Biomedical subjects
Publications and source records attributed to P Klein.
We have developed an integrated computer system for analysis of nucleic acid and protein sequences, which consists of sequence and structure databases, a relational database, and software for structural analysis. The system is potentially applicable to a number of problems in structural biology including predictive classification of the function and location of oncogene products.
Cystoid macular edema after cataract surgery, with or without intraocular lens implantation, has been reported to develop in more than 50% of patients as detected by fluorescein angiography. It is associated with reduced visual acuity in up to 8% of cases. Analysis of ongoing clinical trials at the Wilmer Institute indicates that clinically significant cystoid macular edema develops in a lower percentage of cases (2% total incidence and 0.3% persistent cystoid macular edema) if the intraocular lens implantation was uncomplicated. The factors associated with cystoid macular edema and the importance of considering clinically significant rather than just fluorescein-proven cystoid macular edema are discussed. Results of intraocular lens studies reported to the Federal Drug Administration are updated, and results of an ongoing study of prostaglandin inhibitors at the Wilmer Institute are reported.
In a short-term (14 days) and a long-term (84 days) experiment after pancreatic duct occlusion in the rat, we measured the insulin, glucagon and somatostatin content of the pancreas; in the short-term experiment, in addition, we performed an oral glucose tolerance test on the 14th day. Exocrine pancreatic function in the short-term study was monitored on the 9th day - in the long-term study on the 21st day. In the long-term study, the pancreatic organ was also examined histologically. Occlusion of the pancreatic duct considerably reduces exocrine function. This accords with the histologically observed atrophy of the exocrine parenchyma, above all in the body and tail (after 84 days). 14 days after occlusion, basal plasma glucose and insulin was about the same as in the sham-operated rats. Incremental insulin after the glucose load in occluded rats was delayed for about 30 min, but the pattern of plasma glucose was only insignificantly altered as compared with the sham-operated controls. The insulin content of the pancreas on days 14 and 84 after occlusion was increased, glucagon and somatostatin unchanged. We conclude, that (a) intraductal occlusion of the pancreas is a suitable tool for inducing an atrophy of the exocrine pancreas; (b) in the short-term, after the duct occlusion, oral glucose tolerance is preserved, but the passage of insulin into the blood is delayed and is associated with a high level of insulin in the pancreas; the cause or causes of this coincidence is/are unknown.
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A simple mathematical model has been derived, describing the irreversible inactivation of immature B cells by high doses of antigen during induction of tolerance, and the antigen-independent replacement of B cells by differentiation of their precursors. The latter leads to recovery from tolerance, the rate of which can be used to assess the rate of B cell replacement in experiments. The model has been compared with experimental tolerance to human albumin in newly hatched chickens. (1) It has been shown that this tolerance cannot be explained only by elimination of B cells but (2) the computed rate of B cell replacement agreed with the experimental rate assessed by immunization of tolerant chickens with a cross-reacting antigen. (3) In order to further verify the model, additional experiments to test the rate of B cell replacement were suggested by the model.
A study was conducted to determine the efficacy of low water content, hyper-thin lenses for extended wear by myopic patients. Patients selected had from 1 to 7 D of simple myopia or myopia with up to 2 D of astigmatism. Patients were either first time wearers or previously successful soft lens wearers. All patients were fitted with Bausch & Lomb O3 or O4 series lenses and were evaluated for 6 months. Either heat or a chemical disinfection system was used. The study shows that Bausch & Lomb O Series lenses may be used successfully for up to 1 week of continuous wear. Visual acuity, patient comfort, lens life, and physiological tolerance compared favorably with those achieved when the currently available high water content lenses were used for extended wear.
Allograft rejection is one of the leading causes of corneal graft failure in man when the cornea is heavily vascularised. This paper reports the feasibility and possible benefits of using histocompatibility (HLA) antigen crossmatch testing and HLA-D locus antigen matching for corneal donor selection. Double-masked clinical trials designed to determine the value of these procedures for keratoplasty are discussed.
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The relative efficacies of oral verapamil, a calcium-entry blocking drug, and propranolol, a beta-adrenergic blocking drug, were compared in 12 patients who had both stable angina pectoris and mild to moderate systemic hypertension, using a placebo-controlled, double-blind, randomized crossover protocol. Compared with placebo, both propranolol and verapamil decreased the frequency of anginal attacks and the number of nitroglycerin tablets consumed, and increased exercise duration and total work; there were no significant differences in the antianginal effect of the two drugs. Both verapamil and propranolol reduced the supine and standing systolic and diastolic blood pressure measured at rest; compared with propranolol, however, verapamil had greater effects on standing diastolic blood pressure (p less than 0.002). Resting heart rate was reduced from placebo baseline with large doses of both drugs; compared with verapamil, however, propranolol exerted greater effects on resting heart rate and rate-pressure product. Plasma renin activity was increased from placebo baseline with verapamil (p less than 0.05), but was reduced with propranolol (p less than 0.05); no significant change in plasma aldosterone was seen with either drug. Verapamil appears to be a safe and effective treatment alternative to propranolol for relieving anginal symptoms, improving exercise tolerance, and reducing elevated systemic blood pressure in patients with both angina pectoris and mild to moderate systemic hypertension.
