Biomedical subjects
A H Smith
Publications and source records attributed to A H Smith.
Measurement of organ blood flow with coloured microspheres in the rat.
OBJECTIVE: The aim was to establish a method for measuring organ blood flow in rats using commercially available, coloured, dye extraction microspheres. METHODS: A mixture of radiolabelled and dye extraction microspheres was infused into rats at rest (basal) and during intravenous administration of either angiotensin II (0.5 microgram.kg-1.min-1) or isoprenaline [12.5 ng.(g0.74)-1.min-1]. Tissues were removed and placed in test tubes, counted for radioactivity, then digested with 2N sodium hydroxide. Within the same tube, microspheres were isolated using centrifugation and the dye was extracted with dimethylformamide. The dye was quantified by spectrophotometry. RESULTS: Recovery of microspheres averaged greater than 95% for all tissues studied; larger reagent volumes were required to achieve this level of recovery from white adipose tissue. Statistical analyses showed excellent correlations between blood flow values obtained by the dye extraction and radiolabelled microsphere techniques. Blood flow values obtained with the radioactive technique tended to be slightly higher. There were no differences in the results obtained with the two techniques when they were simultaneously used to measure changes in organ blood flow induced by angiotensin II or isoprenaline. CONCLUSIONS: The coloured, dye extraction microsphere technique accurately measured organ blood flow in rats. This technique is potentially useful for estimating blood flow in any animal, even if tissue sample size is limited.
Long term follow up of patients with IgA nephropathy.
AIM: To assess the long term outcome of patients with IgA nephropathy. METHOD: The outcome of 151 patients (120 male; mean age 32.5, median age 29.6, SD 15.4 years; 146 Caucasian) with biopsy-proven IgA nephropathy. The patients were enrolled between 30 April 1973 and 21 August 1992. RESULTS: Ninety-five (63%) of the patients presented with microscopic haematuria, with or without proteinuria and/or renal insufficiency. At presentation renal insufficiency was present in 34% and hypertension in 48% of patients. During a mean follow up period of 63.3 months (range 0-233 months) 12 patients have reached end stage renal failure, five have died of a nonrenal cause and 25 were lost to follow up. The actuarial renal survival rate was 92.6% at five years and 91.1% at both 10 and 15 years. A significantly poorer renal survival rate was seen in those patients with a plasma creatinine > or = 0.12 mmol/L, hypertension, a serum albumin of < 35 g/L, or a 24 hour urinary albumin excretion > or = 1.0 g at presentation, and this became apparent within the first few years of follow up. CONCLUSIONS: The long term outcome of IgA nephropathy is better than previously reported. Those patients with a poor prognosis can be identified with considerable certainty at presentation.
Assessment of cancer clusters using limited cohort data with spreadsheets: application to a leukemia cluster among rubber workers.
This paper presents methods for initial investigation of occupational cancer clusters using limited data. Phase 1 of the methods developed uses basic data from the cluster of cases, but with cohort data limited to the size of the workforce at the plant. Phase 2 of the methods requires knowledge of the number of workers entering and leaving the workforce in each year. In the absence of data concerning age, the spreadsheet programs explore a variety of worker age distributions in synthetic cohort analyses. The methods were used to assess a cluster of six cases of leukemia with an average duration of work of 11 years in a tire manufacturing plant. It was concluded that the relative risk for the age range 30-50 was at least 7, providing further evidence for the association of leukemia with work in tire manufacture. The use of spreadsheet programs can provide a valuable first step assessment of apparent workplace cancer clusters.
The plasma interleukin-6 and stress hormone responses to acute pyelonephritis.
