Enalapril (MK421) activation in man: importance of liver status.

The in vitro conversion of enalapril (MK421) to enalaprilic acid (MK422) in human autopsy tissues was examined. MK422 was measured by radioimmunoassay. Human cadaver liver was the only tissue in which significant conversion was demonstrated. The esterase activity was stable after post mortem. Autopsy liver tissues from patients with elevated ante mortem liver function tests were found to have a reduced rate of deesterification.     

Magnetic resonance imaging in multiple sclerosis: results in 32 cases

A prospective clinical study was performed in 32 patients with multiple sclerosis (MS) to evaluate the sensitivity of lesion detection and accuracy of lesion localization by neurologic examination, delayed enhanced computed tomography (CT) with a double dose of contrast material, and proton magnetic resonance (MR) imaging. After neurologic examination patients were classified by probability of MS (possible, four patients; probable, three patients; and definite, 25 patients) and by disease activity (acute, chronic with acute exacerbation, or chronic progressive). Subsequently they underwent delayed enhanced CT scanning and MR imaging with more than one spin-echo technique. In five of seven patients with possible or probable MS, both MR imaging and delayed enhanced CT were negative. In 25 cases of definite MS, MR imaging detected pathology in 19 (76%) cases, while CT detected lesions in 15 (60%) of 25 cases. In acute lesions (acute or chronic with acute exacerbation), the two techniques were of similar sensitivity (delayed CT was positive in 65% and MR imaging in 60%), while in chronic progressive MS, MR imaging was superior in lesion detection (MR imaging positive in 75%; delayed CT in 25%). While most lesions (55%) were seen in corresponding locations in both studies, neither MR nor delayed CT correlated well with lesion localization by neurologic examination because a large number of asymptomatic lesions were imaged and many symptomatic lesions were undetected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human caries vulnerability: Is this affected by restorations or cavities at adjacent surfaces?

Silicate restorations contain fluoride. A sound enamel surface on one tooth, adjacent to a silicate restoration on another, might be expected, therefore, to receive some measure of protection from attacks of caries. We test this “protection hypothesis”. An unrestored cavity forms a zone of stagnation. Hence, an initially sound enamel surface on one tooth, adjacent to an unrestored cavity on another, should be rendered especially vulnerable to caries attack. This “stagnation hypothesis” is also tested. The relative frequencies of sound, decayed and filled sites are determined, by age, at adjacent mesial and distal surfaces on maxillary incisor teeth. In addition, the relative frequency with which a sound surface faces: (a) an adjacent restored site, (b) an adjacent unrestored site, is also determined in relation to age. Data from the North East of England and from Gloucestershire are analysed separately. They fail to verify the predictions of both “protection” and “stagnation” hypotheses. The implications of the findings to the aetiology and pathogenesis of dental caries are discussed.     

The effect of aspirin on the response to the rabbit ear artery

Aspirin significantly potentiated the response of the rabbit ear artery to intraluminal noradrenaline and electrical stimulation. The response to methoxamine and extraluminal noradrenaline was unaffected. Treatment of the artery with cocaine partially inhibited these effects of aspirin.     

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.     

Molecular specificity of 5-androstenediol as a systemic radioprotectant in mice

We compared in vivo radioprotective efficacy of 5-androstenediol (5-AED) to that of ten other steroids: 17alpha-androstenediol, dehydroepiandrosterone, 5-androstenetriol (AET), 4-androstenedione (AND), testosterone, estradiol, fluasterone, 16alpha-bromoepiandrosterone, 16alpha-fluoro-androst-5-en-17alpha-ol (alpha-fluorohydrin, AFH), and 16alpha-fluoro-androst-5-en-17beta-ol (beta-fluorohydrin). Steroids were administered 24 or 48 hr before, or 1 hr after, whole-body gamma-irradiation. Two days after irradiation at 3 Gy, blood elements were counted. In addition, after irradiation at 9-12.5 Gy, survival was recorded for 30 days. The results showed radioprotective efficacy was specific for 5-AED. One other steroid, AFH, demonstrated appreciable survival effects but was less efficacious than 5-AED. AND and AET produced slight enhancement of survival in some experiments. This is the first demonstration that the prophylactic window for survival enhancement by 1 subcutaneous (s.c.) injection of 5-AED is as long as 48 hr in mice. Moreover, the results indicate that 1 s.c. injection of 5-AED 1 hr after irradiation is much less effective than 1 injection 24-48 hr before irradiation. Comparing the molecular features of steroids with radioprotective efficacy leads to the following conclusions: 1) these effects are due to interaction with specific receptors, since s.c. injection of extremely similar molecules with the same physicochemical properties as 5-AED were not radioprotective; 2) the 17-hydroxyl group is essential; 3) this group must be in the beta configuration in the absence of nearby side groups; 4) a halogen atom at 16 changes the 17-hydroxyl specificity to alpha; 5) the 3beta-hydroxyl group is not essential; 6) addition of a 7beta-hydroxyl group is deleterious; and 7) the effects are not due to activation of sex steroid receptors.