Evolutionary epidemiology.
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Biomedical subjects
Publications and source records attributed to D R Wilson.
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With respect to salary structure, promotion, and tenure for academic clinical faculty, and based on the issues I have described, we must consider the following five priorities: 1. To provide salary support which is appropriate for responsibilities in teaching, research, and clinical administration, and not dependent on clinical earnings, 2. To maintain flexible salary arrangements which may include a component of clinical fee-for-service earnings, and partial salary support for defined clinical teaching or administration, 3. To design a more integrated management system for these new funding arrangements which brings together medical schools and teaching hospitals and is accountable to the appropriate government agencies. 4. To improve performance review and promotion procedures, based on agreed job descriptions and recognizing the importance of teaching, research, clinical administration, and service, and 5. To review critically the role of tenure for academic clinicians and examine alternatives such as renewable term appointments There is a growing momentum to address these issues and priorities among all of those involved. This will be critical in the continued career development of Canadian academic physicians.
This study developed and evaluated a simple, inexpensive, and safe screening test for assessment of falling risk in elderly persons. Subjects sat in chairs (hips and knees at 90 degrees) with their feet over a force transducer and stood as forcefully as possible. After standing for five seconds, they sat as fast as possible. The rate of change in force (dF/dT) for standing and sitting were calculated from data collected by computer. A group of nonfallers (n = 23, age = 23 to 72 years) and a group of fallers (n = 22, age = 63 to 92 years) were studied. Nonfallers' dF/dT for standing decreased linearly from 4kg.sec-1.kg-1 to 2.5kg.sec-1.kg-1. Values in fallers decreased linearly from 3kg.sec-1.kg-1 to 0.1kg.sec-1.kg-1. The dF/dT for sitting was not dependent on age in either group. Fallers had lower dF/dT than nonfallers (1.3 +/- .6kg.sec-1.kg-1 and 2.3 +/- .01kg.sec-1.kg-1, respectively). Seventeen of 22 fallers were identified by a reduced dF/dT and reduced overshoot force (kg).
For most genetic deficiencies manifested in the liver, maximization of gene expression in hepatocytes will be an important factor in achieving successful gene therapy. A rapid, highly efficient, and nontoxic method for transfecting DNA into hepatocytes was used to compare directly promoter strengths of various cellular and viral promoters. Conditions are described here for transfecting 5-10% of primary hepatocytes using the positively charged liposomes, Lipofectin. Cells are not damaged by this method as they continue to transcribe genes controlled by liver specific promoters and can survive for over 2 weeks in culture. We find that the cytomegalovirus, SR alpha, and beta-actin promoters are more active than the SV40, RSV, RNA polymerase II, albumin, alpha 1-antitrypsin, or phosphoenolpyruvate carboxykinase promoters. A simple TK promoter and a TK promoter with the polyoma enhancer (MCI) were almost completely inactive. This information will be useful in the construction of vectors designed to express genes efficiently in primary hepatocytes for purposes of gene therapy, although the stability of expression from these promoters will need to be demonstrated in hepatocytes in vivo.
In the late distal and cortical collecting tubule, which is the principal regulatory site for potassium (K) excretion, vasopressin stimulates, and epinephrine via beta-adrenergic action, inhibits K secretion. In the inner medullary collecting duct (IMCD) we have shown that vasopressin also stimulates K secretion. The present experiments were designed to determine whether the beta-adrenergic agonist, isoproterenol, would induce K reabsorption in the IMCD, and (or) prevent a secretory response to acute KCl infusion. Two groups of rats, with or without isoproterenol administration (3 micrograms/h), were subjected to retrograde microcatheterization of the IMCD before and during infusion of 0.83 mol/h KCl. Isoproterenol reduced plasma K concentration and urinary K excretion, but the response to acute KCl infusion was qualitatively similar to control. Isoproterenol decreased delivery of potassium, chloride, and fluid to the IMCD, there was no net transport of K along the duct in either group, and KCl infusion did not result in K secretion in either group. The results indicate that isoproterenol may inhibit K secretion in the late distal or cortical collecting tubule. However, there was no statistically significant difference in K transport along the IMCD between isoproterenol and control groups. Reduced sodium excretion, which was found during isoproterenol administration both before and after KCl infusion, was associated with no change in sodium delivery but with increased sodium reabsorption in the IMCD. This increased sodium reabsorption may be a direct effect of isoproterenol, or may be due to reflex cardiovascular adjustments associated with systemic actions of the drug.
The authors describe four cases in which obstructive sleep apnea complicated the course and treatment of mania. An association between weight gain, obstructive sleep apnea, and lithium treatment is also illustrated.
