RESUMEN

Ecological interaction networks, such as those describing the mutualistic interactions between plants and their pollinators or between plants and their frugivores, exhibit non-random structural properties that cannot be explained by simple models of network formation. One factor affecting the formation and eventual structure of such a network is its evolutionary history. We argue that this, in many cases, is closely linked to the evolutionary histories of the species involved in the interactions. Indeed, empirical studies of interaction networks along with the phylogenies of the interacting species have demonstrated significant associations between phylogeny and network structure. To date, however, no generative model explaining the way in which the evolution of individual species affects the evolution of interaction networks has been proposed. We present a model describing the evolution of pairwise interactions as a branching Markov process, drawing on phylogenetic models of molecular evolution. Using knowledge of the phylogenies of the interacting species, our model yielded a significantly better fit to 21% of a set of plant - pollinator and plant - frugivore mutualistic networks. This highlights the importance, in a substantial minority of cases, of inheritance of interaction patterns without excluding the potential role of ecological novelties in forming the current network architecture. We suggest that our model can be used as a null model for controlling evolutionary signals when evaluating the role of other factors in shaping the emergence of ecological networks.

RESUMEN

Highly pathogenic avian influenza (HPAI) virus H5N1 infects water and land fowl and can infect and cause mortality in mammals, including humans. However, HPAI H5N1 strains are not equally virulent in mammals, and some strains have been shown to cause only mild symptoms in experimental infections. Since most experimental studies of the basis of virulence in mammals have been small in scale, we undertook a meta-analysis of available experimental studies and used Bayesian graphical models (BGM) to increase the power of inference. We applied text-mining techniques to identify 27 individual studies that experimentally determined pathogenicity in HPAI H5N1 strains comprising 69 complete genome sequences. Amino acid sequence data in all 11 genes were coded as binary data for the presence or absence of mutations related to virulence in mammals or nonconsensus residues. Sites previously implicated as virulence determinants were examined for association with virulence in mammals in this data set, and the sites with the most significant association were selected for further BGM analysis. The analyses show that virulence in mammals is a complex genetic trait directly influenced by mutations in polymerase basic 1 (PB1) and PB2, nonstructural 1 (NS1), and hemagglutinin (HA) genes. Several intra- and intersegment correlations were also found, and we postulate that there may be two separate virulence mechanisms involving particular combinations of polymerase and NS1 mutations or of NS1 and HA mutations.

Asunto(s)

Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/metabolismo , Mutación , Aminoácidos/química , Animales , Teorema de Bayes , Biología Computacional/métodos , Eliminación de Gen , Genoma Viral , Humanos , Ratones , Modelos Estadísticos , Análisis Multivariante , Fenotipo , Probabilidad , Virulencia

RESUMEN

Human immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 env in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1.

Asunto(s)

VIH-1/patogenicidad , Modelos Estadísticos , Filogenia , Selección Genética , VIH-1/metabolismo , Humanos , Funciones de Verosimilitud , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética

RESUMEN

Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.

Asunto(s)

Evolución Molecular , Regulación Viral de la Expresión Génica , Productos del Gen nef/genética , Productos del Gen nef/metabolismo , Variación Genética , Infecciones por VIH/transmisión , VIH-1/genética , Selección Genética , Secuencia de Aminoácidos , Secuencia de Bases , Western Blotting , Antígenos CD4/metabolismo , Citometría de Flujo , Genes MHC Clase I/fisiología , Infecciones por VIH/metabolismo , Humanos , Funciones de Verosimilitud , Modelos Genéticos , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia , Análisis de Secuencia de ADN , Linfocitos T Citotóxicos/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana

RESUMEN

Dental patients often give a medical history that suggests the possibility of a coagulopathy from drugs, with a corresponding risk for prolonged bleeding during and following an invasive procedure. Identification of patients who may be prone to oral bleeding requires specific medical history information and the proper use of laboratory tests. Some NSAIDs are reported to cause prolonged oral bleeding, but scientific evidence is lacking. Likewise, the risk of oral bleeding from anticoagulants such as warfarin is often over stated, and unnecessary adjustment of NSAID or warfarin dosage puts patients at risk for significant morbidity and mortality. Some commonly employed laboratory tests such as the prothrombin time provide helpful information when used in the appropriate setting, but others, such as the bleeding time test, provide little or no predictive value in the determination of patients at risk for oral bleeding. Dental management of patients with potential coagulopathies from medications requires an understanding of basic principles of coagulation. The vast majority of these patients can be managed in the community setting without risk and without alteration of anticoagulant drug regimes.

