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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Multiregional gene expression profiling identifies MRPS6 as a possible candidate gene for Parkinson's disease.

Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.

Adult↗
PubMed2003

Community and facility surveys illuminate the pathway to child survival in Liben Woreda, Ethiopia.

OBJECTIVES: To apply "Pathway to Survival" analysis to baseline assessments to inform integrated management of childhood illness programmes. DESIGN: A cross-sectional survey evaluating community-based knowledge, practices and coverage and health facility quality. SETTING: Liben Woreda (population 122, 410), a district in Borana Zone, of Ethiopia's Oromia region, from August 1997-Febuary 1998. SUBJECTS: Three hundred and sixty eight mother-child pairs (age < 24 months) seen in the community and 28 children (age < 5 years) in health facilities. RESULTS: Of the 368 mothers interviewed 50% reported that their child was ill in the previous two weeks (184/368). Amongst the 101 mothers of children under the age of six months only 24% reported exclusive breast-feeding (24/101). There were 194 children who should have completed their immunisation schedule; only 17% of them had done so (33/194). Amongst the 111 children who had diarrhoea, only 17% had received home treatment with ORS (19/111). Thirty per cent of mothers of children with possible pneumonia (25/83) and 28% who reported malaria (14/50) sought appropriate care. Amongst those caregivers seen at the health facility only 26% had an understanding of treatment recommendations. CONCLUSIONS: Based on the pathway to survival analysis, mother's knowledge of illness recognition is limited and they practice both home care and care seeking poorly. Thus few children are likely to receive and comply with standard case management.

Adult↗
PubMed2000

Participatory development of a minimum dataset for the Khayelitsha district.

BACKGROUND: Traditional 'data-led' information systems have created excessive amounts of poor-quality and poorly utilised data. The Health Information Systems Pilot Project (HISPP), a Western Cape project that started in 1996, initiated a process in one of its three pilot sites to model an alternative approach to developing a district health information system. OBJECTIVE: To develop a minimum dataset for Khayelitsha as part of an action-led district health and management information system in a participatory 'bottom-up' process. METHOD: The HISPP, in conjunction with health workers in the proposed Khayelitsha district, developed a minimum dataset through a process of defining local goals, targets and indicators. This dataset was integrated with data requirements at regional and provincial levels. RESULTS: A minimum dataset was produced that defined all the data needed according to the frequency of reporting and the level at which it was required. CONCLUSION: The HISPP has demonstrated an alternative model for defining health information needs at district level. This participatory process has enabled health workers to appraise their own information needs critically and has encouraged local use of information for planning and action.

Adult↗
PubMed2001

Stereochemical aspects of vinylcyclohexene bioactivation in rodent hepatic microsomes and purified human cytochrome P450 enzyme systems.

The racemic mixture of 4-vinylcyclohexene (VCH) forms ovotoxic epoxides [VCH-1,2-epoxide, VCH-7,8-epoxide, and vinylcyclohexene diepoxide (VCD)] by cytochrome P450 (CYP) in B6C3F(1) female mice. These epoxides deplete primordial and primary follicles. The current studies compared in vitro epoxidation of (R)-VCH with that of (S)-VCH in hepatic microsomes prepared from adult female B6C3F(1) mice and Fischer 344 rats. Bioactivation of VCH in the rat was significantly less compared with that in the mouse. (R)-VCH formed significantly more VCH-1,2-epoxide as compared with (S)-VCH in both species, and less VCH-7,8-epoxide in the mouse. Neither of the enantiomers formed detectable amounts of VCD in the mouse or rat. Hepatic microsomes prepared from mice and rats pretreated with CYP-inducing agents (phenobarbital and acetone) were also incubated with (R)-VCH or (S)-VCH. Although monoepoxide formation was not increased enantioselectively in the mouse, VCD was formed preferentially from (R)-VCH as compared with (S)-VCH. Pretreatment with VCH resulted in nonstereoselective increases in both monoepoxide and diepoxide formation. In the rat, these pretreatments resulted in nonstereoselective increases in monoepoxide formation, but VCD formation was not detectable. Incubations with human CYP2E1 enzyme revealed that (R)-VCH formed significantly more VCH-1,2-epoxide and less VCH-7,8-epoxide than (S)-VCH. Human CYP2A6 was limited in its ability to form epoxides from either enantiomer of VCH. Human CYP2B6 preferentially formed VCH-7,8-epoxide compared with VCH-1,2-epoxide, and to a greater extent from (R)-VCH than from (S)-VCH. These results demonstrate regioselectivity and enantioselectivity in the bioactivation of VCH in rodent hepatic microsomes as well as in expressed human CYP enzymes.

