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Biomedical subjects

J D Slater

Publications and source records attributed to J D Slater.

At least 91 records · Page 5Linked to original sources
PubMed1989

Inherited diseases in North American Mennonites: focus on Old Colony (Chortitza) Mennonites.

The patterns of migration and the genetic disorders occurring among North American Mennonites are reviewed, and inherited conditions recently recognized in a religious and genetic isolate, the Old Colony (Chortitza) Mennonites, are described. Old Colony Mennonites are of Dutch/German origin and descend from approximately 400 founding families who settled in the Old Colony, Chortitza (the Ukraine, USSR) in the late 1700s, and then migrated to Canada and Central and South America in the past century. We investigated over 6 generations of a Canadian Old Colony kindred in which there was extensive intermarriage, and in whom 28 individuals developed diabetes mellitus. Insulin-dependent diabetes mellitus (IDDM) occurred in 14 affected individuals in 10 closely related sibships; the 11 living IDDM patients were all concordant for the immunogenetic marker HLA-DR4. Fourteen close relatives had other disorders of carbohydrate metabolism, including gestational diabetes and non-insulin-dependent diabetes mellitus. Other close relatives had autoimmune diseases, including rheumatoid arthritis, hyper- and hypothyroidism, multiple sclerosis, and red cell aplasia. Other inherited diseases, including Alport syndrome, congenital defects, and inborn errors of metabolism were also found in the kindred. In the almost exclusively (99%) Old Colony Mennonite public health district in which the kindred was ascertained, there were multiple cases of Tourette syndrome, of malformations (including congenital heart defects and cleft lip +/- palate), and familial clusters of inborn errors of metabolism. We report this Old Colony (Chortitza) Mennonite isolate because 1) there are large familial aggregations of tissue-specific autoimmune diseases, malformations, inborn errors of metabolism, and of some other conditions whose genetic basis is still unknown; 2) there are multiple cases of rare genetic conditions, 3) we have established a computerized genealogic data base on over 1,000 kindred members as well as a cryopreserved lymphocyte/DNA bank on over 100 closely related individuals with various genetic conditions; and 4) this religious isolate, which extends across North, Central, and South America, offers an excellent opportunity for studying the epidemiology and molecular genetics of both common and rare inherited diseases.

Adrenal Hyperplasia, Congenital↗
PubMed1989

Atrial natriuretic peptide: physiological release associated with natriuresis during negative pressure breathing in man.

1. Negative pressure breathing was one of the first physiological tools used to study the renal effects of redistribution of the blood volume from the peripheries to the thorax. The recent discovery of a putative natriuretic hormone (atrial natriuretic peptide, ANP) in cardiac atrial tissue has rekindled interest in the effect of the cardiovascular system on renal function. We have therefore studied the effects of this physiological manoeuvre on plasma ANP concentrations and renal responses. 2. Plasma concentrations of ANP, plasma renin activity and plasma aldosterone concentration were measured during an 80 min period of negative pressure breathing at -12 cmH2O pressure in six hydrated normal subjects. Identical control studies were performed in the same subjects at at least 1 week apart. 3. Negative pressure breathing resulted in a natriuresis and diuresis which were associated with a significant rise in plasma ANP concentration. The natriuresis occurred despite an increase in plasma renin activity and in plasma aldosterone concentration. 4. These findings, under specific carefully controlled conditions, support the previously contentious postulate that negative pressure breathing enhances sodium excretion, in addition to its well-recognized diuretic effect. They add further weight to the hypothesis that expansion of the central blood volume is an important stimulus to the release of ANP from the heart (acting by way of atrial distension), and suggest that changes of plasma ANP concentration may have induced the natriuresis which occurred in the face of a modest activation of the sodium-retaining renin-aldosterone system.

Adult↗
PubMed1989

Intermittent absorption of warfarin caused by an unrecognized pharyngeal pouch.

An 80 year old woman on long term warfarin presented with an acute haemarthrosis of her right knee. Further investigations revealed a large pharyngeal pouch and a history of tablet regurgitation was obtained. Surgical resection was necessary 12 months later to ensure predictable absorption of orally administered drugs. The varying presentation of pharyngeal pouches and the importance of this complication are discussed.

