Biomedical subjects
J M Simpson
Publications and source records attributed to J M Simpson.
Neurological disorders with autosomal dominant transmission.
Neurofibromatosis, Huntington's disease, and myotonic dystrophy are three hereditary disorders affecting the nervous system. They have in common the basic principles of autosomal dominant inheritance: an affected individual has one parent with the disorder; the disorder affects males and females in approximately equal numbers; and an affected individual has a 50 percent risk of transmitting the disorder to every child. Furthermore, each of the three disorders have additional features that complicate genetic counseling and decisions about reproduction. Neurofibromatosis has an extremely variable expressivity, making the identification of affected individuals difficult and allowing for some reduction in the risk figures; although there is a 50 percent risk of a child inheriting the mutant gene, only one-fourth to one-third of these will experience serious consequences. Huntington's disease has a fairly typical course with degeneration occurring over 10 to 20 years. The frequent late onset of the disorder and the lack of any preclinical test for detecting carriers create problems for those at risk who wish to have children but do not want to pass the disorder to future generations. Both variable expressivity and variable onset are found in myotonic dystrophy. In addition, there is a risk of the severe early onset myotonic dystrophy when the mother is the affected parent. Genetic counseling should be available to patients and families with these three disorders. Nurses who have an understanding of the dynamics of these particular disorders can be empathetic to patients who face personal and family problems caused by the conditions. Alert nursing staff, in casual discussion with patients, may learn of hereditary disorders in a family or may notice symptoms that could lead to diagnosis of one of these disorders. Finally, nurses who are aware of the variations in genetic transmission of these disorders, may be in position to instruct and reinforce genetic counseling that the family has received.
Quantitative relationships between sensitizing dose of DNCB and reactivity in normal subjects.
We have developed quantitative methods which enable us to measure susceptibility to sensitization with dinitrochlorobenzene (DNBC) and the degree of responsiveness of groups, and to analyse factors affecting the afferent and efferent components of the response. Five groups of normal subjects (132 individuals) were sensitized with DNCB (1,000, 500, 250, 125 or 62.5 micrograms). One month later, each subject was challenged with 12.5, 6.25 and 3.125 micrograms of DNCB on standard patch test felts. After 48 h the reaction at each challenge site was graded clinically and measured as diameter of induration and increase in skinfold thickness. The proportion of subjects sensitized increased with sensitizing dose; 8% were sensitized by 62.5 and 100% were sensitized by 500 micrograms or more. The 50% sensitizing dose (ED50) was calculated as 116 micrograms. Increase in skinfold thickness proved the best method of assessing response and was linearly related to log challenge dose. There was also a linear relationship between degree of sensitivity and log sensitizing dose so that, on average, each time sensitizing dose was halved, the challenge dose required to produce the same response increased 1.5-fold. These methods can be used to measure sensitizability of a population, the degree of sensitivity and the expression of reactivity. The technique will allow quantitative study of factors altering the induction or expression of such reactivity in disease.
Quantitation of sensitization and responsiveness to dinitrochlorobenzene in normal subjects.
Dinitrochlorobenzene (DNCB) has been used widely to assess cell-mediated immunity in man. However, previous workers have evaluated response qualitatively and subjectively. Such methods cannot elucidate the quantitative relationships between stimulus and response essential to an understanding of the functional components of the system. We have developed quantitative techniques to explore the dose-response relationships of both afferent and efferent limbs of the response, and used this method to examine changes in reactivity to DNCB after exposure to UV radiation and in people with contact allergies.
The inheritance of serum cholesterol: adjustment of observed cholesterol levels for age, sex and body weight using inverse-polynomial regression.
Adjustment of observed serum cholesterol levels for biological and environmental variables is an essential step in studying the mode of inheritance of serum cholesterol. Body weight, measured as weight/height2, is found to be an important variable not previously taken into account in regression equations. A method is given for adjusting cholesterol levels for age, sex and body weight, thus obtaining residuals which represent the deviations of cholesterol levels from the mean of the general population for each category of these three factors. The procedure for incorporating into the model other variables, that are found to have a significant effect on cholesterol level, is described. Polynomials and inverse polynomials of degree three fit the data equally well over a restricted range. However, inverse polynomials are chosen as they appear to have a more appropriate shape and are likely to agree better with observed values over a greater age range.
Estimation of environmental and genetic components of quantitative traits with application to serum cholesterol levels.
A mixed model of environmental, polygenic, and major locus effects is developed, allowing for environmental correlations between first-degree relatives and spouses. Maximum-likelihood techniques are used to determine the relative contributions of each of these effects to a quantitative trait. Inclusion of a nuclear family in the sample is assumed to depend on the value of the quantitative trait of one member of the family, so conditional distributions are used. Application of the method to serum cholesterol data from the general population shows that the addition of a polygenic effect to a model that assumes only an environmental effect makes a significant improvement. A completely dominant single gene is also found to be influencing serum cholesterol levels. Although cholesterol levels have been adjusted for a range of factors, such as age, sex, weight/height, and marital status, environmental factors still account for about half the variability in the residual values.
The effects of body weight on serum cholesterol, serum triglycerides, serum urate and systolic blood pressure.
The effects of body weight and age on serum cholesterol, serum triglycerides, serum urate and systolic blood pressure were examined in 600 male and 400 female blood donors aged 20 to 49 years. In the men significant correlations with body mass index were found for all four variables in each decade. In the women below 40 only the correlation with blood pressure was significant. In the fifth decade the correlations resembled those in the men, save for triglycerides. After adjusting for weight, age had no independent influence on the prevalence of hypertriglyceridaemia or hypertension in either sex. In men the effect of body weight on the prevalence of hypercholesterolaemia was age dependent. Age influenced hyperuricaemia independently of weight. In women only serum cholesterol was affected by age after allowing for weight. There was marked clustering of high values of the four variables in the heavier men and women and this increased with age. The leanest men and women were remarkably free of high values.