The relationships between the "stress hormones" corticotrophin (ACTH), vasopressin (AVP), corticotrophin releasing hormone (CRH) and cortisol, and the cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor were studied during an acute infection. Ten patients (7 female, 3 male, age range 16-56 years) with acute pyelonephritis and normal renal function were studied during the first 72 hours following hospital admission. Peptide hormones were measured by radioimmunoassay, cortisol and cytokines by ELISA. Reference ranges for all hormones were from samples donated by 40 or more volunteers from the electoral roll. The reference data for IL-6 was obtained from 20 normal donor sera. The mean plasma IL-6, AVP and CRH concentrations on admission to hospital were significantly raised above the mean 08:00h values of the normal volunteers (p < 0.001 for AVP and CRH, p < 0.01 for IL-6), but mean plasma ACTH and cortisol were not. Mean plasma IL-6 and AVP were raised more than two standard deviations above the mean of the reference range for 72 hours, although IL-6 tended to fall after 24 hours. No change in plasma IL-1 and tumour necrosis factor was observed in three patients. The correlation between plasma IL-6 and cortisol concentrations at all sampling times and in all subjects was highly significant (p < 0.001). Significant correlations between plasma IL-6 and AVP (p < 0.005), and IL-6 and ACTH (p < 0.05) were also observed. No correlation between IL-6 and CRH could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular effects of chronic arsenic exposure: a review.
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The consistency of reports about feelings and emotions from people with intellectual disability.
Sixty-seven subjects with mild or moderate intellectual disability were assessed on a variety of measures of emotion. All of the measures were self-report measures and all of the data is based on reports by the subjects' themselves. The battery included the Zung Self-Rating Anxiety Scale, the Zung Depression Inventory, the General Health Questionnaire and the Eysenck-Withers Personality Test. The results reveal an impressive amount of convergent validity in the subjects' emotional systems.
CP-71,362: a pentapeptide renin inhibitor selective for the canine enzyme.
Most renin inhibitors are primate-specific. In the present paper, we describe the effects of CP-71,362, a pentapeptide which preferentially inhibits canine (and to a lesser extent, rat) plasma renin. Vs. the canine enzyme, its affinity (IC50 = 3.3 x 10(-12) M) is 1000x greater than for rat renin (IC50 = 3.3 x 10(-9) M), and 1000x greater than for human (IC50 = 2.3 x 10(-8) M), cynomolgus monkey (IC50 = 1.6 x 10(-8) M), or guinea pig (IC50 = 5.2 x 10(-8) M) enzyme. In anesthetized, sodium-depleted dogs, intravenous infusion of CP-71,362 (ED50 = 1.1 micrograms/kg/min) resulted in dose-dependent decreases (up to -35 mm Hg) in mean arterial pressure (MAP). The maximum fall in MAP was equivalent to that produced by i.v. captopril (5 mg/kg). Similar falls in MAP were observed in conscious sodium-depleted SHR (ED50 = 5 micrograms/kg/min). Via bolus injection, the action of CP-71,362 was relatively brief in dog, guinea pig, and SHR. We conclude that CP-71,362 is a potent canine/rat renin inhibitor and causes profound MAP lowering in these species.
Neuroleptic malignant syndrome secondary to droperidol.
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Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic.
Inorganic arsenic (In-As) is an established human carcinogen. Methylation to monomethylarsonate (MMA) and dimethylarsinate (DMA) is believed to be the detoxification mechanism for In-As. Urinary measurement of In-As, MMA, and DMA is considered a good biological marker of internal dose to In-As, since it excludes other ingested forms of arsenic which are much less toxic, and because urinary excretion is the main form of elimination of In-As. A methylation threshold hypothesis for In-As has been proposed, stating that after exposure to In-As reaches a certain level or threshold, methylation capacity begins to decline, thus increasing the toxic effects of In-As. We investigated the validity of this hypothesis by analyzing the data from studies which measured urinary In-As, MMA, and DMA in different populations, ranging from background to high occupational and environmental exposure groups. We also present data from our study of a highly exposed population in California. Our analysis focused on the proportion of urinary In-As remaining in the unmethylated form [In-As/(In-As + MMA + DMA)]. The results indicate that epidemiological and experimental human data do not support the methylation threshold hypothesis. On average, 20-25% In-As remains unmethylated regardless of the exposure level. The wide range of interindividual variability in methylation capacity found in some studies warrants further investigation.
Effect of oral cyclosporin on renal function in Crohn's disease.