Absorption↗
PubMed1988

Antagonism of V2-receptor effect of antidiuretic hormone by atrial natriuretic peptide in man.

Human alpha-atrial natriuretic peptide (h-alpha ANP) makes the urine of dehydrated volunteers hypotonic to plasma despite high circulating concentrations of antidiuretic hormone. Urinary dilution with h-alpha ANP also occurs in subjects receiving indomethacin. Therefore, h-alpha ANP antagonises effects of antidiuretic hormone on distal tubular V2-receptors in man, probably without involving prostaglandins.

Arginine Vasopressin↗
PubMed1988

Unusual clustering of diseases in a Canadian Old Colony (Chortitza) Mennonite kindred and community.

We investigated a large Old Colony (Chortitza) Mennonite kindred with branches across Canada. Six generations of the kindred were traced. There was intermarriage among numerous family members. Insulin-dependent diabetes mellitus (IDDM) was identified in 10 members; all 7 living patients were found to carry the immunogenetic marker HLA-DR4. Nine other close relatives had disorders of carbohydrate metabolism, including gestational diabetes mellitus and non-insulin-dependent diabetes mellitus progressing to insulin use. Ten other relatives had autoimmune diseases, including rheumatoid arthritis, hyperthyroidism, hypothyroidism and multiple sclerosis. Cases of Alport's syndrome, congenital malformations, inborn errors of metabolism and unusual malignant diseases were also found in the kindred. In the small Alberta community in which the kindred was ascertained there were people of Old Colony Mennonite descent with genetic conditions such as Gilles de la Tourette's syndrome and congenital malformations, including congenital heart disease. This kindred represents the largest reported familial aggregation of IDDM. This disease and other disorders of carbohydrate metabolism occur in the context of a strong familial predisposition to autoimmune disease. Study of this family may permit empiric testing of proposed models of inheritance of diseases of complex origin such as IDDM. We report this Old Colony (Chortitza) Mennonite community because it is one of the settlements populated by this religious and genetic isolate, which extends across Canada and Central and South America and affords opportunities for the study of both common and rare inherited diseases.

Adolescent↗
PubMed1988

Endocrine function following high dose proton therapy for tumors of the upper clivus.

The endocrine status of patients receiving proton radiation for tumors of the upper clivus was reviewed to evaluate the effect of high dose treatment on the pituitary gland. The fourteen patients had chordomas or low grade chondrosarcomas and were all treated by the same techniques. The median tumor dose was 69.7 Cobalt Gray Equivalent (CGE) with a range from 66.6 to 74.4 CGE. (CGE is used because modulated protons have an RBE of 1.1 compared to 60Co). The daily fraction size was 1.8-2.1 CGE. The median follow-up time is 48 months, ranging from 30 to 68 months. All treatments were planned using a computerized multi-dimensional system with the position of the pituitary outlined on the planning CT scan. Review of the dose distribution indicated that the dose to the pituitary ranged from 60.5 to 72.3 CGE, with a median of 67.6 CGE. One female patient had decreased thyroid and gonadotropin function at the time of diagnosis and has been on hormone replacement since that time. The other three females were all pre-menopausal at the time of radiotherapy. At this time four patients (3 males and 1 female) have developed endocrine abnormalities 14 to 45 months after irradiation. All four had evidence of hypothyroidism and two have also developed corticotropin deficiency. The three males had decreased testosterone levels; the female patient developed amenorrhea and hyperprolactinemia. All four are asymptomatic with ongoing hormone replacement.

Adolescent↗
PubMed1987

Effects of angiotensin I converting enzyme inhibition and calcium channel blockade on plasma levels of active and inactive renin in conscious rabbits.