Toxicogenetics of niridazole in inbred mice.
The lethal potency of the antischistosomal agent niridazole (NDZ) was compared in C57BL/6J (B6) and DBA/2J (D2) mice and in their F1 hybrid, backcross and F2 progeny. A daily i.p. dosage range was chosen so that the lethal effect, ascribed to central nervous system toxicity, did not occur before 4 to 5 days. Death was always preceded by a generalized tonic-clonic seizure which terminated in respiratory arrest. In B6 mice the LD50 was 202 mg kg-1 day-1 while in D2 mice the LD50 was 146 mg kg-1 day-1; the LD50 for NDZ in similarly treated F1 hybrid mice was found to be the arithmetic mean of the LD50 values for the parental strains (172 mg kg-1 day-1). Determination of the level of NDZ in the plasma and brains of B6 and D2 mice treated subacutely with the same daily dose of NDZ failed to reveal any strain differences. Moreover, there was no evidence of in vivo accumulation of NDZ with subacute treatment which suggests that a NDZ metabolite is responsible for the observed toxicity. An association between susceptibility to the lethal effects of NDZ and the Ah locus is suggested by experiments in backcross and F2 mice. The incidence of death observed after subacute treatment with 162 mg/kg-1 day-1 of NDZ matched that predicted on the basis of genotype, i.e., it was lethal to 72% of nonresponsive and 38% of aromatic hydrocarbon responsive mice.
Pentasomy X with multiple dislocations.
We describe a pentasomy X (49,XXXXX) patient whose multiple dislocations led to a consideration of the Larsen syndrome. Review of the 11 reported cases of pentasomy X showed that elbow dislocations are known to occur in this syndrome. Our patient is the first to present hypoplasia of the glenoid process with consequent should dislocation. Clinical and radiologic findings of previously reported cases of pentasomy X are reviewed.
Effect of niridazole and niridazole immunoregulatory factor (NIF) on cutaneous delayed hypersensitivity in mice.
It has been suggested that the suppression of cell-mediated immune phenomena following niridazole administration is most likely due to a niridazole metabolite rather than the parent drug. This hypothesis was tested using two inbred strains of mice that manifest different rates of microsomal niridazole oxidation and reduction. DBA/2J mice were found to metabolize niridazole at a rate approximately 3-fold greater than C57BL/6J mice under both aerobic and anaerobic conditions. Niridazole was found to be more potent with respect to suppression of cutaneous delayed hypersensitivity in the former than in the latter. An immunosuppressive component was isolated from the urine fraction obtained from niridazole-treated rats. This component was found to be chromatographically pure; have a simple UV absorbance spectrum containing no 360 nm absorbing material characteristic of niridazole; to show no strain difference with respect to potency or efficacy in the ear-swelling assay for cutaneous delayed hypersensitivity; and to be 10(7) times more potent than niridazole with respect to the suppression of cutaneous delayed hypersensitivity.
Aerobic metabolism of niridazole by rat liver microsomes.
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Spatial disorientation in general aviation accidents.
Spatial disorientation (SD) was the third highest "cause" of fatal accidents in small, fixed-wing aircraft and closely related to the second highest "cause"--"continued VFR flight into adverse weather." SD was a cause or factor in 16% of all fatal accidents. When SD was ascribed as a cause or factor in an accident, 90% of the time that accident involved fatalities. Small, fixed-wing aircraft under 12,500 lb (570 kg) accounted for 97.3% of all SD accidents. Inclement weather was associated with 42% of all fatal accidents, and SD was a cause or factor in 35.6% of these. Flight was initiated into and continued into adverse weather in 19.7 and 68.7%, respectively, of SD weather-related fatal accidents. Fog (56.8%) and rain (41.8%) were the most prevalent adverse weather conditions. These and other data attest to the importance of this psychophysiological phenomenon in flight safety.
Identification and purification of immunosuppressive activity in the urine of rats and a human patient treated with niridazole.
Administration of the antischistosomal compound niridazole to mice, guinea pigs, and humans results in the suppression of several manifestations of cell-mediated immunity. Sera from animals treated with niridazole blocked the in vitro production of migration inhibitory factor (MIF) while niridazole itself was inactive, suggesting that these effects are caused by water soluble mediators. We now report that crude extracts prepared from the urine of rats and a patient receiving nirdazole, but not from pretreatment control urine, similarly suppress antigen-induced inhibition of migration of peritoneal exudate cells from sensitized guinea pigs. With immunosuppressive activity monitored by the direct MIF assay, combined solvent extraction and chromatographic techniques were used to fractionate immunosuppressive activity from the urine of niridazole-treated rats and the patient; the most active fractions, purified about 100-to 1000-fold as compared to methanol-water extracts of dried voided urine, inhibited MIF production at 0.1 to 0.01 ng/ml of assay mixture. These purified fractions also showed immunosuppressive activity by an in vivo assay wherein doses as low as 1 mug/kg injected intravenously (i.v.) into mice suppressed cell-mediated granuloma formation around Schistosoma manisoni eggs. Identically purified fractions prepared from urine of rats and the patient before they received niridazole showed no immunosuppressive activity either in the MIF or in the granuloma assay systems.
Prevention of deep-vein thrombosis.
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Letter: Atropine premedication in outpatient dentistry.
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'Suxamethonium pains' following laparoscopy.
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Community services in Norway.
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