Biomedical subjects
Publications and source records attributed to M Sandler.
A case of Kallmann's syndrome (hypogonadotrophic eunochoidism plus anosmia) in which further investigation revealed the association of unilateral renal agenesis is described. The importance of excretory urography in the investigation of patients with Kallmann's syndrome is stressed.
The distribution of monoamine oxidase inhibitor-benzodiazepine receptor binding inhibitor, extractable into ethyl acetate at pH 1, was examined in a range of rat tissues. Great variation in the activity of both inhibitors was found in the different tissues, the highest being present in superior cervical ganglion, and lowest in adrenal gland. There was a highly significant correlation between the distribution of the two activities in different tissues, supporting the concept that they both derive from the same molecule (tribulin). The level of inhibitory activity in some of the tissues was such that variations might conceivably play a significant role in vivo.
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A new in vitro radiometric method has been developed for the direct assay of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine (MPTP) to its main neurotoxic metabolite 1-methyl-4-phenylpyridinium. This assay has been used to show that the rate of oxidation of MPTP parallels that of phenylethylamine in a range of human and rodent tissues, providing strong evidence that this reaction is predominantly catalysed by monoamine oxidase B (MAO-B). In human brain the reaction was inhibited by selective doses of the MAO-B inhibitor (-)-deprenyl. When dopamine was added to the incubation mixture, products of MPTP oxidation appeared to form a complex with it.
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A low molecular weight fraction of human urine (less than 500 daltons) which both inhibits monoamine oxidase and benzodiazepine binding to central and peripheral receptors has been purified by ethyl acetate extractions, HPLC and thin layer chromatography. This material extracted equally well at acid and basic pH and was insoluble in heptane. It competitively inhibited binding of 3H-clonazepam, a central benzodiazepine receptor agonist and, in addition, displaced 3H-Ro 5-4864, a specific peripheral benzodiazepine receptor ligand, from its binding sites. It showed no GABA shift with the benzodiazepine receptor antagonist, Ro-15 1788. MAO A and B were inhibited approximately equipotently and the material competitively inhibited tyramine oxidation by rat liver. It was stable on boiling and is unlikely to be a peptide.
Equol, its methylated derivative, and a carbazole, all isolated from bovine urine, are relatively potent inhibitors of monoamine oxidase with IC50 values of 158, 28, and 16 microM respectively (using 83 microM tyramine as substrate). The probable dietary origin of these compounds suggests that "natural" monoamine oxidase inhibitors may be more widespread than had previously been suspected.
Patients with endogenous unipolar depressive illness show a highly significant decrease in ability to metabolize an oral load of tyramine to its sulphate conjugate compared with controls and neurotic depressives. As this biochemical lesion persists after clinical recovery and is present in about half the non-depressed first degree relatives of endogenously depressed probands, it is likely that the abnormality is a trait marker for depressive illness. It may thus be useful in practice as a predictor of vulnerability to depressive illness. The tyramine test is superior to the dexamethasone suppression test in both sensitivity to, and specificity for, endogenous depression.
Studies were performed on 10 Cape coloured non-obese NIDDY (non-insulin-dependent diabetes in the young) patients and 6 controls of similar age, sex and weight. Fasting plasma glucose, glucose assimilation rate, insulin secretion in response to an intravenous glucose tolerance test and percentage binding of radiolabelled 125I-insulin to red blood cells were assessed in all patients before and after one month of glibenclamide treatment. Both insulin secretion (P less than 0.01) and erythrocyte insulin receptor binding (P less than 0.01) were significantly reduced when compared to controls. Although glibenclamide markedly improved the second phase of insulin secretion, the intravenous glucose tolerance test stimulated the total insulin secretion to only 40% of control values. The percentage binding of 125I-insulin to red cell receptors improved considerably with therapy, and did not differ significantly from that of control values.
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To clarify the issue of pulmonary dysfunction in diabetes mellitus, lung mechanics and CO transfer were investigated in 22 young (mean age 19.5 +/- 5 years) non-smoking, insulin-dependent diabetic patients and an equal number of matched healthy subjects. Mean closing capacity/total lung capacity (CC/TLC) was significantly greater in the diabetic than in the control group (31.4 +/- 6.8 vs 27.2 +/- 2.9 percent, p less than 0.01), as was the mean value of the volume independent index of lung elasticity (exponent constant, Kst(L)) (0.148 +/- 0.045 vs 0.118 +/- 0.030, p less than 0.05). The transfer factor expressed per unit alveolar volume (TL/VA) was also significantly lower in the diabetic than in the control group (5.25 +/- 0.68 vs 5.61 +/- 0.57 ml/min/mm Hg/L, p less than 0.05) and this could be ascribed to a lower pulmonary capillary blood volume. There was evidence of mildly abnormal lung mechanics and/or a decreased pulmonary capillary blood volume in 16 (73 percent) of the diabetic group. Since pulmonary dysfunction was either an isolated non-endocrine finding or was associated with only early systemic complications in these young patients, our findings suggest that pulmonary dysfunction is an early measurable complication in insulin-dependent diabetes mellitus.
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MPTP is oxidized to its toxic metabolite MPP+ by MAO B in both primate and rodent brains and this reaction can be inhibited by (-)-deprenyl. MPTP can also act as an inhibitor of both MAO A and B. There is some evidence that MAO B is localized predominantly in glia, and this would explain why dopamine uptake blockers also can prevent MPTP toxicity. The possibility that molecules with a similar action to MPTP cause idiopathic Parkinson's disease is discussed.
Idiopathic Parkinson's disease may derive from the action of an environmental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-like compound. Monoamine oxidase (MAO) B converts MPTP to an actual neurotoxin, 1-methyl-4-phenylpyridinium (MPP+) whilst prior administration of an MAO B inhibitor, (-)deprenyl, prevents the conversion. There is preliminary evidence that this drug can interrupt the pathological process in Parkinson's disease and prolong life expectancy. Thus, markers should be sought to identify the premorbid parkinsonian condition, prior to long-term (-)deprenyl treatment. Possibly approaches are by monitoring putative overactivity of the dopamine degrading enzymes, phenolsulphotransferase and MAO B, narrowing the field down further by PET-scan after administering a positron-emitting dopa analogue, 6-18F-labelled dopa.
Free and conjugated plasma phenylacetic acid concentrations were significantly higher in dominant male vervet monkeys than in non-dominant males living in stable social groups. These findings may be connected with an earlier observation that plasma from aggressive human psychopaths contains higher concentrations of phenylacetic acid than non-aggressive controls; whether they reflect an increased production of phenylethylamine is still unknown.
A case of primary hyperparathyroidism with advanced osteitis fibrosa cystica but without any subperiosteal phalangeal bone resorption is described. A review of this unusual radiological feature is presented. High-detail magnification radiography (microradiography) is advocated for the early diagnosis of bony defects in hyperparathyroidism.
Although earlier results, employing intravenous tyramine challenge, had indicated that a tricyclic antidepressant plus monoamine oxidase inhibitor drug combination might be free from the 'cheese effect', the experiments reported here, involving oral tyramine challenge during the combined therapy, showed that relaxation of a tyramine-free diet during such a drug regimen might be unsafe. Preliminary observations indicated that combined (-)-deprenyl plus nonselective monoamine oxidase inhibitor therapy might lead to an unacceptable degree of orthostatic hypotension without reduction in tyramine sensitivity.