cost requirements, and return on investment will improve business decisions by eliminating risk and increasing the possibility of successful ventures.     

"Worst case" aerosol testing parameters: I. Sodium chloride and dioctyl phthalate aerosol filter efficiency as a function of particle size and flow rate

The efficiency of filter media is dependent on the characteristics of the challenge aerosol and the filter's construction. Challenge aerosol parameters, such as particle size, density, shape, electrical charge, and flow rate, are influential in determining the filter's efficiency. In this regard, a so-called "worst case" set of conditions has been proposed for testing respirator filter efficiency in order to ensure wearer protection. Data collected on various types of filters (dust and mist; dust, fume, and mist; paint, lacquer, and enamel mist; and high efficiency) challenged with a worst case-type sodium chloride (NaCl) and dioctyl phthalate (DOP) aerosol are presented. The particle size of maximum penetration varies as a function of filter type and was less than 0.25-micron count mean diameter (CMD) in all cases. The count efficiency for high efficiency filters was greater than 99.97% at worst case testing conditions, but the worst case count efficiencies for dust and mist; dust, fume and mist; and paint, lacquer and enamel mist filters were not nearly as efficient as existing test methods indicate. Also, as the test flow rate is increased, the count efficiency decreases. Thus, respirator filters were found to conform to the prediction of single-fiber filtration theory.     

Reduced cortical noradrenergic neurotransmission is associated with increased neophobia and impaired spatial memory in aged rats

In the present study, young (5-month-old (mo)) and aged (24 mo) adult male Fischer-344 (F344) rats were assigned to experimental groups based upon their performance of a reference memory task in the Morris water maze and reactivity to a novel palatable taste in a gustatory neophobia task. Levels of norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) were assayed via high performance liquid chromatography (HPLC) in brain regions associated with the locus coeruleus (LC)-hippocampus-cortex system and A1/A2-hypothalamic system. Binding of ligands specific for alpha-1, alpha-2, beta-1, and beta-2 receptors was assessed in hippocampus and cortex with receptor autoradiography. Impaired acquisition and retention of the water maze task and gustatory neophobia in aged rats was primarily associated with decreased NE activity in cingulate cortex (CC) as indicated by a significant reduction in the MHPG/NE ratio coupled with increased NE content. No significant changes in adrenergic receptor binding were detected in any region sampled. The results suggest that an aging-related reduction in cortical NE neurotransmission is associated with the expression of increased neophobia and deficits in spatial learning and memory performance occurring with advanced age in rats.