Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel,potent and selective inhibitor of dopamine-β-hydroxylase

1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
2. Nepicastat produced concentration-dependent inhibition of bovine (IC₅₀=8.5±0.8 nM) and human (IC₅₀=9.0±0.8  nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg⁻¹, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg⁻¹, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg⁻¹, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
4. Administration of nepicastat (2 mg kg⁻¹, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.

     

Detection of p53 mutations in gynecologic tumors by means of a simple, nonradioactive minigel method of PCR-SSCP analysis

We studied 22 gynecological tumors for mutations in exons 5 through 8 of the p53 gene by means of SSCP analysis, using a simplified, nonradioactive technique developed at our laboratory. In order to test the procedure, we carried it out in parallel with the usual radioactive one. Two coincident mutations (in exons 5 and 8) were found by means of both methods. However, an additional one in exon 6 was found by means of our nonradioactive technique. This simplified method for SSCP-analysis of the p53 gene in human tumors is faster, easier and cheaper to perform than the conventional radioactive method, and yields equivalent results. It could be thus an excellent candidate for routine use in the clinical setting.     

Facial haemangioma,agenesis of the internal carotid artery and dysplasia of cerebral cortex: case report

We describe a girl with a facial haemangioma, associated with other vascular anomalies: agenesis of the internal carotid artery, cerebral cortical dysplasia and hypoplasia of the cerebral hemisphere on the same side of the angioma. We studied the patient by conventional arteriography, T1- and T2-weighted MRI and magnetic resonance angiography.     

Iron content of infant diets cooked in iron utensils

Iron deficiency is the most frequent form of nutritional anemia, and infants represent one of the major risk groups. The present study was meant to evaluate the iron content of infant diets cooked in iron utensils and in aluminum utensils prepared by volunteer mothers at home. The iron content was analyzed by atomic absorption spectrophotometry. The increase of iron in diets cooked in iron utensils was 12 to 44 times greater than in diets cooked in aluminum utensils. The pH and moisture of the diets cooked in the two types of utensils did not differ in a statistically significant manner. On the basis of these results, it was estimated that the increase in daily iron supply obtained by cooking the diet in iron utensils would be sufficient to satisfy the iron requirements of infants.     

Varus deformity of the distal end of the femur secondary to a focal fibrous lesion

Severe unilateral varus deformity of the distal end of the femur secondary to a focal fibrous lesion is reported. It is a malformative process rare at this level, this being the first report of it in the radiological literature. The conventional radiograph is pathognomonic and CT is useful in the confirmation of the fibrous tissue. Osteotomy is indicated only if the deformity progresses or the angle of varus is severe.     

Urinary tract infection: detection of Escherichia coli antigens in human urine with an ELIEDA immunoenzymatic assay.

Escherichia coli is the most common causative agent of urinary tract infection (UTI), and diagnosing this infection usually relies on bacteriologic methods. Nevertheless, screening methods can be useful for a rapid presumptive diagnosis even though some of these screening methods have low sensitivity or are expensive. To investigate a possible new alternative approach, an antigen-based immunoassay--enzyme-linked immunoelectrodiffusion assay (ELIEDA)--was standardized for screening for this bacterial infection. Combining counter-immunoelectrophoresis with an immunoenzymatic assay, the ELIEDA requires concentrated urine specimens, a cellulose acetate membrane, polyclonal antibodies to E. coli raised in rabbits, and peroxidase-labeled sheep antibodies to rabbit immunoglobulin G (IgG). This ELIEDA technique was evaluated using 244 urine specimens, 76 of them with E. coli, 47 with heterologous bacteria, and 121 without bacteria. In comparison to bacteriologic methods, the sensitivity, specificity, and positive and negative predictive values for the ELIEDA were 93.4%, 98.2%, 95.9%, and 97.1%, respectively. The data obtained suggest that this assay is useful for routine diagnostic screening for UTI caused by E. coli. In addition, since the ELIEDA stained membranes can be stored, this assay makes retrospective studies possible.     

Influence of parental smoking on respiratory symptoms during the first decade of life: the Tucson Children's Respiratory Study.