Animals↗
PubMed2001

Drug interactions with the dopamine transporter in cryopreserved human caudate.

Although several model systems have been developed to characterize the function of the dopamine transporter (DAT), there is a relative lack of data regarding dopamine (DA) uptake by human caudate, as contrasted to binding studies. Cryopreserved human brain tissue can be used for functional as well as radioligand binding studies of neuronal proteins. The drug-induced inhibition of [125I]RTI-55 binding to, and [3H]DA uptake by, cryopreserved human caudate preparations has now been characterized. Using human caudate membranes, a single site for [125I]RTI-55 binding was observed in association and saturation experiments. The relative potencies of 22 drugs for inhibition of [125I]RTI-55 binding to membranes prepared from cryopreserved human caudate, fresh rat striatum, and HEK293 cells expressing the recombinant human DAT (HEK-hDAT) were highly correlated. The affinity of DA for the DAT, as measured by [3H]DA uptake experiments, was higher in both the cryopreserved human caudate and freshly prepared rat striatum than in HEK-hDAT cells. Although affinities were similar in rat and human brain tissue preparations, the maximal uptake rate in the cryopreserved human caudate was approximately 1 to 4% and 7% of the rate in fresh and cryopreserved rat striatal preparations, respectively. The relative potencies of 22 drugs for inhibition of [3H]DA uptake were similar for tissue prepared from cryopreserved human caudate, nonfrozen rat striatum, and intact HEK-hDAT cells. These data suggest that cryopreserved human caudate can be used to characterize drug interactions with the DAT, and that HEK-hDAT cells provide a comparable system for modeling the initial interaction of drugs with native hDAT.

Animals↗
PubMed2001

In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats.

Ibogaine is a naturally occurring compound with purported antiaddictive properties. When administered to primates, ibogaine is rapidly o-demethylated to form the metabolite 12-hydroxyibogamine (noribogaine). Peak blood levels of noribogaine exceed those of ibogaine, and noribogaine persists in the bloodstream for at least 1 day. Very few studies have systematically evaluated the neurobiological effects of noribogaine in vivo. In the present series of experiments, we compared the effects of i.v. administration of ibogaine and noribogaine (1 and 10 mg/kg) on motor behaviors, stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. Ibogaine caused dose-related increases in tremors, whereas noribogaine did not. Both ibogaine and noribogaine produced significant elevations in plasma corticosterone and prolactin, but ibogaine was a more potent stimulator of corticosterone secretion. Neither drug altered extracellular DA levels in the nucleus accumbens. However, both drugs increased extracellular 5-HT levels, and noribogaine was more potent in this respect. Results from in vitro experiments indicated that ibogaine and noribogaine interact with 5-HT transporters to inhibit 5-HT uptake. The present findings demonstrate that noribogaine is biologically active and undoubtedly contributes to the in vivo pharmacological profile of ibogaine in rats. Noribogaine is approximately 10 times more potent than ibogaine as an indirect 5-HT agonist. More importantly, noribogaine appears less apt to produce the adverse effects associated with ibogaine, indicating the metabolite may be a safer alternative for medication development.

Animals↗
PubMed1975

Quantitative guidelines for exotropia surgery.

The effect of numerous preoperative variables on the amount of surgical correction attained was assessed in a population of intermittent exotropic patients; 54 had bilateral recession surgery, 48 had recess resect surgery. By appropriate multivariate statistical analyses, about 95 per cent of the variance in results of surgery (expressed as change in deviation from preoperative to the postoperative time in prism diopters per millimeter of surgical correction) could be accounted for. A workable scheme for utilizing this data base to guide future surgery is presented in the form of quantitative formulae. In addition to this empirical derivation, insights are provided into the mechanics of ocular muscle operations and the maturation of the eye as it affects strabismus sergery. Expansion of this approach to a wider ranger of cases and to additional types of cases should result in a greater descriptive and surgical accuracy from strabismus surgery.

