Age changes in bovine lens endopeptidase activity

Lens endopeptidase activity and thermal stability have been determined as a function of cell development, cell age, and animal age. Lenses from animals aged 3 months to 15 years (lens weights 1.15-2.80 g) were divided into epithelial (outermost), cortical (peripheral), and nuclear (central) regions. Changes accompanying cell development were determined by measuring specific activity in epithelial (undifferentiated), outer cortical (differentiating), inner cortical (mature) and nuclear (aged) regions of individual lenses. Thermal stability of the enzyme activity obtained from the outer cortical and nuclear regions of the same lenses was also determined. Specific activity and thermal stability were found to decrease as a function of lens cell development. Changes with cell development represent the effects of both differentiation and increasing cell age. To determine the effects of cell age alone, activity was determined in the same population of aged, fully differentiated cells in lenses of different ages. Specific activity decreased as a function of cell age alone. Changes with animal age were determined by comparing cells of the same developmental stage from animals of different ages (e.g., differentiating cells of the cortex in animals 3 months to 15 years old). Specific activity for the cortical region increased with animal age while specific activity in the nuclear region appeared to remain constant or decrease slightly with increasing animal age. Thermal stability of the enzyme activity from the cortex was different in young and adult lenses. The change in stability occurred early in the lifespan and was therefore more closely related to animal development than to aging.     

Stability of drinking prior to alcoholism treatment

This study assessed how many months of pretreatment drinking data would represent a stable baseline. Fifty-one couples were interviewed using the time-line follow-back interviewing procedure to obtain 365 days of pretreatment drinking data. The pattern (binge, episodic, steady) and frequency of drinking did not differ when comparing 30 days prior to treatment with the rest of the year. However, there were significantly more abstinent days in the last 3 months than in the remainder of the pretreatment year. Implications for baseline data collection in alcoholism treatment research are discussed.     

The Effect of Hypothermic Cardiopulmonary Bypass on Patients with Low-Titer,Nonspecific Cold Agglutinins

The effect of hypothermic cardiopulmonary bypass (CPB) was studied in 5 patients with strongly positive cold agglutination at 4°C (experimental group) and in 10 controls. In the in vitro part of the study, the characteristics of the cold agglutinin antibodies in the experimental group included a low thermal amplitude (28°C or less), a low 4°C agglutination titer (1:32 or less), and non-specificity (non-anti-I and non-anti-i). The in vivo portion of the study revealed a fall in total urine and serum free hemoglobin in both groups on going on bypass, followed by a rise for the remainder of bypass. Statistical comparison between observed and expected total free hemoglobin for both groups showed a significant rise (p < 0.05) after bypass, thereby indicating ongoing hemolysis. No statistically significant difference between preoperative and postoperative blood urea nitrogen and creatinine levels and gross neurological status was observed in the experimental group.It was concluded that the patient with nonspecific cold agglutinins whose antibody is characterized by a low titer, a low thermal amplitude, and a lack of clinical symptomatology can undergo hypothermic CPB without increased threat of a hemolytic or vascular occlusive crisis.     

Effect of prostaglandin on cell membrane permeability and hepatic high-energy stores following hemorrhagic shock

Infusion of prostaglandin E₁ is known to exert a beneficial effect in hemorrhagic shock. It is also known that hemorrhagic shock lowers hepatic stores of high-energy phosphates and that restoration of hepatic ATP is associated with improved organ function and survival. The present study was undertaken to evaluate the effect of infusion of exogenous prostaglandin E₁ on (1) hepatic ATP levels and (2) restoration of hepatic ATP-dependent intracellular function. Rats were subjected to hemorrhagic shock, resuscitated, and then treated with either prostaglandin E₁ or a saline placebo. Ten minutes after the completion of treatment, hepatic ATP levels were significantly higher in prostaglandin-treated animals (1.37 ± 0.43 μmol/g) than in animals receiving the placebo (0.70 ± 0.11 μmol/g). Creatine phosphate levels were also higher in the prostaglandin-treated group (1.59 ± 0.16 μmol/g) than in the placebo-treated group (0.89 ± 0.14 μmol/g). Lactate production ratios, an index of ATP-dependent membrane function, were near the theoretical normal of 100% in unshocked, untreated animals (95 ± 10%). They were significantly reduced (57 ± 10%) in animals receiving only placebo, but were not significantly different from unshocked animals in those receiving prostaglandin E₁ following shock (91 ± 10%). It is concluded that prostaglandin infusion improves both hepatic high-energy phosphate levels and ATP-dependent intracellular function following hemorrhagic shock. This might be due to replenishing the purine base, selectively increasing hepatic blood flow, or both.     