Compelling evidence suggests a causal relation between exposure to parental cigarette smoking and respiratory symptoms during childhood. Still, the roles of prenatal versus postnatal parental smoking need clarification. In this study, the authors assessed the effects of passive smoking on respiratory symptoms in a cohort of over 1,000 children born during 1980-1984. The children were enrolled in the Tucson Children's Respiratory Study in Tucson, Arizona, and were followed from birth to age 11 years. The population was generally middle class and consisted of two main ethnic groups, non-Hispanic Whites (75%) and Hispanics (20%), reflecting Tucson's population. Information on parental smoking and on wheeze and cough in their children was elicited from parents by using questionnaires at five different surveys. Data were analyzed both cross-sectionally and by using the generalized estimation equation approach, a longitudinal mixed-effects model. The best-fitting model indicated that maternal prenatal but not postnatal smoking was associated with current wheeze (odds ratio = 2.3, 95% confidence interval 1.4-3.8) independently of a family history of asthma, socioeconomic factors, and birth weight. This effect was time dependent and significant only below age 3 years; although independent of gender, the association was stronger for girls (odds ratio = 3.6, 95% confidence interval 1.6-8.0). Cough was not associated with parental smoking during the first decade of life. This transitory effect of maternal prenatal smoking on wheezing could be due to changes that affect the early stages of lung development.     

Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients.

The present study aimed to investigate the prevalence and seasonal variation of hypovitaminosis D (defined as serum 25-hydroxyvitamin D level below 30 nmol/l) among healthy subjects and hospitalized patients living in central Italy. We studied 297 subjects, 131 in February 1997 and 166 in July 1997, subdivided into four groups: (a) young healthy blood donors; (b) healthy postmenopausal women; (c) inpatients with various medical diseases and (d) inpatients engaged in long-term rehabilitation programmes because of various neurological disorders. In all subjects and patients serum levels of 25-hydroxyvitamin D were measured by radioimmunoassay. We found a significant seasonal variation (P < 0.0001) of serum 25-hydroxyvitamin D levels, mean values being higher in summer in all groups, except in patients with a longer hospitalization time (group (d)). In each group, a significantly higher prevalence of hypovitaminosis D was found in winter compared with summer time (P < 0.001), being unexpectedly high in postmenopausal women (winter 32% and summer 4.5%); furthermore, in both seasons, inpatients were characterized by the highest incidences of hypovitaminosis, particularly those in group (d) (winter 82.3% and summer 57.8%). The results of the present study emphasize the importance of 25-hydroxyvitamin D measurement, and the need to increase vitamin D intake in Italy; foodstuff fortification and supplement use must be considered in order to prevent negative effects of vitamin D deficiency on skeletal integrity.     

Involvement of Fas-Fas ligand interactions in graft rejection

The Fas/Fas ligand (FasL) pathway has been shown to be important in T lymphocyte-mediated cell death and is a key peripheral immunoregulatory mechanism that limits expansion of antigen-activated lymphocytes. The expression of Fas by commonly transplanted organs such as the heart, lung, kidney, and liver suggests that these tissues may be targets of FasL-expressing allospecific cytotoxic T lymphocytes. In this review the current literature examining the Fas/FasL system as a potential cellular effector pathway in tissue injury is discussed. In addition to a deleterious role in destruction of graft tissue, Fas/FasL interactions may have a beneficial role in transplantation. Recent studies suggest that modulation of FasL in target tissue leads to deletion, via apoptosis, of graft infiltrating lymphoid cells. However, an equally compelling series of reports indicate that overexpression of FasL can lead to a heightened immune response. These data are reviewed in the context of strategies to achieve long term allograft survival.     

Interfering with Greg Louganis, your sister's bobby pins and glycoprotein 41

The rate of HIV replication is estimated to be about 10 billion particles a day, and the cell's structure is its primary defense against infection. Cell membranes provide a defense against infection by forming a tight bond, preventing cells from being invaded by other organisms. The complex process of how HIV enters a cell is explained, and various parts of the process are illustrated. One key step in the process is fusion, which is when a virus particle attaches to a T cell, and the virus and cell merge together, allowing the virus to enter the cell. Researchers hope to find ways to interfere with fusion, so as to prevent HIV infection. Trimeris, Inc. has developed a new drug called T-20, or pentafuside, that is capable of preventing HIV from infecting a target cell. Results from studies of T-20 are provided, and ongoing studies are described.