Adolescent↗
PubMed1975

Genetic analysis of indices of corneal power and corneal astigmatism in human populations with varying incidences of strabismus.

Heritability estimates for corneal power were found to be high and similar for two populations which differed in their incidence of esotropia. This similarity suggest (1) that genetic differences for corneal power do not contribute to the difference in heritability for spherical refractive error reported for these populations and (2) that this character is not a critical variable contributing to the pathophysiology of esotropia. Heritability estimates for corneal astigmatism were, in most cases, rather low. The pattern of population and sex differences among heritability estimates was consistent with those previously reported for cylindrical refractive error. These population differences in heritability suggest that they contribute to population differences found for cylindrical refractive error.

Adult↗
PubMed2002

Response of rats to low levels of sarin.

The purpose of this study was to determine whether exposure to levels of sarin causing no overt clinical signs would cause more subtle, adverse health effects that persisted after the exposure ended. Inhalation exposures of male Fischer 344 rats to 0, 0.2, or 0.4 mg/m(3) of sarin for 1 h/day for 1, 5, or 10 days under normal (25 degrees C) and heat-stressed (32 degrees C) conditions were completed and observations were made at 1 day and 1 month after the exposures. The sarin exposures had no observed effects on body weight, respiration rate, and minute volume during exposure nor in body temperature and activity during the 30-day recovery period. There was no evidence of cellular changes in brain determined by routine histopathology nor of any increase in apoptosis. Brain mRNA for interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was increased in a dose-dependent manner. Autoradiographic studies demonstrated that M1 cholinergic receptor site densities were unchanged at 1 day after repeated exposures with or without heat stress. At 30 days, there was a decrease in M1 receptors in the olfactory tubercle (with and without heat), and, with heat stress, M1 sites also decreased in a dose-dependent manner in the frontal cortex, anterior olfactory nucleus, and hippocampus. M3 receptor sites were not affected by sarin exposure alone. In the presence of heat stress, there was an upregulation in binding site densities in the frontal cortex, olfactory tubercle, anterior nucleus, and striatum immediately after exposure, and these effects persisted at 30 days. Although red blood cell acetylcholinesterase (AChE) was not greatly inhibited by the 1-day exposure, there were 30 and 60% inhibitions after repeated exposures at the low and high doses, respectively. Histochemical staining for AChE demonstrated that sarin exposure alone reduced AChE in the cerebral cortex, striatum, and olfactory bulb. Sarin exposure under heat stress reduced AChE staining in the hippocampus, an area important for memory function. Thus, repeated exposures under heat-stress conditions, to levels of sarin that would not be noticed clinically, resulted in delayed development of brain alterations in cholinergic receptor subtypes that may be associated with memory loss and cognitive dysfunction.

Acetylcholinesterase↗
PubMed2003

Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons.

Alpha-synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease. The native protein is a major component of nigral Lewy bodies in Parkinson's disease, and full-length alpha-synuclein accumulates in Lewy neurites. Here we present evidence that alpha-synuclein levels are elevated in midbrain dopamine (DA) neurons of chronic cocaine abusers. Western blot and immunoautoradiographic studies were conducted on postmortem neuropathological specimens from cocaine users and age-matched drug-free control subjects. The results demonstrated that alpha-synuclein levels in the DA cell groups of the substantia nigra/ventral tegmental complex were elevated threefold in chronic cocaine users compared with normal age-matched subjects. The increased protein levels in chronic cocaine users were accompanied by changes in the expression of alpha-synuclein mRNA in the substantia nigra and ventral tegmental area. Although alpha-synuclein expression is prominent in the hippocampus, there was no increase in protein expression in this brain region. The levels of beta-synuclein, a possible negative regulator of alpha-synuclein, also were not affected by cocaine exposure. Alpha-synuclein protein levels were increased in the ventral tegmental area, but not the substantia nigra, in victims of excited cocaine delirium who experienced paranoia, marked agitation, and hyperthermia before death. The overexpression of alpha-synuclein may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse. However, the accumulation of alpha-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.

Blotting, Western↗
PubMed1992

Interactions of cocaine with primary and secondary recognition sites on muscarinic receptors.