Asunto(s)

Trastornos de la Coagulación Sanguínea/inducido químicamente , Atención Dental para Enfermos Crónicos , Hemorragia Bucal/prevención & control , Consumo de Bebidas Alcohólicas/efectos adversos , Algoritmos , Analgésicos/efectos adversos , Antibacterianos/efectos adversos , Antiinflamatorios no Esteroideos/efectos adversos , Anticoagulantes/efectos adversos , Antineoplásicos/efectos adversos , Pruebas de Coagulación Sanguínea , Suplementos Dietéticos/efectos adversos , Humanos , Warfarina/efectos adversos

Asunto(s)

Trastornos de la Coagulación Sanguínea , Atención Dental para Enfermos Crónicos , Coagulación Sanguínea/fisiología , Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/etiología , Pruebas de Coagulación Sanguínea , Enfermedades de la Médula Ósea/complicaciones , Atención Dental para Enfermos Crónicos/efectos adversos , Humanos , Fallo Renal Crónico/complicaciones , Fallo Hepático/complicaciones , Anamnesis , Hemorragia Bucal/etiología , Hemorragia Posoperatoria/etiología , Factores de Riesgo

RESUMEN

We surveyed the molecular evolutionary characteristics of 25 plant gene families, with the goal of better understanding general processes in plant gene family evolution. The survey was based on 247 GenBank sequences representing four grass species (maize, rice, wheat, and barley). For each gene family, orthology and paralogy relationships were uncertain. Recognizing this uncertainty, we characterized the molecular evolution of each gene family in four ways. First, we calculated the ratio of nonsynonymous to synonymous substitutions (d(N)/d(S)) both on branches of gene phylogenies and across codons. Our results indicated that the d(N)/d(S) ratio was statistically heterogeneous across branches in 17 of 25 (68%) gene families. The vast majority of d(N)/d(S) estimates were <<1.0, suggestive of selective constraint on amino acid replacements, and no estimates were >1.0, either across phylogenetic lineages or across codons. Second, we tested separately for nonsynonymous and synonymous molecular clocks. Sixty-eight percent of gene families rejected a nonsynonymous molecular clock, and 52% of gene families rejected a synonymous molecular clock. Thus, most gene families in this study deviated from clock-like evolution at either synonymous or nonsynonymous sites. Third, we calculated the effective number of codons and the proportion of G+C synonymous sites for each sequence in each gene family. One or both quantities vary significantly within 18 of 25 gene families. Finally, we tested for gene conversion, and only six gene families provided evidence of gene conversion events. Altogether, evolution for these 25 gene families is marked by selective constraint that varies among gene family members, a lack of molecular clock at both synonymous and nonsynonymous sites, and substantial variation in codon usage.

Asunto(s)

Evolución Molecular , Genes de Plantas/genética , Hordeum/genética , Familia de Multigenes/genética , Oryza/genética , Triticum/genética , Zea mays/genética , ADN/análisis , Bases de Datos Factuales , Secuencia Rica en GC , Conversión Génica , Filogenia

RESUMEN

Dysfunction in the serotonin (5-hydroxytryptamine) system and reduced serotonin concentrations have been reported in patients with Parkinson's disease (PD). Serotonin concentrations in neural tissue are controlled by a presynaptic serotonin transporter protein that is encoded by a single gene. Therefore, we investigated whether a polymorphic region in the serotonin transporter gene is associated with PD. Three variable-number tandem repeat (VNTR) elements of the serotonin transporter gene were detected by polymerase chain reaction, those with 9, 10, 11 and 12 copies of the repeat element. The 10-copy VNTR element was significantly less common in patients with PD than controls in the univariate analysis (p < 0.05). Logistic regression analysis revealed no significant differences between patients (n = 198) and controls (n = 200) in the distribution frequencies of 9- and 12-copy alleles and combined genotypes (odds ratio = 1.20; p = 1.71). A positive family history of PD was a strong predictor of disease risk (odds ratio = 2.98; 95% confidence interval 1.51-5.87; p = 0.001). Although slight differences were observed between patient and control groups, these data suggest that defects in serotonin concentrations in patients with PD are unlikely to be due to polymorphisms in the serotonin transporter gene in this large Australian cohort; however, the inverse association observed with the 10-copy allele warrants further investigation.

