The narcolepsy susceptibility gene.
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Biomedical subjects
Publications and source records attributed to R Vaughan.
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In an across study analysis of five multicenter, placebo-controlled trials of the synthetic surfactant, Exosurf Neonatal, involving infants with birth weights 700 gm or greater the incidence of clinical pulmonary hemorrhage was 1.9% in treated infants and 1.0% in control infants. To determine whether this apparent increase in pulmonary hemorrhage was the result of a bleeding diathesis, we retrospectively reviewed charts for 39 of 41 infants with clinical pulmonary hemorrhage. The incidence of nonpulmonary bleeding was the same in control- and surfactant-treated infants. Platelet counts, hematocrit values, and the number of transfusions with platelets or red blood cells did not differ between the two groups. There was no evidence that surfactant treatment was specifically associated with a generalized bleeding diathesis.
Deletion of the HLA class III complement gene, C4A, has been linked with susceptibility to a number of autoimmune diseases. In this study, we show a strong positive association between C4A gene deletion and development of idiopathic membranous nephropathy (IMN) in European Caucasoids [patients, 17/27 (63%); healthy controls, 13/65 (20%); RR 6.8; P = 0.003]. To clarify whether C4A deletion is an independent risk factor for IMN or is increased secondarily to the Caucasoid HLA A1, B8, DR3 extended haplotype, we examined the frequency of C4A deletion in Japanese patients, in whom the disease is associated with another HLA haplotype (DR2-DQw1). Analysis of 31 Japanese patients and 46 healthy controls showed that C4A deletion was present in only one patient (3%) and one control (2%). In addition, examination of the C4B locus in Japanese patients showed that there was no significant increase in the estimated frequency of C4B deletion in patients against controls (31 vs. 27%) and no difference in the frequency of the C4B long gene (73 vs. 87%) or C4B short gene (77 vs. 78%). We conclude that although C4A deletion confers significant risk of IMN in Caucasoids, there is no significant association between C4 polymorphism, as detected here, and risk of IMN in Japanese. This suggests that either C4A deletion is irrelevant to the pathogenesis of IMN or that more than one genetic mechanism is involved.
Four female members of the same family suffering from a rare combination of oesophageal leiomyomatosis and an Alport-like nephropathy are described. The disease is characterized by marked thickening of the oesophageal wall, usually also involving the proximal stomach, with or without discernible leiomyomatous nodule formation. All cases were treated surgically by oesophagectomy with symptomatic relief, and there was no evidence of recurrence on follow-up (2-37 years). The syndrome appears to be dominantly inherited, affects children and young adults, and may also be associated with leiomyomatosis of other viscera. Previously reported cases and possible aetiologies are reviewed, and evidence that this association represents a new variant of Alport's syndrome is discussed.
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Tocainide carbamoyl-O-beta-D-glucuronide, a major urinary metabolite of the antiarrhythmic drug tocainide [2-amino-N-(2',6'-xylyl)propanoxylidide], was isolated by preparative-TLC and preparative-HPLC. The isolated glucuronide was hydrolyzed in sodium hydroxide (pH greater than 12) to 3-(2',6'-xylyl)-5-methylhydantoin. This hydantoin product was also identified when tocainide was reacted with urea in urine. Structural characterization of the isolated tocainide glucuronide was carried out using GC-MS of the permethylated derivative. The molecular ion of the permethylated glucuronide was not observed, but ion fragments at m/z 232(244), 277(288), and 334(349) were found to correspond to the postulated novel carbamoyl ester structure of the permethylated (perdeuteromethylated) glucuronide. Structural evidence for the underivatized tocainide glucuronide was obtained using fast atom bombardment-MS. The [M + H]+ ion at m/z 413 was observed. Characteristic sodium ion adducts [M + Na]+ and [M-H + 2Na]+ were also observed at m/z 435 and 457, respectively.
The disposition of tocainide enantiomers were examined in healthy human subjects and uraemic patients following a single i.v. dose (200 mg) of racemic tocainide hydrochloride. In the healthy subjects, the total body clearance of R(-)-tocainide was significantly greater than that of S(+)-tocainide (2.62 vs 1.70 ml.min-1.kg-1). Renal clearance also favoured R(-)-tocainide and appeared to contribute significantly to the stereoselective total body clearance. The volume of distribution of the enantiomers did not differ significantly. Uraemia produced a marked decrease in the total body clearance with no apparent effect on the volume of distribution of both enantiomers. The S/R ratio for total body clearance decreased significantly from 0.66 in healthy subjects to 0.54 in the uraemics, while the ratio for terminal elimination half-life significantly increased from 1.43 to 1.59. These results indicate that uraemia alters the degree of stereoselectivity in the pharmacokinetic parameters of tocainide enantiomers.
Patients with mild inflammatory arthritis (IA) were compared with patients with definite rheumatoid arthritis (RA) for abnormal frequencies of major histocompatibility complex (MHC) antigens and haplotypes to determine whether a genetic predisposition either to RA or to mild self-limiting arthritis/arthralgia was present in the patients with IA. In general the MHC antigens with abnormal frequencies found in patients with IA differed from those in patients with RA and were mainly at the A and B loci. In patients with IA the frequencies of HLA-A24, A25, B27, and B35 antigens were significantly higher than those of controls and HLA-DR5 and C4A4 were slightly raised. In contrast, in patients with RA abnormal frequencies of the MHC antigens DR4 and DR2 and the extended haplotypes associated with them [B62 BfS C4A3 C4B3 DR4 GLO2] and [B7 BfS C4A3 C4B1 DR2] confirmed the observations reported on other white populations. Thus MHC antigen associations with IA and RA differ sufficiently to suggest a different genetic basis for the two conditions.
