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Biomedical subjects

B Roth

Publications and source records attributed to B Roth.

At least 181 records · Page 10Linked to original sources
PubMed1984

Species-specific irreversible inhibition of Neisseria gonorrhoeae dihydrofolate reductase by a substituted 2,4-diamino-5-benzylpyrimidine.

Neisseria gonorrhoeae dihydrofolate reductase undergoes a time-dependent, irreversible inactivation by 2,4-diamino-5-[3,5-dimethoxy-4-(p-bromoacetamidophenoxy)benzyl] pyrimidine. The kinetics of inactivation are consistent with the reversible formation of an enzyme-inhibitor complex followed by covalent binding to the enzyme. The reversible component is competitive with dihydrofolate and has an inhibitor binding constant of 10 nM. Irreversible inactivation proceeds as a pseudo first-order process with a minimum inactivation half-time of 20 min and a Ki of 28 nM. Using radiolabeled inhibitor, it was shown that approximately 1 mol of ligand was covalently bound to the enzyme/mol of methotrexate binding site when the enzyme was completely inhibited. Radiolabeled inhibitor remained associated with the enzyme following denaturation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cyanogen bromide cleavage of the 14C-labeled enzyme-inhibitor complex yielded only one radioactive polypeptide, and sequence determinations showed that His-25 was modified by covalent attachment of the inhibitor. When dihydrofolate reductases from Lactobacillus casei, Streptococcus faecium, Escherichia coli, SR-1 rodent lymphoma, and chicken liver were tested with the affinity label, only the L. casei enzyme showed a time-dependent increase in inhibition. These data, along with comparisons of known amino acid sequences and x-ray crystal structures, were used to make predictions concerning the three-dimensional conformation of the gonococcal enzyme.

Folic Acid Antagonists↗
PubMed1984

Deficiency of antithrombin III in children with hemolytic-uremic syndrome.

In nine patients with hemolytic-uremic syndrome, the plasma activity and plasma concentrations of antithrombin III were determined on admission to the hospital and during the clinical course of the disease. Hemodialysis was necessary in six of the patients. In seven children the plasma AT III activity was moderately to markedly below the lower limit of normal at 75%, and did not rise after plasmapheresis with fresh frozen plasma. Replacement therapy with AT III concentrate was started in these patients. During the first 2 days an average dose of AT III concentrate of 2.1 U/kg in 24 h was necessary to raise plasma AT III activity by 1%. No side effects were observed. An already pre-existing procoagulant status and the administration of heparin may lead to AT III deficiency in hemolytic-uremic syndrome.

Antithrombin III Deficiency↗
PubMed1984

Ammonium sulphate precipitation overestimates titres of anti-peptide antisera.

Precipitation by 50% final saturation of ammonium sulphate, a method commonly used to estimate titres and affinity constants of antibodies, was found consistently to overestimate the titre of anti-peptide antisera when compared with other antibody precipitants. The effect could not be attributed to non-IgG fractions, and similar overestimations were found when pure IgG was used. We suggest that the lower values represent a more physiologically relevant estimation.

Ammonium Sulfate↗
PubMed1984

Penetration of parenterally administered rifampicin into bone tissue.

This study in 32 patients was undertaken to determine the penetration of rifampicin into bone tissue using the recently developed intravenous formulation of this antibiotic. 300 mg rifampicin given as an intravenous injection over 5 min followed by 300 mg slow intravenous drip infusion over 1 h give a plasma level of rifampicin of more than 2 micrograms/ml for 6 h. In patients with osteomyelitis, bone rifampicin concentrations ranged from 1.4 to 8.8 micrograms/g at 2.5-3.5 h after the start of treatment. Osteomyelitis due to gram-positive organisms and to Haemophilus can be treated with rifampicin in combination with a second antibiotic, depending on the minimum inhibitory concentration of the infecting organism(s).

Adult↗
PubMed1984

A quantitative polygraphic study of daytime somnolence and sleep in patients with excessive diurnal sleepiness.

The authors propose a method of quantitative evaluation of excessive diurnal sleepiness intensity. They perform in each patient a 45-minute polygraphic examination to evaluate the occurrence of manifestations of wakefulness as well as all forms and stages of sleep, together with their latencies and total durations. In this way it is possible to describe the patients' sleepiness both quantitatively and qualitatively. The above test was used in the study of 8 healthy controls, 8 patients with narcolepsy-cataplexy, 8 patients with idiopathic hypersomnia and 8 patients suffering from the syndrome of hypersomnia with sleep apnea. All three groups of patients differed significantly from the control group showing deeper sleep stages of shorter latency and longer total duration. The three groups of patients differed also in some aspects from each other.

Circadian Rhythm↗
PubMed1983

Protonated state of methotrexate, trimethoprim, and pyrimethamine bound to dihydrofolate reductase.