The interplay of juxtaglomerular (jg) calcium fluxes and exposure to AII in the regulation of jg renin secretion, was examined in vivo. An inhibitor of angiotensin I converting enzyme (captopril), a blocker of calcium channels (verapamil) and AII amide were infused, singly or in combination, into the ear vein of conscious rabbits. The effects on arterial pressure, and on levels of active and inactive plasma renin were monitored. Captopril (50 micrograms X min-1 X kg-1) produced a greater percentage increase in renin secretion than did verapamil (20 micrograms X min-1 X kg-1), whilst the percentage fall in arterial pressure was similar. AII amide counteracted more effectively the actions of captopril than those of verapamil. When captopril was infused first, addition of verapamil did not enhance renin secretion (P greater than 0.2). When verapamil was infused first, addition of captopril greatly enhance renin secretion (P less than 0.01). However, when captopril was infused first, and its actions then suppressed by AII amide, addition of verapamil led to extremely high rates of renin secretion. The findings suggest the following: the short loop negative feedback plays in vivo an important role in the rapid modulation of jg renin secretion and the action of AII may involve up- and down-regulation at the receptor and/or post-receptor level; infused agents have rapid access to the critical sites of jg cells; exposure to raised concentrations to AII not only reduces the effectiveness of AII, but also enhances jg secretory responses to lack of AII, as well as to calcium channel blockade. Thus, at least some of the jg calcium channels appear to respond both to AII and to blockers; extreme changes in the levels of active renin are possible without changes of inactive renin levels. Secretion of the latter may be under separate control, or its secretion rate parallelled by the rate of its activation.

Angiotensin Amide↗
PubMed1987

Atrial natriuretic peptide: evidence of action as a natriuretic hormone at physiological plasma concentrations in man.

The administration of exogenous atrial natriuretic peptide (ANP) causes a natriuresis and diuresis in man, but this has, to date, only been demonstrated at plasma ANP concentrations within the high pathological or pharmacological ranges. Evidence that ANP acts physiologically requires the demonstration of a natriuretic effect when it is infused to recreate plasma concentrations similar to those observed after physiological stimuli. We infused human alpha-ANP (1-28) at a calculated rate of 1.2 pmol min-1 kg-1 for 3 h into seven water-loaded normal subjects, achieving plasma ANP concentrations within the upper part of the physiological range. The subjects' resting plasma ANP concentration increased from 3.8 +/- 1.5 to 20.9 +/- 1.9 pmol/l. The infusion of ANP caused a 60% increase of mean urinary sodium excretion from 111 +/- 18 to 182 +/- 30 mumol/min (P less than 0.001) and a 28% increase of mean water excretion from 10.8 +/- 0.8 to 13.8 +/- 1.6 ml/min (P less than 0.01). The infusion suppressed mean plasma renin activity from 1.55 +/- 0.10 to 1.17 +/- 0.06 pmol of ANG I h-1 ml-1 (P less than 0.001). Mean plasma aldosterone concentration (242 +/- 16 basally and 215 +/- 15 pmol/l at the end of ANP infusion) did not change significantly. Pulse rate and blood pressure were unchanged throughout the study. No significant change in any of the variables mentioned above occurred during the infusion of the vehicle alone on a separate study day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

The renin-angiotensinogen reaction during pregnancy and oral contraception: estimation of kinetic parameters by an autologous plasma renin assay.

A method has been developed which allows estimation of the kinetic parameters of the plasma renin-angiotensinogen reaction from data obtained by autologous renin assays at several plasma dilutions. The quantitative aspects of the renin-angiotensin system were examined in 28 plasma samples from 23 healthy, normotensive pregnant women. They were compared with 20 women who were not pregnant, of whom 12 were taking oral contraceptives and eight were not. In the first 3 months of pregnancy, there was a sharp increase in plasma renin activity and concentration. Plasma angiotensinogen rose steadily throughout pregnancy. The higher concentrations of renin and angiotensinogen would lead to an increase in angiotensin formation with potentially adverse consequences. However, this increase may be reduced by the fall in the affinity between renin and angiotensinogen which is suggested by the present observation that the Michaelis-Menten constant (Km) attained values five to six times higher than those seen in women not taking oral contraceptives. The smaller increases in plasma renin and angiotensinogen induced by oral contraceptives were less effectively compensated by lower affinity. Circumstantial evidence is provided which suggests that the observed high Km values may be due to oestrogen/pregnancy-induced synthesis of an angiotensinogen with a lower affinity for renin.

