Evidence that 3α-hydroxy-5α-pregnan-20-one is a physiologically relevant modulator of gaba-ergic neurotransmission

3α-Hydroxy-5α-pregnan-20-one (HPO) is a progesterone metabolite which exhibits narcotic properties at high concentrations by interactions with the receptor for gamma-aminobutyric acid (GABA). The present investigation characterized low-dose effects of HPO on GABA_A receptor binding, by determining the allosteric properties of HPO on the in vitro binding of ³H-muscimol to membrane fractions from the cerebella of ovariectomized rats. A newly developed method for tissue preparation was used to wash out endogenous ligands interfering with the assay. HPO reduced the affinity of ³H-muscimol to GABA_A receptor sites by 52% and enhanced the number of accessible binding sites from 5.5±0.5 to 7.5±1.3 pmol/mg protein at subnanomolar (0.1 nM) HPO concentrations. The modulatory effects of HPO on GABA_A receptor binding provide evidence that this pregnane steroid might be a physiologically relevant modulator of GABAergic neurotransmission.     

Platelet 5-hydroxytryptamine increases with platelet age in dogs.

Thrombocytopenia was induced in mongrel dogs by two mechanisms: immunologically, by intravenous injection of heterologous antiplatelet antibody, and non-immunologically, by circulating the blood through glass beads in anesthetized animals. The platelet content of 5-HT was monitored before and during the recovery of the blood platelet counts. This period is associated with the normalization of the mean platelet survival time and with a progressive increase in the mean age of the circulating platelet population. A continuous increment in platelet 5-HT closely followed the increase in platelet counts in both models of thrombocytopenia, and a strong correlation was found between the platelet age and 5-HT content. These findings support the concept that platelets accumulate 5-HT during their physiological aging process, contradicting the notion that a negative balance in 5-HT content results at the end of their physiological lifespan in circulation. These results are not in conflict with the concept that circulating platelets release and re-uptake 5-HT.     

Differences in the abilities of human tau isoforms to promote microtubule assembly.

Three isoforms of human tau protein were compared for their abilities to induce microtubule assembly. The three isoforms, tau 3 (tau containing three microtubule-binding domains), tau 4 (tau containing four microtubule-binding domains) and tau 4L (tau containing four microtubule binding domains plus a 58-amino-acid insert near the N-terminus) were expressed in E. coli and purified using ammonium sulfate precipitation, ion exchange, and size exclusion chromatography. All three isoforms induced microtubule assembly at micromolar concentrations and showed similar critical concentrations for assembly of 0.4-0.45 microM. However, tau 4 induced microtubule formation at a rate five- to tenfold faster than either tau 3 or tau 4L. The rate of microtubule elongation seen with tau 4 was twofold greater than with tau 3 or tau 4L, suggesting that the faster rate of microtubule assembly seen with tau 4 was due, at least in part, to faster elongation. Tau 4 induced a greater number of microtubules to form at steady state than did tau 3 or tau 4L. The microtubules generated with each tau isoform had similar steady-state length distributions and were equally susceptible to cold-induced disassembly. These results indicate that the additional microtubule-binding domain in tau 4 enhances microtubule assembly, while the 58-amino-acid insert negates the stimulatory effect of the fourth microtubule-binding domain.     

Development of rostrocaudal dendritic bundles in rat thoracic spinal cord: analysis of cholinergic sympathetic preganglionic neurons.

Using monoclonal antibodies to choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP), we have analyzed the development of the dendritic bundles formed by cholinergic sympathetic preganglionic neurons (SPNs) in relationship to changes in the organization of glial fibers. In adult rat thoracic spinal cord, SPNs in the intermediolateral (IML) and central autonomic (CA) regions extend dendrites in both the mediolateral and rostrocaudal directions, forming a ladder-like pattern in horizontal sections of thoracic spinal cord. We report that, while the mediolateral dendrites form prenatally, the rostrocaudal dendritic bundles are not detected until at least a week later, during early postnatal life. The rostrocaudal dendrites develop rapidly during the first postnatal week, and achieve an adult-like pattern by postnatal day 14. The observed ontogenetic arrangements of dendritic bundles were correlated with the developing organization of astroglial processes with which they are intimately associated. While the appearance of mediolateral dendrites is consistent with the radial organization of glial in the embryonic spinal cord, the developmental time course of the rostrocaudal dendritic bundles coincides with the transformation of glial cells from this predominantly radial or transverse orientation to the randomly-oriented, stellate pattern of mature astrocytes. This temporal association suggests that ontogenetic changes in the organization of glial cells may contribute to the differential development of mediolateral and rostrocaudal dendritic patterns in the spinal cord.     