Asunto(s)

Proteínas Portadoras/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/genética , Polimorfismo Genético/genética , Alelos , Femenino , Genotipo , Humanos , Masculino , Factores de Riesgo , Proteínas de Transporte de Serotonina en la Membrana Plasmática

RESUMEN

It has been proposed that the extrapyramidal symptoms such as tardive dyskinesia developed by patients on long-term haloperidol treatment may be the result of uptake of haloperidol metabolites into neurons via the monoamine neurotransmitter transporters followed by neurotoxic events, as occurs for MPP+, the pyridinium metabolite of MPTP. We recently showed that haloperidol and its metabolites are inhibitors of the human noradrenaline transporter (NAT), dopamine transporter (DAT) and serotonin transporter (SERT), and determined their Ki values for inhibition of the three transporters expressed in transfected COS-7 cells. In this study, we extended the investigation of these compounds to their inhibitory effects on DAT, SERT and the high affinity choline uptake (HACU) in neuronal cultures from embryonic rat brain, and investigated whether the compounds are substrates or non-transported inhibitors of the NAT, DAT and SERT in transfected COS-7 cells and DAT and SERT in the neuronal cultures. Haloperidol and its metabolites inhibited DAT, SERT and HACU in the neuronal cultures, indicating that they are not specific inhibitors of the monoamine neurotransmitter transporters. The ratio of the Ki values of the least and most potent inhibitors were found to be 2.8 for DAT, 24 for SERT and 7.6 for HACU. The compounds were more potent inhibitors of DAT and SERT in neuronal cultures than we found previously in transfected COS-7 cells. The question of whether the compounds are substrates or non-transported inhibitors of the monoamine transporters was investigated by determining whether they caused an increase in efflux of [3H]amine in transfected COS-7 cells or neuronal cultures preloaded with [3H]amine. Haloperidol metabolites were weak substrates for SERT, but not for NAT or DAT, in transporter-transfected COS-7 cells. In neuronal cultures, the metabolites appeared to be non-transported inhibitors or very weak substrates of DAT and SERT. Despite inhibition of the monoamine transporters by haloperidol and its metabolites, there is little evidence to support the proposal that these compounds are likely to cause neurotoxic effects via neuronal uptake using the monoamine transporters. The mechanisms of the side effects of haloperidol therapy, such as tardive dyskinesia, are still unclear, but are unlikely to depend on interactions of the drug or its metabolites with NAT, DAT or SERT.

Asunto(s)

Antipsicóticos/farmacología , Células COS/efectos de los fármacos , Proteínas Portadoras/antagonistas & inhibidores , Haloperidol/farmacología , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Neuronas/efectos de los fármacos , Simportadores , Animales , Antipsicóticos/metabolismo , Células Cultivadas , Chlorocebus aethiops , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Haloperidol/metabolismo , Humanos , Neuronas/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Relación Estructura-Actividad , Transfección

RESUMEN

The use of neuroleptic drugs to treat schizophrenia is almost invariably associated with extrapyramidal movement disorders. One of these disorders, tardive dyskinesia (TD), can persist long after neuroleptic withdrawal suggesting that permanent neurological damage is produced. However, there appears to be no convincing pathology of TD and its pathogenesis remains unknown. Findings that neuroleptics interfere with normal mitochondrial function and produce mitochondrial ultrastructural changes in the basal ganglia of patients and animals suggest that mitochondrial dysfunction plays a role in TD. We have established a model for persistent TD in baboons that appears to involve compromised mitochondrial function. In this study, we evaluated two animals treated for 41 weeks with a derivative of haloperidol and two treated with vehicle only. Treatment was then withdrawn and the animals observed for a further 17-18 weeks. Treated animals developed abnormal orofacial signs that were consistent with TD. These symptoms persisted during the drug-free period. The animals were euthanased, the brains perfused-fixed then post-fixed in 4% paraformaldehyde and the caudate and putamen prepared for electron microscopy. Regardless of whether mitochondria were located in neural soma, excitatory terminals, glia or in non-somal neuropil there was no consistent difference either in size or number between treated and control animals. Thus, even if mitochondria in striatal neurons undergo ultrastructural alterations during neuroleptic therapy, these changes do not persist after drug withdrawal.

