Treatment of primary hypogonadism in men by the transdermal administration of testosterone

We tested the efficacy of a thin flexible testosterone-impregnated membrane applied to the scrotum for the long term treatment of male hypogonadism. Ten men with primary hypogonadism were treated for 3 months (2 men) or 13 months (8 men). Serum testosterone concentrations increased in all 10 men, to within the normal range in 8. Serum dihydrotestosterone concentrations increased to supranormal values in all of the men, decreased to the normal range in 6, indicating the biological effectiveness of the testosterone in those subjects. Two men whose serum LH concentrations did not fall to normal had small or distorted scrotal surfaces. Seven of the 8 men whose serum testosterone concentrations became normal said that their hypogonadal symptoms were corrected by this treatment. We conclude that the transdermal administration of testosterone is an effective means of treating the majority of hypogonadal men who have a normal scrotum.     

Effects of sensory and motor functioning on adult intellectual performance

This study examined longitudinal health and intelligence data to determine whether sensory or motor deficits account for some of the age-related intellectual changes that are commonly seen from midlife onward. Although sensory and motor functioning did not account for the age-related decrements in performance on speeded, visual perceptual tasks found for this sample in previous work, we did find that hearing deficits added error variance to performance estimates on two verbal subtests of the Wechsler scales.     

Recovery of memory after severe closed head injury: dissociations in recovery of memory parameters and predictors of outcome

This study examined selective reminding and recognition memory performance of 21 severe closed-head injured patients tested within 6 months of regaining consciousness and then again after at least 1 year. Performances on selective reminding parameters were highly correlated and patients performed significantly worse at both testings than did hospitalized controls matched for age, education, and sex. Patients improved from testing 1 to testing 2 on only four of six memory variables. Average Impairment Rating at testing 1 was a marginally better predictor of memory performance at testing 2 than was length of coma. Results are discussed in terms of (a) utility of selective reminding parameters and predictors of outcome and (b) dissociations in recovery of memory parameters.     

Amphotericin B: a novel class of antiscrapie drugs

Amphotericin B (AmB) has been able to lengthen the incubation period of intracerebrally (ic) scrapie-injected hamsters to 45 d. This article reports a linear relationship between AmB doses and the duration of the incubation periods of ic-treated animals compared with controls, a greater effect of AmB treatment administered 2 w before or the same day of ic scrapie incubation, and the ineffectiveness of mepartricin, an AmB analogue, in prolonging the incubation period of ic scrapie-injected hamsters. The beneficial effect of AmB appears due to a delay in the replication of the scrapie agent in the brain of infected hamsters. Moreover, AmB suppresses scrapie replication in the spleen of treated animals. Three hypotheses may explain these results: (1) AmB alters a hypothetical scrapie receptor, preventing the entry of the agent into central nervous system (CNS) target cells; (2) AmB interferes with mechanisms involved in scrapie replication; (3) AmB prevents the formation and accumulation of a scrapie-specific amyloid protein responsible for the disease. Whatever the mechanism of action, AmB is the only currently available drug to modify experimental CNS scrapie infection, so AmB is proposed as a novel class of antiscrapie drugs.     

Positive genetic selection for gene disruption in mammalian cells by homologous recombination.

Efficient modification of genes in mammalian cells by homologous recombination has not been possible because of the high frequency of nonhomologous recombination. An efficient method for targeted gene disruption has been developed. Cells with substitution of exogenous sequences into a chromosomal locus were enriched, by a factor of 100, using a positive genetic selection that specifically selects for homologous recombination at the targeted site. The selection is based on the conditional expression of a dominant selectable marker by virtue of in-frame gene fusion with the target gene. The dominant selectable marker was derived by modification of the Escherichia coli neo gene so that it retains significant activity in mammalian cells after in-frame fusion with heterologous coding sequences. In the example presented here, homologous recombinants were efficiently recovered from a pool in which the targeted gene was disrupted in 1 per 10,000 cells incorporating exogenous DNA.     

In situ hybridization analysis for herpes simplex virus nucleic acids in Alzheimer disease

Histological sections of brain from patients showing evidence of advanced pathology of Alzheimer disease (AD) were examined for the presence of herpes simplex type-1 (HSV-1) nucleic acids by a sensitive in-situ hybridization technique. Samples from neurologically normal patients were examined in parallel. Sensitivity of the assay was verified by the detection of HSV-1 nucleic acids in neurons of trigeminal ganglia taken from cases of AD and normal controls. This indicated that the hybridization reaction was sufficiently sensitive to detect latent HSV-1 infections. Positive hybridization in the brain was only detected in a confirmed case of herpes simplex virus encephalitis. These results appear to confirm previous reports that HSV-1 infection is not directly involved in the pathology associated with AD.     

Effect of glucocorticosteroid hormones on T lymphocytes in patients with pulmonary tuberculosis

Results of clinicoimmunological observation of 75 patients are presented. The aim of the observation was to show clinical efficiency of glucocorticosteroid hormones, their influence on T-immunity and immunoregulatory subpopulations in the patients with pulmonary tuberculosis The glucocorticosteroid hormones used in combination with tuberculostatics accelerated fading of the exudative phase of tuberculous inflammation and at the early stages of the treatment increased the frequency of destructions healing in the lungs. However, 10 to 15 days after the start of their use immunodepressive action on T-lymphocytes was detected. The hormones had the most pronounced suppressive effect on lymphocyte blast cell transformation with mitogen persisting even after discontinuation of their use.     

The pharmacology of dichloroacetate

Dichloroacetate (DCA) exerts multiple effects on pathways of intermediary metabolism. It stimulates peripheral glucose utilization and inhibits gluconeogeneis, thereby reducing hyperglycemia in animals and humans with diabetes mellitus. It inhibits lipogenesis and cholesterolgenesis, thereby decreasing circulating lipid and lipoprotein levels in short-term studies in patients with acquired or hereditary disorders of lipoprotein metabolism. By stimulating the activity of pyruvate dehydrogenase, DCA facilitates oxidation of lactate and decreases morbidity in acquired and congenital forms of lactic acidosis. The drug improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and lactate as opposed to fat. DCA may also enhance regional lactate removal and restoration of brain function in experimental states of cerebral ischemia. DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity. DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation. Other toxic effects of DCA may be species-specific and reflect marked interspecies variation in pharmacokinetics. Despite its potential toxicity and limited clinical experience, DCA and its derivatives may prove to be useful in probing regulatory aspects of intermediary metabolism and in the acute or chronic treatment of several metabolic disorders.