Family history evaluation as a predictive screen for childhood hypercholesterolemia. Pediatric Practice Research Group

A study was conducted to evaluate the efficacy of family history factors as screening criteria for childhood hypercholesterolemia. When they were seen for routine care at one of eight office practices, 1005 prepubertal children underwent random serum cholesterol determinations. Parental and grandparental histories of cardiovascular risk factors and atherosclerotic complications prior to 55 years of age were also obtained. Of the initial group, 274 children had total cholesterol levels greater than or equal to 175 mg/dL, and 175 of these children returned for retesting after an overnight fast. A total of 88 children were found to have low-density lipoprotein-cholesterol (LDL-C) values greater than or equal to 90th percentile for age and sex. Maternal and paternal histories of hypercholesterolemia were significantly associated with elevated LDL-C (odds ratio = 7.3 and 2.9, respectively), but had extremely low sensitivities (0.09, 0.15) despite modest positive predictive values (0.42, 0.22). Grandparental histories of sudden death, peripheral vascular disease, and gout were associated with elevated LDL-C, but sensitivities and positive predictive values for all of these factors were less than 0.22. Family history factors most commonly recommended as criteria for cholesterol screening in children did not identify half of all the children with elevated LDL-C and did not selectively identify the most severely affected children. Adding information concerning the presence of childhood obesity did not result in appreciable improvement in LDL-C detection beyond that achieved by family history factors alone. It was concluded that if thorough identification of young children with elevated LDL-C is desired, inclusive population screening rather than a family history-based strategy would be the most effective approach.     

Patterns of care: an analysis of the quality of nutritional care routinely provided to elderly hospitalized veterans

To assess the adequacy of the nutritional care provided, a prospective noninterventional study was carried out on 250 randomly selected patients aged 65 and over who were admitted to a Veterans Administration Hospital. Of this group, 97 patients (39%) were found to be at high risk of having clinically significant protein-energy malnutrition. In 43 cases (17%), an assessment of the patient's nutritional status was not possible because the available data were inadequate. No patient had a diagnosis of malnutrition recorded on the problem list. Only 13 percent of the high-risk patients received some form of nutrition support therapy; 10 (10%) received oral supplements, and four (4%) were started on enteral feedings. Patients who received enteral feedings experienced a high rate of complications resulting from use of the feeding tubes. Over all, none of the high risk study patients received optimal nutrition support therapy. These findings indicate that elderly patients hospitalized in the Veterans Administration hospital in this study are usually not screened appropriately for protein-energy malnutrition, the diagnosis is frequently missed or ignored, and nutrition support therapy is underutilized and often ineffectually managed.     

Occupation and bladder cancer in Spain: a multi-centre case-control study

A case-control study on bladder cancer was carried out in four regions of Spain. The study included 497 cases (438 males and 59 females), 583 hospital controls and 530 population controls matched by sex, age and residence. The present paper reports the results of the analyses on occupational history. Among men, an increased risk of bladder cancer was found for textile workers (OR = 1.97, 95% CL 1.2-3.3), mechanics and maintenance workers (OR = 1.86, 95% CL 1.2-2.8), workers in the printing industry (OR = 2.06, 95% CL 1.0-4.3) and for managers (OR = 2.03, 95% CL 1.2-3.5). The risk was highest among those first employed in the textile industry before the age of 25 and prior to 1960. Among mechanics the risk was highest for those who started after the age of 25 and later than 1960. The OR for smokers who had also been employed in one of the high risk occupations was 7.82 (95% CL 4.4-14.0) which is compatible with a multiplicative effect of joint exposure to tobacco and occupational hazards.     

Epidemiology of acute diarrhea in children living in Sicily

A longitudinal survey (February 1984 - January 1985) on the incidence of acute diarrhea episodes in a sample of 8,164 children (aged 0–12 years) living in southeastern Sicily was carried out by means of weekly telephone interviews with doctors practising in the territory. The incidence rate was 0.479 (0.472–0.485 95% C.I.) per child per year and the frequency of episodes was significantly higher (p < 0.001) in children aged 0–4 years (0.86). Diarrhea was more frequent in industrial areas than in rural ones, and almost half (45.1%) of the total episodes had a mild course. No death from diarrhea occurred and admission to hospital was reported for 8.4% of all cases.Corresponding author.     

Free light chains in multiple sclerosis and infections of the CNS

The intrathecal humoral immune response was analyzed in 83 patients with MS and 35 patients with acute CNS infections. CSF free kappa chains and CSF free lambda chains were quantified by radioimmunoassay; CSF IgG and albumin were measured by electroimmunodiffusion. The MS patients were characterized by higher levels of free kappa chains; free kappa:free lambda chain ratio; free kappa chain:albumin ratio; and IgG:albumin ratio. There were no differences in the level of free lambda chains or absolute concentration of IgG. A significant correlation was observed between free kappa chains and total IgG in MS and between free lambda chains and total IgG in infections, suggesting that the immune response was predominantly IgG-kappa in MS and IgG-lambda in infections.