Adult↗
PubMed1986

Reduced activation and affinity of renin during pregnancy and oral contraception: determination of kinetic parameters by a fully autologous plasma renin assay.

In healthy normotensive pregnancy, a complex functional network develops between the cardiovascular system, the volume and composition of the extracellular fluid and the renin-angiotensin system (RAS). Cardiac output and heart rate increase, but blood pressure is reduced. The kidneys increase in size and both the glomerular filtration rate and renal blood flow increase early. Renal tubular water and sodium reabsorption is even more enhanced, so that the total body water of mother and foetus rises in the course of pregnancy by 6-8 litres. Plasma osmolality falls by about 10 mosm/kg. yet total body sodium increases by about 1 mol. Understandably, in the face of such complex fluid and pressure adjustments, data on the changes of the RAS in normal pregnancy are often contradictory. However, there is general agreement that the angiotensinogen and inactive renin in plasma are greatly raised. Most groups have also found a considerable increase in active renin. These changes could lead to higher rates of angiotensin I (AI) formation (and hence high circulating angiotensin II levels), with adverse consequences for mother and foetus. The high proportion of inactive renin may reflect a reduction in the rate of activation of prorenin in order to avoid these consequences. This reduction may involve kallikreins which have been listed amongst the putative in vivo activators of prorenin. Excessive AI formation in pregnancy could also be avoided by the production of functionally different renins or angiotensinogens. Such changes will be difficult to detect with assays which require addition of extraneous renin or angiotensinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular Physiological Phenomena↗
PubMed1986

The effect of atrial natriuretic peptide on plasma renin activity, plasma aldosterone, and urinary dopamine in man.

The acute natriuretic effect of human atrial natriuretic peptide (ANP) has been well described in man. We have now studied possible hormonal mediators of this effect. We studied six healthy volunteers on two occasions when they received either an infusion of ANP of 1.5 pmol X kg-1 X min-1 for 30 min followed by 15 pmol X kg-1 X min-1 for a further 30 min, or matching vehicle infusions in a randomized single-blind fashion. On the placebo day, plasma renin activity (PRA) rose from 1.26 +/- 0.08 to 1.57 +/- 0.14 ng A1 X ml-1 X h-1, while on the ANP study day PRA fell from 1.45 +/- 0.15 to 1.28 +/- 0.05 ng A1 X ml-1 X h-1 (p less than 0.01). No significant changes were found in plasma aldosterone concentrations or in urinary dopamine excretion. These results provide evidence that ANP suppresses renin release in man.

Aldosterone↗
PubMed1986

Radiation therapy for unresectable soft tissue sarcomas.

Between 1954 and 1981, 72 patients with unresectable soft tissue sarcomas were treated with radiotherapy at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, 57 with photons alone and 15 with neutrons for at least part of the treatment. Twenty-three patients received systemic chemotherapy in addition to radiation therapy. The absolute 2-year and actuarial 5-year tumor control rates were 39 and 29%, respectively. In this heterogeneous series, the malignancy group (based on pathologic diagnosis) was the only factor significantly affecting tumor control probability, which at 5 years was 58% for 12 patients with group I tumors, 32% for 10 patients with group II tumors, and 17% for 50 patients with group III tumors. No relationship between total dose and tumor control probability was found in this group of patients, though the duration of tumor control was longer in those receiving 65 Gy or more. No apparent improvement in tumor control was observed in the subsets of patients receiving fast neutron therapy or combined modality treatment with chemotherapy, but because of the many unmatched variables between the groups, no meaningful comparison of treatment modalities can be made. Distant metastasis were seen more frequently in higher malignancy groups, whereas size or site of tumors did not significantly influence the incidence of distant metastasis. Six patients sustained major complications of radiotherapy, of whom five received total doses in excess of 70 Gy or its estimated biologic equivalent.

Adolescent↗
PubMed1986

Atrial natriuretic peptide inhibits the aldosterone response to angiotensin II in man.

