Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

Human mdm2 mediates multiple mono-ubiquitination of p53 by a mechanism requiring enzyme isomerization.

The mdm2 gene product is an important regulator of p53 function and stability. mdm2 is an E3 ubiquitin ligase for p53 and the RING finger domain of mdm2 is critical for ligase activity. Ubiquitin (Ub) conjugation is a general targeting modification and poly-ubiquitin chains specifically target proteins to the proteasome for degradation. In this report, we show that the multistep cascade of mdm2-mediated p53 ubiquitination can be reduced to three purified recombinant proteins: ubiquitin-conjugated E2, mdm2, and p53. This simplification allows enzymatic analysis of the isolated ligase reaction. The simplified reaction recapitulates the ubiquitination of p53 observed with individual components and the p53-Ub((n)) is qualitatively similar to p53-Ub((n)) detected in lactacystin-treated cells. Surprisingly, we find that p53 is modified with multiple mono-ubiquitin moieties as opposed to a poly-ubiquitin chain. Finally, kinetic analysis indicates the transfer reaction proceeds either through a modified Ping Pong mechanism involving requisite enzyme isomerization steps, or through a Rapid Equilibrium Random Bi Bi mechanism involving very large anti-cooperative interactions between the two substrate binding pockets on the enzyme, mediated through allosteric changes in enzyme structure.

Milestones in the treatment of acute myocardial infarction.

The last half-century has witnessed momentous improvement in the treatment of acute myocardial infarction resulting in significantly reduced mortality. The most significant advances are suggested to be "chair" treatment, coronary care units, anticoagulation and thrombolytic therapy.

Efficacy of DMP 840: a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity.

DMP 840, a novel bis-naphthalimide, was evaluated for antitumor efficacy in several tumor models in mice. As measured by a tumor growth inhibition assay, i.v. administration of DMP 840 to athymic nude mice at doses at or below the maximum tolerated dose resulted in curative activity against four human solid tumor xenografts, MX-1 mammary carcinoma, CX-1 and DLD-2 colon adenocarcinomas, and LX-1 lung carcinoma, producing full or incomplete regressions and/or percent tumor growth inhibition of > or = 96%. The efficacy of DMP 840 in the models was dose dependent. The activity of DMP 840 against the human tumors surpassed that demonstrated by several clinically used and investigational anticancer agents. In long-term growth delay studies, DMP 840 induced full regressions in 20 of 20 mice bearing MX-1 tumors, and tumors in one-half of these mice remained regressed for over 5 months. In addition, DMP 840 was curative against exponentially growing DLD-2 tumors staged at 500 mg and MX-1 tumors staged at 1000 mg. The bis-naphthalimide was equally efficacious when administered i.v. or i.p. but was slightly less active after oral dosing. Against both the MX-1 mammary carcinoma and the DLD-2 colon adenocarcinoma, some measure of schedule dependence was observed; the optimum schedule was daily for 9 days. Against L1210 and P388 murine leukemias, DMP 840 demonstrated little or no activity and was inactive against B16 murine melanoma. Overall, these results suggest that DMP 840 may be a human solid tumor selective cytotoxic agent.

Office aeroallergen sampling.

Aeroallergen sampling is a simple procedure that can be performed in any physician's office. The necessary equipment is a pollen and mold collecting device, a microscope with an eye-piece micrometer, pollen stain, and appropriate slides. The inexperienced observer can learn to count easily recognizable pollen and mold, such as ragweed and Alternaria in a matter of minutes. The counting can be simple (of one or two pollens) and can be complex, including counting of various molds under oil immersion.

Managing stress and anxiety in clinical laboratories. Guidelines for psychologically informed interventions.