Primary lymphomas of the central nervous system (CNS) account for 0.3% to 1.5% of all intracranial neoplasms. Several reports have noted a coincidence between this neoplasm and serologic evidence of Epstein-Barr virus (EBV) infection, but in only a few instances has the EBV genome been demonstrated in these tumors. To further evaluate the frequency of this occurrence, we analyzed primary CNS lymphomas using nucleic acid hybridization methods and the polymerase chain reaction (PCR). In situ hybridization was used in selected cases. Sequences of EBV were found in two of nine cases by PCR and in situ hybridization. Southern blot hybridization of genomic DNA from these samples was negative for EBV. Both tumors arose in patients with conditions shown to produce secondary immunodeficiency, namely, chronic alcohol abuse and diabetes mellitus. We conclude that the association of EBV and CNS lymphoma is not restricted to patients with severe primary immune deficiency, and that PCR can be applied successfully to paraffin-embedded tissue for the detection of low-abundance viral sequences.
For a series of bases, which penetrate through human skin in vitro at similar rates (0.056-0.49 microM/cm2/hr), penetrant pKa is shown to correlate with erythema, edema, and color meter readings. As estimates of irritation, erythema, edema, and redness measurements are highly linearly correlated. For the selected series, irritation becomes significant for bases with a pKa greater than 8. The irritation potential of acids with pKa less than or equal to 4 has been previously reported; pKa appears highly predictive of acute skin irritation for acids and bases in man.
A method is described that allows perfusion of the inner medullary collecting duct (IMCD) of the rat kidney in situ and in vivo. Fine polyethylene catheters connected to a microperfusion pump were inserted into collecting ducts via the openings at the exposed papilla tip. Perfusate contained 22Na as well as [3H]inulin. During perfusion at 30 nl/min, urine was simultaneously collected. A decrease in the Na-to-inulin concentration ratio in the urinary sample, compared with the perfusate, was taken as indicating unidirectional efflux of Na from the perfused duct system. The effects of luminal amiloride (2 X 10(-4) M) or atrial natriuretic factor (ANF, 10(-8) M) were studied. Compared with control perfusions, both agonists reduced Na efflux from the IMCD to approximately 50%, indicating luminal sites of action. Combination of amiloride and ANF at their respective concentrations had no further effect. The lack of statistically significant additivity suggests, but does not prove, that ANF, administered from the luminal side, is able to block amiloride-sensitive Na channels in the apical membrane of IMCD cells.
Modern biomedical research spans a variety of clinical and basic medical sciences and may not fit the departmental structure of a traditional medical school, which is determined by patient care and teaching responsibilities. Interdisciplinary research has therefore often been developed in research institutes with limited relationship to regular university departments. This paper outlines the important organizational initiatives which contribute to an integrated model of interdisciplinary research more closely linked with the medical school. The establishment of close working relationships among Department Chairs is essential for the integration of interdisciplinary research with existing clinical and basic medical science departments. Department of Chairs must see the development of interdisciplinary research groups as a means of enhancing research related to their disciplines. It is important to identify priority research areas using broad-based interdisciplinary committees (for example in neuroscience), and to establish guidelines for recruitment of selected research groups which include both Ph.D. and M.D. scientists who maintain appointments in a regular department for teaching and other academic functions. Physical proximity for the group may require reorganization of departmental research space which is maintained under the overall control of the Dean. The ability to maintain and renew interdisciplinary research groups, or to phase them out if necessary, can also be strengthened by using this integrated model.
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The propensity of urine to promote calcium stone formation was compared in 64 patients with recurrent idiopathic calcium nephrolithiasis and 30 healthy individuals without such a history. The rates of excretion of urine crystalloids, the urine saturation with brushite (CaHPO4-2H2O), the ability of the urine to calcify collagen in vitro, and the concentration of urine inhibitors of collagen calcification were measured. The patients had a reduced urine citrate excretion rate in addition to an increased urine calcium excretion rate, while the rates for urine magnesium, phosphate, uric acid and oxalate were not significantly different in the two groups of subjects. The urine concentration of magnesium, phosphate and uric acid was decreased in the patients because of the higher urine volume. The urine creatinine excretion rate correlated with the rates of excretion of urine calcium, magnesium, phosphate, uric acid and oxalate in both groups, which suggested that increased lean body mass, possibly associated with greater food intake, may be an important determinant of crystalloid excretion. The urine of the patients was significantly more saturated with brushite than the urine of the control subjects and resulted in greater collagen calcification when incubated in vitro. The urine concentration of inhibitors of collagen calcification, however, was not significantly different in the two groups. Thus, the urine of patients with recurrent idiopathic calcium nephrolithiasis is more highly saturated with brushite, largely as a result of an increased urine calcium excretion rate, and contains a lower concentration of magnesium and citrate, substances that tend to prevent the precipitation and growth of crystals in urine.