The potential hazards of abrupt withdrawal of propranolol have been described in patients with angina pectoris; however, the effects of abrupt withdrawal from long-term therapy with verapamil have not previously been investigated. The comparative effects of withdrawal from long-term treatment with propranolol and verapamil were assessed in a placebo-controlled double-blind randomized crossover study of 20 patients received placebo for 2 weeks, then increasing doses of propranolol (60 to 320 mg/day) or verapamil (240 to 480 mg/day) for 3 weeks. Patients were then abruptly withdrawn from drug onto placebo for 1 week, followed by crossover to the other drug treatment and a second withdrawal period. All 20 patients were withdrawn from verapamil without evidence of a rebound increase in frequency of anginal attacks, blood pressure, heart rate, or rate-pressure product and without a rebound deterioration in exercise tolerance. In contrast, with propranolol withdrawal, 2 patients (with the highest baseline angina attack rate) had a severe exacerbation of their anginal syndrome and could not undergo formal exercise testing; the other 18 patients were withdrawn from propranolol without incident. Plasma catecholamines were increased during exercise compared with rest during all treatments; however, the levels of catecholamines during exercise were significantly higher with propranolol than with verapamil and placebo (p less than 0.05). Levels of exercise catecholamines returned to placebo baseline values after withdrawal of propranolol.
The authors have studied the transmission of body weight in several positions. Two methods have been used - strain gauges and injection of dye into the joint capsules to show areas with contact during weight-bearing and non weight-bearing. The findings have shown the role of the fibula and of both malleoli during weight-bearing which causes a noticeable increase in the area of surface contact. The lateral aspect of the talus and the medial aspect of the lateral malleolus are always in contact in any position of the talus. The fundamental role of the tibio-fibular ligaments in the mechanics of the ankle is demonstrated.
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A mathematical model of B lymphocyte differentiation, based on experimental results, has been developed. The model focuses on the role of antigen in initiating and regulating B cell differentiation while other mechanisms, acting in concert with antigen but the functioning of which can be circumvented under appropriate conditions, are not considered. The importance of presence of antigen at individual stages of B cell differentiation was studied in experiments with an easily metabolizable antigen. Immunocompetent cells (ICC), arising by antigen-independent differentiation of stem cells, are activated by antigen (they become immunologically activated cells--IAC). Excess of antigen drives IAC into the terminal stage (antibody-forming cells--AFC) thereby restricting proliferation. Exhaustive terminal differentiation results in tolerance. A low primary dose permits IAC to escape antigen; IAC proliferate and later give rise to resting memory cells (MC) which are amenable to reactivation. MC have higher avidity for antigen (due to higher affinity, number and density of receptors) and the effect of different doses of antigen on MC is diverse. A very low secondary dose induces tolerance, a medium dose secondary response, and the administration of a high dose of antigen also brings about tolerance. The model suggests that the fate of memory cells is controlled by the ratio R:Ag, of the number of immunoglobulin receptors on B cells (R) to the number of available antigenic molecules (Ag), low values R:Ag favouring stimulation to differentiation while high values of R:Ag favouring inactivation. A nonlinear system of ordinary differential equations, describing the development of the populations involved in antigen-driven B cell differentiation, was used to simulate experiments and good qualitative agreement was achieved.
1. The human thymus-brain antigen, which corresponds to the murine (mouse or rat) Thy-1 antigen complex, was isolated from brain after solubilization in deoxycholate by gel-permeation chromatography, wheat-germ-lectin affinity chromatography and ion-exchange chromatography. 2. The isolated antigen is a glycoprotein displaying an apparent molecular weight of 26 000-29 000 in sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. 3. No antigen activity was found with the lipid fraction from human brain. 4. The protein has a tendency for spontaneous self-association (dimerization), leading to aggregates resistant to dissociating and reducing agents on prolonged storage. 5. The antigen is microheterogeneous with respect to size, charge (approximate isoelectric points of the monomer 7.7, 7.0 and 6.5) and to lectin-binding affinity. 6. The antigen can be reconstituted to protein-lipid vesicles. The antigen activity of solubilized antigen is strongly increased by reconstitution and that of membranes decreased by solubilization with detergent.
An antigen triggers the clonal expansion of B lymphocytes accompanied by antibody production. This paper presents and compares the basic ideas of three mathematical models of B cell differentiation and proliferation.