In data from two cohorts of urban adolescents, measures of coping through support-seeking from peers and adults were related to indices of cigarette smoking and alcohol use. Peer support was positively related to substance use, whereas parental and other adult support were inversely related to substance use. Peer support had interactive relationships (positively weighted) with peer smoking and alcohol use: support had no effect when there were no friends who smoked/drank but had an increasingly greater effect for higher levels of peer smoking/drinking. Adult support had a similar (negatively weighted) interactive effect in relation to peer smoking and alcohol use. Peer and adult support interacted, with an increasingly greater effect of peer support on substance use for subjects with lower levels of adult support. Interactions with gender indicated peer support more strongly related to substance use for females than males. Implications for the theory of social networks and the prevention of substance use are discussed.
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A monospecific polyclonal antiserum to the surface cAMP receptor of Dictyostelium has been developed by immunization with purified receptor immobilized on particles of polyacrylamide and on nitrocellulose paper. In Western blots, the antiserum displays high affinity and specificity for both the R (Mr 40,000) and D (Mr 43,000) forms of the receptor previously identified by photoaffinity labeling with 8-azido-[32P] cAMP. These bands, labeled with the photoaffinity label or with 32 Pi, were quantitatively and specifically immunoprecipitated, supporting co-purification data that all represent the same polypeptide. The R form, found in unstimulated cells, contained at least 0.2 mol of phosphate/mol of receptor. The D form, generated by cAMP stimulation of intact cells, contained at least 4 mol of phosphate/mol of receptor. In the absence of detergents, the receptor was exclusively located on membranes. The receptor was solubilized effectively in Triton X-100 and sedimented as a broad peak of 5-7 S on sucrose velocity gradients. Western blots of membranes isolated at different times after starvation indicate that the appearance of cell surface cAMP binding sites during the aggregation stage of development (5-6 h) is due to de novo synthesis of receptor protein. Pulse labeling with [35S]methionine indicated that the receptor is most rapidly synthesized during the preaggregation stage of development (1-3 h), prior to its maximal accumulation in membranes. The serum specifically immunoprecipitates a polypeptide of Mr 37,000 from an in vitro translation reaction using RNA isolated from preaggregation stage cells. The time course of expression of the mRNA coding for the Mr 37,000 polypeptide parallels the rate of receptor synthesis in vivo.
An actinomycete identified as a Dactylosporangium sp. produces a new tetracycline, 4a-hydroxy-8-methoxychlortetracycline (Sch 34164). The addition of magnesium ions to complex fermentation media increased the antibiotic titers. Sch 34164 was isolated by solvent extraction and Sephadex G-25 column chromatography. The novel structure was proposed based on spectroscopic analysis. The shift of C-4a (35 to 77 ppm) and C-8 (140 to 163 ppm) in the 13C NMR as compared to chlortetracycline was indicative of the novel hydroxyl and methoxy substituents, respectively.
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The development of murine proliferative response assays has been initiated to begin to evaluate T-lymphocyte responses to the antigens of Mycobacterium leprae. In this study, M. leprae and 13 related strains of mycobacteria have been tested for stimulatory effects in proliferation assays using murine spleen, thymus or lymph node cultures. A number of mycobacteria were found to directly stimulate the proliferation of spleen and lymph node cells of all mouse strains tested including C3H/HeJ mice. Thymocyte cultures showed no response. The mitogenic effects of mycobacteria in spleen cultures were not dependent upon the presence of T cells or adherent cells, and resulted in the production of antibody-forming cells. Thus, these bacteria acted as polyclonal B-cell mitogens and could be readily distinguished from the lipopolysaccharide of Gram-negative bacteria by their mitogenic activity on C3H/HeJ spleen cells. The species of mycobacteria which exhibit direct mitogenic effects in spleen and lymph node cultures are a particular problem when specific immune responses to the antigens of these bacteria are compared. Such comparisons are necessary if in vitro assays are to be used to determine the nature of crossreactive antigens between M. leprae and other mycobacteria.
Four cases of hemobilia treated by transcatheter arterial occlusion are presented and reviewed with 30 similar cases reported in the literature. Transcatheter vascular occlusion successfully controlled hemorrhage in all 34 patients. No obvious liver parenchymal damage appeared in 26 patients; transient elevation of liver enzymes occurred in 6 patients (18%) including one in our series; two of the patients reviewed died of acute hepatic insufficiency following nonselective hepatic artery embolization. Hemobilia should be considered when gastrointestinal hemorrhage occurs after abdominal trauma, liver biopsy or other manipulative liver procedures. Hepatic angiography establishes the diagnosis and selective vascular occlusion is the treatment of choice for control of intractable or recurrent hemorrhage. Techniques and precautions for the diagnosis and transcatheter therapy of hemobilia are discussed.
Epidermal growth factor is a polypeptide that stimulates proliferation and differentiation of a variety of cell types, including the developing intestinal epithelium; it is the agent in human milk that induces mitosis in human fibroblast culture. We systematically evaluated the EGF content of milk from 20 women delivering prematurely and from 11 women delivering at term. In preterm mothers, the concentration of EGF was 70 +/- 5 ng/ml (mean +/- SEM), with no significant change during seven weeks of lactation. EGF concentration in milk of term mothers was 68 +/- 19 ng/ml (mean +/- SEM). No diurnal variation in the concentration was found. Total EGF content was closely correlated with the volume of milk expressed, suggesting a passive transport from the circulation. These observations confirm that a substantial amount of EGF is present in human milk and that EGF concentrations are not affected by duration of gestation, time of day, or duration of lactation.