Normocalciuric and hypercalciuric patients with idiopathic recurrent calcium nephrolithiasis were compared with healthy individuals without such a history to examine the factors that predispose normocalciuric patients to stone formation. The urine calcium excretion rate was higher in the normocalciuric patients than in the control subjects (227 v. 183 mg/24 h; P less than 0.01), but the urine calcium concentration was not significantly different. The urine magnesium and citrate excretion rates and concentrations were lower in the normocalciuric patients than in the control subjects (P less than 0.001), while the urine uric acid and oxalate excretion rates and concentrations and the urine saturation with brushite (CaHPO4-2H2O) were not significantly different. These results suggest the importance of slight increases in the urine calcium excretion rate together with decreased urine magnesium and citrate excretion rates in normocalciuric persons with recurrent calcium stone formation. The urine of the hypercalciuric patients was more highly saturated with brushite than the urine of the normocalciuric patients and the control subjects, and the excretion rates of uric acid and oxalate were increased in the hypercalciuric patients. The hypercalciuric patients had a higher urine creatinine excretion rate than the normocalciuric patients and a higher daily urine volume than the control subjects, which suggests that differences in lean body mass or fluid and food intake, or both, may be important determinants of these differences in crystalloid excretion. As in the normocalciuric patients, the urine citrate excretion rate and concentration were decreased in the hypercalciuric patients compared with the control subjects.
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The role of the medullary collecting ducts (CD) in the regulation of water and electrolyte excretion by the remnant kidney has not been determined. Medullary CD function was therefore studied by the microcatheterization technique during hydropenia and after volume expansion with an isotonic saline load in rats with sham-operated normal kidney (stage I), remnant kidney (stage II), remnant kidney after contralateral nephrectomy (stage III), and sham-operated normal kidney after contralateral nephrectomy (stage-III control). Sodium, potassium, water, and solute reabsorption along the medullary CD were not altered in stage II during hydropenia when compared to normal control (stage I), but water reabsorption proximal to the medullary CD was decreased. In stage III, where the uremia was mild (BUN, 41 mg/dl), the fractions of the filtered load of sodium (72%) and water (62%) which were reabsorbed along the medullary CD were reduced in comparison to stage II (94% and 83%, respectively), stage I, or stage-III control. The fraction of filtered potassium entering the medullary CD was increased to 53% in stage III, compared to 16% in stage II, and 10 or 11% in stage I or stage-III control. No change in the fraction of filtered potassium remaining along the collecting ducts was observed. After volume expansion, there was no significant change in the fraction of filtered sodium and water remaining along the medullary CD in stage I, II, or III. The greater fractional excretion in stage III resulted from decreased reabsorption in more proximal nephron segments. The results indicate that (a) during hydropenia, fractional reabsorption of sodium and water is decreased along the medullary CD of the stage-III remnant kidney in the presence of mild uremia, (b) the increased fractional excretion of potassium in the remnant kidney with uremia is not determined by altered potassium handling in the medullary CD but occurs proximal to this nephron segment, and (c) extracellular fluid volume expansion with isotonic saline results in similar inhibition of fractional sodium and water reabsorption in the collecting ducts of both remnant and normal kidneys.
Continuous ambulatory peritoneal dialysis (CAPD) has been initiated on 51 patients: 27 females (mean age -- 43.9 years) and 24 males (mean age -- 46.4 years). This group has been observed for a total of 1420 patient weeks of treatment (27.3 patient years). Thirty-six episodes of peritonitis have been noted among 19 patients. The overall incidence was one episode per 39.4 patient weeks. Recurrent episodes of peritonitis resulted in discontinuation of CAPD in five (9.8%) of the patients. Three (5.9%) of the patients were unable to continue with CAPD because of its inability to control extracellular fluid balance. In the patients who transferred from intermittent peritoneal dialysis to CAPD, there was a 4.5 mg/dl drop in serum creatinine and a 34 mg/dl drop in mean BUN values. There was a rise of approximately 2 gm in the hemoglobin levels of this group of patients. If the problem of peritonitis can be solved, CAPD will become the dialytic treatment of choice for the majority of patients with end-stage renal disease.
The role of the kidney as a source or as the excretory route for natriuretic and kaliuretic factors present in acute uremia was studied using the technique of isovolemic cross-circulation in 49 pairs (eight groups) of anaesthetized rats. Marked and similar natriuresis, kaliuresis, and diuresis occurred in recipients undergoing cross-circulation with donors subjected to either bilateral nephrectomy or total intravenous urine reinfusion for 18 h previously, and were not seen with sham-operated donors. Similar and significant, but less marked, changes occurred in two groups with bilateral nephrectomy or urine reinfusion of only 3 h duration. Urea-loaded normal donors caused a natriuresis and kaliuresis which was similar to the two 18-h uremic donor groups. When donor animals were sodium depleted prior to bilateral nephrectomy the natriuretic response in the recipients was significantly reduced. The results indicate that the kidney is not necessary for the rapid appearance of natriuretic and kaliuretic activity in the blood of acutely uremic animals, and that such activity results from the retention of factors of extrarenal origin. Natriuresis and kaliuresis result from inhibition of tubular reabsorption and are not dependent on changes in glomerular filtration or renal hemodynamics. Pitressin or aldosterone levels. Urea appears to be a major component of the circulating natriuretic and kaliuretic activity in acute uremia but evidence of other factors was also obtained.