Asunto(s)

Ganglios Basales/patología , Discinesia Inducida por Medicamentos/patología , Mitocondrias/ultraestructura , Papio/fisiología , Animales , Antipsicóticos/farmacología , Ganglios Basales/efectos de los fármacos , Ganglios Basales/ultraestructura , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/patología , Núcleo Caudado/ultraestructura , Haloperidol/análogos & derivados , Haloperidol/farmacología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/patología , Neuroglía/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/ultraestructura , Neurópilo/efectos de los fármacos , Neurópilo/patología , Neurópilo/ultraestructura , Putamen/efectos de los fármacos , Putamen/patología , Putamen/ultraestructura

RESUMEN

Extrapyramidal symptoms, such as tardive dyskinesia, often develop in patients on long-term treatment with haloperidol. It has been proposed that these symptoms could be caused by neurotoxic effects of haloperidol metabolites following uptake by monoamine transporters, in an analogous mechanism to the neurotoxic effect of MPP+ (1-methyl-4-phenylpyridinium) metabolised from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this study, the hypothesis was partially investigated by determining the potencies of haloperidol and reduced haloperidol and the corresponding pyridinium and tetrahydropyridine metabolites, compared with MPP+ and MPTP, as inhibitors of the noradrenaline transporter (NAT), dopamine transporter (DAT) and 5-HT transporter (SERT). Two days after COS-7 cells were transiently transfected with the cDNA for the human NAT, DAT or SERT (Lipofectamine method), the cells were incubated with 10 nM [3H]noradrenaline, dopamine or 5-HT, respectively, for 2 min at 37 C, in the absence or presence of various concentrations of the eight compounds or a specific uptake inhibitor (NAT: nisoxetine 1 microM; DAT: GBR 12909 1 microM; SERT: citalopram 10 microM). Specific amine uptake (fmol/ mg protein) was calculated as the difference in uptake in the absence and presence of the specific uptake inhibitor. Ki values were calculated for the eight compounds for inhibition of NAT, DAT and SERT. Haloperidol, its five metabolites and MPP+ and MPTP all inhibited NAT, DAT and SERT. For the pyridinium and tetrahydropyridine metabolites of haloperidol, there were not marked differences between their potencies as inhibitors between each other for NAT or DAT or between NAT and DAT, with all of the Ki values in the range of 5.8-16 microM. However, there were more marked differences for SERT, with all but one of the metabolites showing selectivity for inhibition of SERT relative to NAT and DAT. Haloperidol and reduced haloperidol had similar inhibitory potencies for all three transporters, and were clearly less potent than the other haloperidol metabolites only for inhibition of SERT. The lack of correlation between the inhibitory potencies of the haloperidol metabolites and their structural analogues, MPTP and MPP+, suggests that they are not likely to cause neurotoxicity by a mechanism analogous to that of the latter neurotoxin.

Asunto(s)

Monoaminas Biogénicas/antagonistas & inhibidores , Dopamina/metabolismo , Haloperidol/metabolismo , Haloperidol/farmacología , Norepinefrina/metabolismo , Serotonina/metabolismo , Animales , Antidiscinéticos/metabolismo , Antidiscinéticos/farmacología , Transporte Biológico Activo/efectos de los fármacos , Células COS , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Humanos , Transfección

RESUMEN

Tardive dyskinesia (TD) is relatively common among psychiatric patients on maintenance therapy with typical neuroleptics and persists in more than 20% even after withdrawal of the medication. Such persistence suggests an underlying pathology due to neurotoxicity. We present evidence for such a neurotoxic mechanism in a baboon model of TD. Four baboons were treated chronically with the dehydration product of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HPTP), which is metabolized, similarly to haloperidol, to two neurotoxic pyridinium species. The animals developed orofacial dyskinesia which persisted after HPTP was ceased. Serial sections of the entire brain from the four treated animals and four vehicle-treated controls revealed volume loss in the basal forebrain and hypothalamus. Histological evaluation demonstrated a reduction in the density of magnocellular neurons in the anterior region of the nucleus basalis of Meynert (NbM). We speculate that the loss of these NbM neurons may be associated with the persistent orofacial dyskinesia observed in the HPTP-treated animals. These findings may contribute to a better understanding of neuroleptic-induced TD.