We have investigated the interaction between the recently discovered natriuretic factor alpha human atrial natriuretic peptide (alpha h-ANP) and the renin-angiotensin-aldosterone system in man. Angiotensin II infused with placebo produced a significant rise of plasma aldosterone concentration (mean +/- SEM increment 352 +/- 23 pmol/l, n = 7, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II largely abolished the aldosterone response (P less than 0.001). Diastolic blood pressure rose in response to the infusion of angiotensin II with placebo (mean increment 21.0 +/- 0.9 mmHg, P less than 0.001). Systolic blood pressure increased to a lesser degree (mean increment 12.5 +/- 0.7 mmHg, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II significantly blunted the diastolic pressor response (P less than 0.01). This ability of alpha h-ANP to blunt the pressor effect of angiotensin II may be important in the control of systemic blood pressure. The inhibition of angiotensin II-stimulated aldosterone release demonstrates that alpha h-ANP may not only be a circulating natriuretic factor in its own right but that it may also act as a modulator of a related endocrine system.

Adult↗
PubMed1986

Muscle 'contractures' and the 'stiff-man' syndrome.

The aetiology of the clinical stiff-man syndrome is likely to be heterogenous, but until we have more precise methods of identifying an individual cause the need will continue for this rather flippant appellation in patients whose condition cannot be described in any other way. It is also important because patients may otherwise become labelled as suffering from a psychiatric disorder and may even be falsely accused of abusing diazepam (Westblom, 1978). The reverse is also true, and patients may masquerade as stiff men or women (Price and Allott, 1958; Casati and Rossi, 1969). The endocrine dimension remains and should be tested for carefully, particularly in patients with predominantly lower-limb rigidity whose spasms are a relatively minor aspect of their clinical syndrome. Clearly those patients described by George et al (1984) and Slater (1960) as suffering from the stiff-man syndrome need to be reclassified as examples of the hormonal stiff muscle syndrome, and there may be others so misclassified. An endocrine aetiology may easily be missed in a patient with relatively minor muscle stiffness, pain and cramps, such as the man described by Yunus et al (1981) whose myalgia, 'arthralgia' and muscle tenderness vanished completely within four days of taking physiological replacement doses of cortisone acetate as treatment for his hypopituitarism. The rarity of the stiff-man syndrome makes prospective studies of its aetiology and treatment impossible, yet the dramatic and devastating nature of the syndrome suggests that such cases may be extreme examples of a much more common condition. On the other hand, it is possible to argue that once the psychiatric, the overtly neurological and the endocrine cases are omitted we are left with nothing. However, this is just where Moersch and Woltman came in; they could not explain 14 of their cases. Despite modern technology, despite refinements of diagnosis and despite the increasing recognition of the stiff-man syndrome as a heterogeneous condition, there still remains--albeit very rarely--a cohort of patients with progressive proximal muscular stiffness and spasms who defy proper scientific explanation, but who are likely to suffer from a chronic myelitis which destroys normal feedback mechanisms between muscle spindles and the spinal cord. Experience over the last 30 years has served at least to alert people to the psychiatric possibilities, to remove any question of primary muscle or tendon disease and to point to the usefulness of diazepam. With hope, this chapter provides an endocrine dimension which offers an actual cure and therefore deserves to be more widely recognized.

Adrenal Insufficiency↗
PubMed1983

Aldosterone 21-sulphate in man.

Using a rigorous extraction procedure and radioimmunoassay we have established that aldosterone 21-sulphate concentrations in adrenal vein specimens are higher than peripheral concentrations. Incubations of homogenates of adrenal glands and adenomata in vitro also produced aldosterone 21-sulphate. Peripheral plasma concentrations in normal and hypertensive subjects are about one-tenth those of aldosterone. Mineralocorticoid activity, as assessed in adrenalectomized rats, is less than 1% of that of aldosterone. [3H]-Aldosterone 21-sulphate administered to normal and hypertensive subjects is excreted in an irregular manner, and in four out of six subjects the major metabolite was an unidentified less polar compound. We have characterized this compound chromatographically and discussed the mechanism which may be involved in its production.

Adrenal Cortex Hormones↗