Pressures to improve the cost effectiveness of the health-care delivery industry promise to make life stressful for those who work within the industry during the 1990s. Employees who work in stressful conditions eventually feel anxious about themselves, their performance, how they are being treated, and others. Employees cope with these anxieties by using psychological defenses that have a major impact on interpersonal relations and work performance. This article shows how stress and anxiety diminish employee effectiveness and illustrates the connection between managing employee defensiveness and performance. Intervention guidelines are provided to help clinical laboratory managers develop insightful, informed, and effective interventions when performance problems occur.

Small male body size in garter snake depends on testes.

In the red-sided garter snake (Thamnophis sirtalis parietalis) adult females are larger than adult males; this difference is apparent within 3 wk of birth, a time coinciding with high circulating levels of androgens. To study the ontogeny and regulation of this sexual dimorphism, male neonates were either castrated, castrated and given Silastic capsules containing testosterone or estradiol, or given a sham operation at 8, 9, or 10 wk of age. Female neonates were either given a Silastic capsule containing testosterone or dihydrotestosterone or given a sham operation at 8, 9, 10, or 14 wk of age. The sex difference in body size and growth rate in neonates was abolished by castration; the pattern of growth of castrated males was similar to sham-operated females. Androgens in the amounts administered failed to reverse the effects of castration, because castrated male and female neonates receiving exogenous androgens grew at the same rate as did sham-operated females. Males castrated as adults grow larger than adult males given a sham operation, indicating the inhibitory role of the testes on body size exists after sexual maturity. Treatment of adult males with testosterone, however, prevented the increase in body size after castration, suggesting that the mechanism regulating weight gain in the garter snake depends on gonadal androgen.

A comparison of the intradermal and subcutaneous routes of influenza vaccination with A/New Jersey/76 (swine flu) and A/Victoria/75: report of a study and review of the literature.

A trail of influenza vaccination, with use of bivalent split virus vaccine (A/New Jersey/76 and A/Victoria/75), was conducted to compare the immunogenicity and reactions when vaccine was given by the subcutaneous and intradermal routes. Volunteers 18 to 24 years old were randomized into equal groups, one group receiving 0.1 ml of vaccine intradermally and the other receiving 0.5 ml subcutaneously. For the A/Victoria vaccine, the immunogenicity of the intradermal route seemed superior; for A/New Jersey vaccine, the routes were equivalent. Adverse reactions were minimal and equivalent for both groups. In times of vaccine shortage, the intradermal route is considered to stretch vaccine supplies. Field trials of new influenza vaccines should include evaluation of the immunogenicity of and adverse reactions caused by the same vaccine given by different routes in varied dosages.

Idiopathic postural hypotension: physiologic observations and report of a new mode of therapy.

Two patients with severe postural hypotension associated with upper motor neuron and cerebellar impairment (Shy-Drager syndrome) have been studied. Head-up tilt and lower body negative pressure application caused marked falls in arterial pressure; in one patient, paradoxical vasodilatation was observed. Ice application did not increase arterial pressure or calculated forearm vascular resistance. Intravenous atropine in one patient increased heart rate by 18 beats per min, a cardioacceleratory response similar to exhausting recumbent exercise in that patient. 24 hr urinary catecholamine excretion was low, but aldosterone secretory rate was normal in the more severely afflicted patient. A prolonged elevation of plasma renin activity was noted when post-tilt hypertension occurred. When head-up tilt was not followed by this hypertensive period, plasma renin activity response to tilting was normal. Intra-arterial norepinephrine and tyramine both elicited a vasoconstrictor response. Intra-arterial infusions of norepinephrine and tyramine were repeated after administration of the monoamine oxidase inhibitor tranylcypromine. Norepinephrine was potentiated 4.1- and 0.5-fold in the two patients; tyramine was potentiated 3.7-and 1.1-fold in the two patients, respectively. A therapeutic program of tranylcypromine and tyramine (in the form of cheddar cheese) resulted in substantial clinical improvement. It is concluded that in at least some patients with idiopathic postural hypotension, norepinephrine is present in postganglionic sympathetic fibers. A therapeutic program of tyramine and a monoamine oxidase inhibitor may be of value when more conventional modes of therapy fail.