Asunto(s)

Antipsicóticos/efectos adversos , Discinesia Inducida por Medicamentos/etiología , Haloperidol/análogos & derivados , Hipotálamo/efectos de los fármacos , Prosencéfalo/efectos de los fármacos , Animales , Discinesia Inducida por Medicamentos/fisiopatología , Músculos Faciales/fisiopatología , Haloperidol/efectos adversos , Hipotálamo/patología , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Papio , Prosencéfalo/patología

RESUMEN

A prevalence study of Parkinson's disease (PD) was conducted in the rural town of Nambour, Australia. There were 5 cases of PD in a study population of 1207, yielding a crude prevalence ratio of 414 per 100,000 (95% confidence interval; 53-775). We performed a separate case-control study involving 224 patients with PD and 310 controls from South East Queensland and Central West New South Wales, to determine which factors increase the risk for PD in Australia. A positive family history of PD was the strongest risk factor for the development of the disease (odds ratio = 3.4; p < 0.001). In addition, rural residency was a significant risk factor for PD (odds ratio = 1.8, p < 0.001). Hypertension, stroke and well water ingestion were inversely correlated with the development of PD. There was no significant difference between patients and controls for exposure to herbicides and pesticides, head injury, smoking or depression. The high prevalence of PD in Nambour may be explained by rural residency. However, the most significant risk factor for PD was a positive family hisotry. This demonstrates the need for improved understanding of the genetic nature of the disease.

Asunto(s)

Enfermedad de Parkinson/epidemiología , Edad de Inicio , Anciano , Análisis de Varianza , Australia/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Prevalencia , Factores de Riesgo

RESUMEN

In vitro, cytosolic human ketone reductases catalyse the stereospecific (i.e. >99%) formation of S(-) reduced haloperidol (RHP) from haloperidol (HP). Whether this situation is reflected in patients taking the drug is unknown. In this study in nine patients taking HP, only 73.2+/-18.2% of the RHP excreted in urine was the S(-) enantiomer. Thus, enzymes other than cytosolic ketone reductases must be responsible for the formation of the minor enantiomer.

Asunto(s)

Antipsicóticos/química , Haloperidol/análogos & derivados , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/orina , Cromatografía Líquida de Alta Presión , Haloperidol/química , Haloperidol/farmacocinética , Haloperidol/orina , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Estereoisomerismo

RESUMEN

To facilitate quantitative analysis of cyclosporin A in low volume blood samples we developed a sensitive and specific microscale reversed-phase HPLC-electrospray tandem mass spectrometry assay. Blood samples (100 microl) were prepared by acetonitrile precipitation and C18 solid-phase extraction. Detection was by multiple-reactant monitoring. The method was linear over the range 5-1000 microg/l (r> or =0.997) with accuracy between 95.4 and 102.0% over this range. Total imprecision was 11.1% at 10 microg/l and 2.8% at 800 microg/l. Absolute recovery of cyclosporin A and internal standard was 72.5 and 73.3%, respectively. When this method was evaluated against a conventional HPLC with UV detection, in patient samples, they were interchangeable (y=0.988x + 10.0, r=0.996). This HPLC-ESI-MS-MS method will be applicable to therapeutic monitoring in paediatric transplant patients and multiple point pharmacokinetic studies in animals and humans.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Ciclosporina/sangre , Espectrometría de Masas , Microquímica , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta

RESUMEN

The present study evaluates the cytoarchitecture of midbrain dopaminergic regions in baboons using similar methodology to that recently applied to compare humans and rats. This information is relevant for the interpretation of nonhuman primate models of Parkinson's disease (PD). The midbrains of four alpha male baboons were serially sectioned into 10 evenly spaced series of 50 microm sections. Series were stained with either cresyl violet or immunohistochemically reacted for tyrosine hydroxylase, substance P, calbindin-D28k, or parvalbumin. The organization of dopaminergic cell groups and the distribution of proteins within these groups were found to be very similar to that previously described in humans [McRitchie et al., J. Comp. Neurol. 364:121-150; 1996]. Dorsal and ventral tiers of the A9 substantia nigra (SN) pars compacta and all divisions of the A8 and A10 cell groups were identified revealing a high degree of homology in the arrangement of chemically distinct midbrain neurons between primates. The major difference between the organization of human and baboon midbrain dopaminergic neurons is the anteroposterior extent of the dense cell clusters within the SN pars compacta. In baboons the dorsomedial cell cluster is absent at posterior levels. The ventral tier cell clusters, which are targeted by PD in humans, are restricted to the posterior and ventral regions of the SN pars compacta of the baboon. In humans these cell clusters are found throughout the rostrocaudal extent of the SN. These ventral cell clusters have been previously shown to have reciprocal connections with sensorimotor regions of the putamen.