Twenty-one patients with Crohn's disease were followed prospectively for 24 weeks to examine the effect of a low-dose cyclosporin regime on renal function (initial dose 5 mg/kg reduced by 1 mg/kg every two months to a maintenance of 2 mg/kg). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by radioisotope clearance at 0, 6 and 24 weeks. GFR and ERPF fell significantly (mean GFR at baseline: 120.9 ml/min/1.73 m2; at six weeks: 100.9 ml/min/1.73 m2; mean ERPF at baseline: 497.3 ml/min/1.73 m2; at six weeks: 398.5 ml/min/1.73 m2). Following dose reduction, the ERPF remained lower than baseline (mean 408.6 ml/min/1.73 m2), and there was a trend towards the GFR remaining low (mean 111.8 ml/min/1.73 m2). Serum creatinine rose significantly (median pretreatment 72 mumol/liter; median at four weeks 86 mumol/liter) but returned to baseline after dose reduction. Plasma cyclosporin levels and serum creatinine did not help predict the extent of changes in renal function. At low doses, cyclosporin causes changes in renal hemodynamics that may not be reversed by dose reduction.
Out-of-hours scintigraphy: a survey of current practice.
A questionnaire was sent to 221 nuclear medicine departments in the UK asking about their staffing and work patterns. In particular, we wanted to know how many of them offered an on-call service. In those cases where departments wished to offer this service but did not do so, they were asked what was stopping them. Replies were received from 150 departments, a response rate of 68%. Of these, 43 (29%) offered an on-call service, although only 21 (14%) performed ten or more out-of-hours scans in an average year. The examinations most commonly offered were lung scans, localization of gastrointestinal bleeding and renography. In those centres wishing to offer an on-call service but which were unable to do so, limitation of resources was the reason most frequently advanced. Lack of clinical demand was the factor most often quoted by those not wishing to extend their service. The issue of emergency scintigraphy is discussed in the light of these results.
Observations on the dose-response curve for arsenic exposure and lung cancer.
Occupational studies in three countries have related quantitative estimates of arsenic exposure to lung cancer risks. Mine exposures in China appear to incur a higher relative risk than arsenic exposures elsewhere. All of the studies with quantitative data are consistent with a supralinear dose-response relationship. Two studies are also consistent with a linear relationship over an elevated background risk of lung cancer among arsenic-exposed workers. Neither toxicokinetic mechanisms nor confounding from age, smoking, or other workplace carcinogens that differ by exposure level appear likely to explain this curvilinearity. Plausible explanations include (i) synergism (with smoking) which varies in magnitude according to the level of arsenic exposure, (ii) long-term survivorship in higher exposure jobs among the healthier, less susceptible individuals, (iii) exposure estimate errors that were more prominent at higher exposure levels as a result of past industrial hygiene sampling or worker protection practices.
Some genetic aspects of adaptation to hyperdynamic environments.
Reports by many investigators have described a wide variety of biological changes in man and animals exposed to gravitational fields, some of these having a beneficial effect but others are detrimental. These changes are considered to result from the alteration in the gravitational field since (a) they appear when the field is changed, (b) the degree of change tends to be proportional to the change in acceleration strength, and (c) these changes disappear, and at varying rates, when the gravitational field is returned to normal gravity. However, little information has been developed concerning the reception and transduction of the gravitational stimulus, or its lack, to produce these biological changes.
Alpha-fetoprotein: a biomarker for pregnancy outcome.
Beginning in 1977, numerous studies have reported an association between high levels of maternal serum alpha-fetoprotein, measured in early pregnancy, and low birthweight and perinatal death. It has been suggested, however, that these findings may be explained by bias. We reviewed 21 studies and found that they were unanimous in reporting this association and that the association cannot be explained by any of the proposed biases. Comparing women whose alpha-fetoprotein levels were 2.5 times the median or more with all other women, the highest relative risk of fetal death was 21.0, with a 95% confidence interval of 8.4-52.2, and the lowest relative risk of fetal death was 4.4, with a 95% confidence interval of 2.8-7.0. For low birthweight (< 2,500 grams), the highest relative risk was 6.4 (95% confidence interval = 3.1-13.1) and the lowest relative risk was 1.9 (95% confidence interval = 1.5-2.5).
