Use of the "jackknife" as a statistical tool for construction of both point and confidence interval estimators for parameters which are functions of regression coefficients and/or iteratively ...estimated parameters is described. Examples are presented demonstrating its utility in constructing estimators for log P0 and pi 0 using the parabolic and bilinear quantitative structure-activity relationship (QSAR) models relating nonlinear dependence of activity on hydrophobicity and for log 1/Ki(app) assuming competitive enzyme inhibition.
Understanding the sequence of events responsible for pressure-related natriuresis and their pathophysiologic alterations may be useful in distinguishing various types of essential hypertension of ...renal origin. The perturbation of a distal step in the sequence is likely to be reflected in a simple physiologic defect. For instance, pathophysiologic alterations in the medullary production of prostaglandin E2 might directly influence natriuresis and diuresis because of its modulatory effect on tubular reabsorption of sodium and water. Perturbation of more proximal steps in the sequence could influence all the distal events as well. For instance, prostaglandin I2 and endothelium-derived relaxing factor may be produced by the preglomerular vasculature in response to alterations in renal perfusion pressure and may modulate the release of renin from the juxtaglomerular cells. Thus, variations in the production of prostaglandin I2 or endothelium-derived relaxing factor may be reflected by various renal vascular, tubular, and systemic homeostatic events related to the renin-angiotensin system.
Although corticosteroids are effective in improving asthma symptoms and bronchial responsiveness, their mechanism of action is unknown. We examined whether changes in bronchial responsiveness with ...corticosteroid therapy of asthma are accompanied by a reduction in cytokine gene expression and eosinophil infiltration in the airways. Bronchoalveolar lavage (BAL) was performed in 18 patients with moderate asthma before and after 2 wk of treatment with prednisolone, 0.6 mg/kg/day, or matched placebo in a randomized double-blind parallel group study. Cells were counted in BAL cytocentrifuge preparations, and the numbers of cells expressing cytokine mRNA were assessed by in situ hybridization using 35S-labeled RNA probes. When the actively treated and placebo groups were compared, there was a decrease in airway methacholine responsiveness (p < 0.01) after prednisolone. This was accompanied by a decrease in bronchoalveolar lavage eosinophils (p < 0.05), a reduction in the numbers of BAL cells per 1,000 expressing mRNA for interleukin-4 (IL-4, p < 0.01) and interleukin-5 (IL-5, p < 0.005), and an increase in numbers of cells expressing mRNA for interferon-gamma (p < 0.005). These results are compatible with the hypothesis that the beneficial effects of corticosteroids in asthma may result from modulation of cytokine production, with consequent inhibition of local bronchial eosinophilia.
The kidneys of five hypertensive dogs with experimental unilateral renal artery stenosis were examined by 99mTc-diethylenetriaminepentaacetic acid (DTPA) and 131I-hippuran radionuclide dynamic ...scintigraphy at 10 and 40 min (respectively) following the administration of intravenous bolus injections of captopril. Doses of 0.2, 0.5, and 1.0 mg/kg captopril reduced mean arterial pressure by 33 +/- 4, 31 +/- 7, and 51 +/- 4 mm Hg and increased plasma renin activity by 40.1 +/- 9.8, 57.6 +/- 3.2, and 34.4 +/- 15.2 ng A1/mL/h, respectively. The time-activity curves of both 99mTc-DTPA and 131I-hippuran indicated that renal excretory function in the stenotic kidney was compromised with all three doses of captopril. However, if nitroprusside was used to reduce the mean arterial pressure to a level comparable to that with captopril, there was no appreciable increase in plasma renin activity and renal excretory function was only partially affected in the stenotic kidney. One hour after the administration of 0.5 mg/kg captopril, the function of the stenotic kidneys was partially restored and, by two hours, the time-activity curves were comparable to control scans. These data demonstrate a reversible, time-limited suppression of stenotic kidney function by captopril in renovascular hypertension and provide support for the use of captopril in the diagnosis of renovascular hypertension by radionuclide dynamic scintigraphy.
Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in ...the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2 , the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32 P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or depletion of T cells. Results. As compared with the control subjects, the subjects with asthma had more BAL cells per 1000 cells that were positive for mRNA for interleukin-2 (P<0.05), 3 (P<0.01), 4 (P<0.001), and 5 (P<0.001) and GM-CSF (P<0.001). There was no significant difference between the two groups in the number of cells expressing mRNA for interferon gamma. In the subjects with asthma, mRNA for interleukin-4 and 5 was expressed predominantly by T lymphocytes. Conclusions. Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2 -like T-cell population. (N Engl J Med 1992;326:298-304.)
A clinical study using exclusion diets and a double-blind food provocation assessed the frequency of food hypersensitivity as a cause of abdominal symptoms in 27 patients diagnosed with irritable ...bowel syndrome. Food hypersensitivity was confirmed by double-blind provocation with 3 of the subjects who also evidenced associated atopic disease and positive skin tests to common inhalant allergens. Minor psychiatric disorders were independently observed in 12 of 14 patients examined. Such disorders may be involved in the generation or experience of symptoms in some patients. Food hypersensitivity should be considered in the presence of other atopic manifestations, since dietary manipulation is simple once diagnosis is confirmed. (wz)
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