Several lines of evidence have suggested that muscarinic receptors may possess more than one ligand binding site. In this study, the interactions of cocaine with primary and secondary (allosteric) sites on muscarinic receptors in membrane homogenates from post-mortem human brainstem were examined. (-)-Cocaine inhibited the binding of the tritiated muscarinic antagonists N-methylscopolamine (NMS) and pirenzepine to an apparent single class of sites, with Ki values of 200-300 microM. The binding of the muscarinic agonist [3H]oxotremorine-M was inhibited with a similar Ki value (200 microM). (+)-Cocaine, although not the naturally occurring stereoisomer, was 10-20-fold more potent than (-)-cocaine in competing for binding to the primary muscarinic recognition site. The binding of cocaine was unaffected by guanine nucleotides or N-ethylmaleimide, consistent with its purported action as a competitive antagonist. Cocaine was not selective for muscarinic receptor subtypes. Rosenthal analysis of the [3H]NMS saturation binding data in the presence of increasing concentrations of either (-)-cocaine or (+)-cocaine indicated that both isomers produced an apparent competitive-like reduction in the [3H]NMS affinity. Schild regression analysis of the saturation binding data resulted in curvilinear plots suggestive of cooperative or allosteric interactions of (-)-cocaine with the [3H]NMS-labeled receptors. The effects of (-)-cocaine on the kinetics of [3H]NMS binding were consistent with an allosteric interaction with the receptor. Increasing concentrations of cocaine markedly slowed the rate of [3H]NMS dissociation from the primary recognition site. The allosteric modulation of [3H] NMS binding by (-)-cocaine was abolished with increasing ionic strength. Taken together, these data demonstrate that (-)-cocaine interacts with primary and allosteric recognition sites on muscarinic receptors.

Adult↗
PubMed2006

The effects of a language barrier in a South African district hospital.

BACKGROUND: Communication between health workers and patients at Hottentots Holland Hospital (HHH) is hindered by staff and patients not speaking the same language. HHH is a district hospital in the Cape Town Metropolitan District of the Western Cape where staff mainly speak Afrikaans or English and a large number of patients mainly Xhosa. OBJECTIVES: The study aimed to explore the effects of this language barrier on health workers and patients at HHH. DESIGN: Three focus group interviews were held with 21 members of staff and 5 in-depth patient interviews were conducted. RESULTS: The language barrier was found to interfere with working efficiently, create uncertainty about the accuracy of interpretation, be enhanced by a lack of education or training, cause significant ethical dilemmas, negatively influence the attitudes of patients and staff towards each other, decrease the quality of and satisfaction with care, and cause cross-cultural misunderstandings. CONCLUSION: The effects of the language barrier were considerable and persistent despite an official language policy in the province. The training and employment of professional interpreters as well as teaching of basic Xhosa to staff are recommended.

Communication Barriers↗
PubMed1991

Characterization of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) binding sites in C57BL/6 mouse brain: mutual effects of monoamine oxidase inhibitors and sigma ligands on MPTP and sigma binding sites.

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenyl-pyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the sigma binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 nM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 nM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the sigma binding sites labeled with [(+)-[3H]-3-PPP]. The sigma receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the sigma binding sites, may suggest a possible relationship between MAO-A and sigma binding sites. In turn, the kinetic experiments imply that sigma ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids.

The inactivation by 21-chlorinated steroids of rat liver cytochromes P-450 involved in the hydroxylation of progesterone and androstenedione has been investigated. Preincubation of intact liver microsomes from phenobarbital-treated rats with 21-chloropregnenolone, 21,21-dichloropregnenolone, or 21,21-dichloroprogesterone in the presence of NADPH caused a time-dependent decrease in progesterone 21-hydroxylase and in progesterone or androstenedione 6 beta-hydroxylase activity but had negligible or only minor effects on five other steroid hydroxylases. The compounds differed, however, with regard to the relative rate constants for inactivation of the 21- and 6 beta-hydroxylases. For example, 21,21-dichloroprogesterone and 21,21-dichloropregnenolone inactivated the progesterone 6 beta-hydroxylase at similar rates, but the dichloroprogesterone was a more effective inactivator of the 21-hydroxylase. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few isozymes of cytochrome P-450 may be a rational means of designing isozyme-selective inhibitors but that target and nontarget enzymes may not totally retain the regioselectivity they exhibit towards the underivatized substrate.

Animals↗