13C nuclear magnetic resonance (NMR) of methotrexate, trimethoprim, and pyrimethamine enriched 90% with 13C at C2 has provided a sensitive means of detecting the state of protonation of the heterocyclic rings of these inhibitors. In each case, protonation of N1 causes an upfield movement of the chemical shift of C2 by more than 6 ppm. By this method it has been shown that, at pH values up to 9.2, methotrexate is bound to bovine liver dihydrofolate reductase with N1 of the inhibitor protonated, just as in the case of the complex with reductase from Streptococcus faecium and Lactobacillus casei. Furthermore, trimethoprim bound to reductase from any of the three sources, and pyrimethamine bound to either of the bacterial reductases also have N1 protonated even at pH values up to 10. This implies that in all cases there is a strong interaction between protonated N1 of the inhibitor and the carboxylate group of the active site aspartate or glutamate. In every case pKa of the bound inhibitor is increased by several units, a finding in accord with crystallographic evidence that inhibitor bound to L. casei reductase is in a hydrophobic environment and that N1 is not hydrogen-bonded to water. It was confirmed by titration of protein fluorescence that trimethoprim has greater affinity for bacterial reductase than for vertebrate (bovine) reductase, and that this selectivity is more marked in ternary complexes in which NADPH is also bound to the active site. However, the data cited above indicate that this difference in affinities is not due to a weaker ionic interaction between protonated N1 of trimethoprim and the bovine enzyme. Instead, binding of the trimethoprim side chain to hydrophobic sites on the enzyme must provide less binding energy in the case of the mammalian enzyme.

Animals↗
PubMed1983

Plasmapheresis as a therapeutic measure in hemolytic-uremic syndrome in children.

Three children with hemolytic-uremic syndrome (HUS) were successfully treated with plasmapheresis (HUS) were successfully treated with plasmapheresis (PP) combined with early hemodialysis and administration of Aspirin and dipyridamole. Stimulation of vascular prostacyclin release with patients' plasma was measured before and after PP. It was reduced before and increased after plasma exchange. The data indicate that PP might be a useful tool in treatment of (HUS) in children.

Aspirin↗
PubMed1983

Laryngo-tracheo-oesophageal cleft. Clinical features, diagnosis and therapy.

The laryngo-tracheo-oesophageal cleft is marked by a missing anatomical separation of the oesophagus and the larynx. The cleft can be restricted to the dorsal part of the larynx (type I), extend to the upper area of the trachea (type II) or involve the whole of the trachea (type III). In reviewing our three cases and 82 cases in the literature, clinical features, diagnosis, and therapy of this rare condition are presented. The condition leads almost always to life-threatening disturbances in the form of asphyxia and aspiration pneumonia. The diagnosis is made through direct laryngoscopy. Radiological demonstration of swallowing and tracheo-oesophagoscopy are necessary additional investigations. In many cases further severe malformations of organs are found, i.e., oesophageal atresia and tracheo-oesophageal fistulae. Despite early detection the prognosis remains unfavourable with a mortality of 46%. With few exceptions, an early operative correction of the defect is required. Access to the dorsal laryngeal area is achieved usually by a lateral pharyngotomy. Difficulties arise in securing adequate closure of the dorsal larynx, because of lack of sufficient tissue material. Despite secure closure of the laryngo-tracheo-oesophageal cleft, disturbances of swallowing often persist. Development of speech is not impaired.

Asphyxia↗
PubMed1983

Life effects of narcolepsy: relationships to geographic origin (North American, Asian or European) and to other patient and illness variables.

A recent questionnaire survey of the life-effects of narcolepsy in 180 patients, 60 each from North American, Asian and European populations, compared to similarly distributed age and sex matched controls, documented multiple and marked effects on work, education, driving, accidents, recreation, personality, memory and other parameters. The data have now been further analysed according to the patients' geographic (culturo-genetic) origin and to a number of other patient and illness variables. The three different geographic populations showed few significant differences for the some 160 life-effects items in the questionnaire. This strongly indicates that these are an integral part of the disease or of the human reactions to it. Most of the few significant population differences appeared cultural in origin (e.g., concerning driving records, personality changes), although a few may possibly reflect genetic differences (e.g., visual problems). Analysis of the pooled data according to respondees' age, sex, age at illness onset, duration of illness and treatment led again to relatively few significant findings. It is concluded that, in general, once the disease has been diagnosed, all the major life effects are present and remain so. The results strongly support the contention that most life-effects are not related to the diagnostic 'tetrad' symptoms themselves but rather to excessive daytime sleepiness, the symptoms most resistant to ant-narcoleptic treatment.

Accidents, Traffic↗
PubMed1983

2,4-diamino-5-benzylpyrimidines and analogues as antibacterial agents. 6. A one-step synthesis of new trimethoprim derivatives and activity analysis by molecular modeling.

A new route to 2,4-diamino-5-(4-hydroxybenzyl)pyrimidines has been developed that involves the condensation of 2,4-diamino-5-(hydroxymethyl)pyrimidine with phenols in acidic medium. The use of phenol and its 2,6-dialkyl derivatives produces 5-(4-hydroxybenzyl)pyrimidines exclusively. However, 2,6-dimethoxyphenol produces a mixture of 5-(3-hydroxy-2,4-dimethoxybenzyl)- and 5-(4-hydroxy-3,5-dimethoxybenzyl)pyrimidines. The phenolic condensation has been used to prepare a series of alkyl-substituted 5-(4-hydroxybenzyl)- and 5-(4-alkoxybenzyl)pyrimidines. The use of 1,2,3-trimethoxybenzene in place of a phenol produces 2,4-diamino-5-(2,3,4-trimethoxybenzyl)pyrimidine, a trimethoprim isomer with low antibacterial activity. The use of molecular models of several of the new ortho-substituted derivatives in the active site of dihydrofolate reductase has provided a rational explanation for their activities relative to trimethoprim.

Anti-Bacterial Agents↗