Asunto(s)

Dopamina/fisiología , Neuronas/química , Papio/anatomía & histología , Sustancia Negra/citología , Área Tegmental Ventral/citología , Animales , Proteínas de Unión al Calcio/fisiología , Tamaño de la Célula/fisiología , Humanos , Masculino , Vías Nerviosas , Neuronas/citología , Neuronas/enzimología , Enfermedad de Parkinson Secundaria/fisiopatología , Sustancia Negra/química , Sustancia Negra/fisiología , Tirosina 3-Monooxigenasa/análisis , Área Tegmental Ventral/química , Área Tegmental Ventral/fisiología

RESUMEN

We studied a variable number tandem repeat polymorphism within the dopamine transporter gene (DAT) for an association with Parkinson's disease in a Chinese population. Five alleles were detected, consisting of 6, 8, 9, 10, and 11 copies of the 40 base pair repeat sequence. The 10-copy allele was most common, accounting for 90% of alleles. There were no significant differences between the patients and the control subjects in the distribution frequencies of the alleles or genotypes. Therefore, this polymorphism is not associated with Parkinson's disease in Chinese populations.

Asunto(s)

Pueblo Asiatico/genética , Proteínas Portadoras/genética , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/genética , Anciano , Anciano de 80 o más Años , Alelos , China/etnología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Frecuencia de los Genes , Genotipo , Hong Kong/etnología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/etnología

Asunto(s)

Monitoreo de Drogas/métodos , Inmunosupresores/sangre , Tacrolimus/sangre , Cromatografía Líquida de Alta Presión/métodos , Humanos , Espectrometría de Masas , Sensibilidad y Especificidad

RESUMEN

The presynaptic dopamine transporter in nigral dopaminergic neurons confers susceptibility to the cytotoxic effects of the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Polymorphisms in the dopamine transporter might influence the susceptibility to such toxins. Therefore, we investigated whether a polymorphic region in the 3'-untranslated region of the dopamine-transporter gene is associated with idiopathic Parkinson's disease (PD). The frequency distribution of the alleles was significantly different between the patients (n = 100) and controls (n = 200, p < 0.05). The rare 11-copy allele was more common in the patients (odds ratio = 10.2, 95% confidence interval - 1.2-87.9, p < 0.025). The susceptibility of some people to PD may be conferred by polymorphisms in the dopamine-transporter gene that could lead to increased cellular accumulation of neurotoxic compounds in dopaminergic neurons.

Asunto(s)

Proteínas Portadoras/genética , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/genética , Polimorfismo Genético/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Edad de Inicio , Anciano , Alelos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Intervalos de Confianza , Susceptibilidad a Enfermedades , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Oportunidad Relativa , Secuencias Repetitivas de Ácidos Nucleicos/fisiología

RESUMEN

We have previously reported the placental metabolism of prednisolone to prednisone, 20alpha- and beta-dihydroprednisone and 20beta-dihydroprednisolone. In this study, the disposition of cortisol was investigated in vitro in the dual perfused, isolated human placental lobule after the addition of cortisol (1.2 micromol, n = 3 and 12 micromol, n = 4) to the maternal compartment. Analysis of 5 h maternal and fetal perfusate samples by high performance liquid chromatography-electrospray-tandem mass spectrometry (HPLC-ESI-MS/MS) revealed that cortisol was mainly metabolized to cortisone, but a significant production of 20alpha-dihydrocortisone, 20beta-dihydrocortisone, 20alpha-dihydrocortisol and 20beta-dihydrocortisol was also detected. Saturability of metabolism but not transfer was demonstrated. Metabolism was eliminated by co-perfusion with the potent 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzyme inhibitor 18beta-glycyrrhetinic acid (GA). The disposition of GA was analysed using HPLC-atmospheric pressure chemical ionisation-MS/MS (HPLC-APCI-MS/MS). GA was found to transfer from the maternal to the fetal circulations without detectable metabolism during 6 h of perfusion.

Asunto(s)

Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Ácido Glicirretínico/farmacología , Hidrocortisona/metabolismo , Placenta/efectos de los fármacos , 11-beta-Hidroxiesteroide Deshidrogenasas , Administración Tópica , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Espectrometría de Masas , Perfusión , Placenta/metabolismo