Arsenic ingestion and internal cancers: a review.
Inorganic arsenic is known to cause skin cancer by ingestion and lung cancer by inhalation. However, whether arsenic ingestion causes internal cancers is still a matter of debate. This paper has reviewed the epidemiologic literature that bears on this question. Published studies of populations who have ingested arsenic in medicines, wine substitutes, or water supplies, as well as workers exposed to arsenic by inhalation, were considered in terms of whether the observed associations might be explained by the presence of biases, the consistency of the evidence, and the biologic plausibility of the associations. Many studies were found to be uninformative because of low statistical power or potential biases. The most informative studies, which were from Taiwan and Japan, involved exposure to arsenic in drinking water. These studies strongly suggest that ingested inorganic arsenic does cause cancers of the bladder, kidney, lung, and liver, and possibly other sites. However, confirmatory studies are needed.
Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses.
BACKGROUND: The phenoxyherbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) has been widely used by professional pesticide applicators in New Zealand since before 1950. Epidemiologic studies of the risk of cancer and birth defects have been conducted in this group of workers, but little is known about the extent of their exposure to the 2,4,5-T contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent carcinogen in animals. PURPOSE: The objective of this study was to determine whether the blood serum levels of TCDD in a group of professional 2,4,5-T applicators in New Zealand were greater than those of a matched control group not involved in 2,4,5-T spraying. METHODS: Of 548 men employed as professional pesticide applicators in New Zealand from 1979 through 1982, nine were selected who had sprayed pesticides, although not necessarily 2,4,5-T, for at least 180 months. These applicators had sprayed 2,4,5-T for a range of 83-372 months. We measured the blood serum levels of polychlorinated dibenzo-p-dioxins and dibenzofurans, which were substituted with chlorine at the 2,3,7,8 position, in the nine pesticide applicators and in a matched group of nine control subjects. RESULTS: The average serum level of TCDD for applicators was almost 10 times that for the matched control subjects, while the average levels of all other congeners and isomers measured in the two groups did not differ substantially. TCDD levels in eight of the nine applicators were higher than those in the control subjects (mean difference, 47.7 parts per trilion). The variation in TCDD levels among the applicators was related to their duration of work exposure to 2,4,5-T. CONCLUSIONS: On the basis of our findings in these subjects in New Zealand, we conclude that increased risks of cancer from brief exposure to phenoxyherbicides reported in other countries are probably not attributable to the TCDD that contaminates 2,4,5-T. We cannot determine from these results, however, whether TCDD exposure from prolonged use of 2,4,5-T poses significant health risks.
Long-term followup of infants with gross vesicoureteral reflux.
The majority of children (1 year old or less) with gross vesicoureteral reflux already have renal damage at the time of presentation or reflux nephropathy develops during the first few years of life. We report the long-term followup of 31 patients (16 boys) presenting in infancy with gross vesicoureteral reflux (Rolleston classification) between 1952 and 1970. They had a total of 44 grossly refluxing ureters (13 bilateral, 18 unilateral) and presented between ages 1 day and 48 weeks (mean 15.3 weeks). Of the 31 infants 5 died within the first year of life, 4 were followed for up to 11 years before being lost to followup and 1 was killed in a motor vehicle accident after 19.5 years of followup. The remaining 21 patients have been followed for 16 to 37 years (mean 23.9 years); 4 have normal kidneys, and 13 have unilateral and 4 have bilateral reflux nephropathy. Of those patients with unilateral reflux nephropathy proteinuria, hypertension and renal failure developed in 1 born with a single kidney and he is now on hemodialysis, while 2 others have a diastolic blood pressure of 90 mm. Hg or greater. Of the 4 patients with bilateral reflux nephropathy 2 have proteinuria and renal insufficiency, with 1 progressing towards end stage renal failure. Infants who present with gross vesicoureteral reflux within the first year of life appear to do well if free of severe bilateral reflux nephropathy at presentation. Patients with reflux nephropathy should remain under regular nephrological supervision with particular attention given to proteinuria, renal function and blood pressure.