Pharmaceutical considerations of transdermal nitroglycerin delivery: The various approaches

When formulated as a sublingual or an oral sustained-release dosage form, nitroglycerin has certain shortcomings, i.e., decreased duration of antianginal action and extensive hepatic first-pass elimination, which limit its efficacy. The finding that administration of nitroglycerin in the form of topical ointment decreases the extent of hepatic first-pass elimination and increases the duration of therapeutic activity has pointed the way to the possibility of developing a more effective transdermal drug delivery device. Three such devices are the Nitrodisc, Nitro-Dur, and Transderm-Nitro systems. All three systems generate effective plasma drug levels within 30 minutes and maintain steady-state drug plasma levels as follows: the 16 cm² Nitrodisc at 280.6 ± 18.7 pg/ml for 32 hours; the 20 cm² Nitro-Dur at 201.4 ± 60.7 pg/ml for 24 hours; and the 20 cm² Transderm-Nitro system at 209.8 ± 22.8 pg/ml for 24 hours. In vitro studies show that the drug penetrates the skin with zero-order kinetics in all three systems, the rate for Nitrodisc being 20% greater than that of the other systems. When the daily nitroglycerin dose is calculated in terms of skin permeation rate and the device's surface area, the three transdermal systems become clinically interchangeable.     

Design of new antihypertensive drugs: Potent and specific inhibitors of angiotensin-converting enzyme

The similarity of the biologically important enzyme angiotensin-converting enzyme to the structurally characterized digestive enzyme carboxypeptidase A has led us to develop a hypothetical model of the mechanism of binding of substrates to its active site. In this model, a positively charged group on the enzyme forms an ionic bond with the negatively charged carboxyl group of the substrate; a hydrogen bonding group of the enzyme binds with the terminal peptide bond of the substrate, and the tightly bound zinc ion of the enzyme binds to the penultimate (scissile) peptide bond of the substrate. Succinyl-l-proline (SQ 13,745) was synthesized as a potential inhibitor of angiotensin-converting enzyme by analogy to d-2-benzylsuccinic acid, an inhibitor of carboxypeptidase A; it was a moderately potent but specific inhibitor of the enzyme. Structure-activity studies carried out using the hypothetical model as a guide led to the synthesis of d-2-methyl-succinyl-l-proline (SQ 13,-297) and d-2-methylglutaryl-l-proline (SQ 14,-102), more potent inhibitors of the enzyme that were shown to be orally active in rats. Attempts to replace the zinc-binding carboxyl group of these compounds with groups with greater affinity for zinc have led to the synthesis of extremely potent inhibitors such as 3-mercapto-propanoyl-l-proline (SQ 13,863) and d-3-mercapto-2-methylpropanoyl-l-proline (SQ 14,225). The most active compound, SQ 14,225, is a purely competitive inhibitor of angiotensin-converting enzyme with an enzyme-inhibitor dissociation constant (K_i) of 1.7 × 10⁻⁹M. It is an extremely potent and specific inhibitor of angiotensin-converting enzyme and appears to have great potential for the treatment of hypertensive disease.     

Sebaceous glands within the thymus: report of three cases

Sebaceous glands in the thymus were discovered in three patients--two with myasthenia gravis and the other, who was operated on because of aortic valvular disease--with an unsuspected thymoma. Sebaceous glands not associated with hair follicles occur in diverse sites, the majority of which are in the head and neck or anogenital regions. Although most of these sites arise from the ectoderm, sebaceous glands have been reported in a thyroglossal duct, the larynx, and the esophagus, which are entodermal structures. Thus, precedents for ectodermally derived sebaceous glands in endodermal sites exist, but sebaceous glands have not previously been reported in the thymus. The authors speculate that their occurrence in the thymus may be related to the reported ectodermal contribution to the developing thymus by the epibranchial placode or cervical sinus.