RESUMO
Black cisgender sexually minoritized men (SMM) and transgender women (TW) are subgroups at highest risk of HIV and sexually transmitted infections (STIs) in the US. We sought to identify factors facilitating continued conversations - social reinforcement - surrounding HIV/STI prevention among this subgroup. Participants were recruited in Chicago from 2018 to 2019 from community health spaces. Participants provided information about themselves (level 2) and ⩽5 confidants (level 1). We used multinomial multilevel modeling to identify associations with HIV/STI prevention conversation frequency. A total of 370 participants provided information on 987 confidants (mean = 2.6). We found significantly positive associations between having biweekly or more often HIV/STI prevention conversations and a confidant being a kin family member, older by 15 years or more, racially homophilous, and emotionally close. Future interventions should harness social networks by including components that consider racial homophily, respect for elders, and strong ties, in addition to applying kin family systems interventions approaches and decreasing stigma surrounding HIV/STIs.
Assuntos
Infecções por HIV , Infecções Sexualmente Transmissíveis , Rede Social , Humanos , Masculino , Chicago/epidemiologia , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Infecções Sexualmente Transmissíveis/epidemiologia , Adulto , Estudos de Coortes , Adulto Jovem , Adolescente , Pessoas Transgênero/psicologia , Pessoas Transgênero/estatística & dados numéricos , Pessoa de Meia-Idade , Negro ou Afro-Americano/psicologia , Negro ou Afro-Americano/estatística & dados numéricos , Apoio Social , Comunicação , Estigma Social , Minorias Sexuais e de Gênero/psicologia , Minorias Sexuais e de Gênero/estatística & dados numéricos , Comportamento Sexual/psicologiaRESUMO
Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical ß-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with ß-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with ß-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with ß-amyloid. AWS arteriolosclerosis was not associated with ß-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not ß-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.
Assuntos
Doença de Alzheimer , Proteômica , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Encéfalo/patologia , Feminino , Humanos , Masculino , Proteínas tau/metabolismoRESUMO
BACKGROUND AND PURPOSE: There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aß (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aß or tau tangle burden. METHODS: Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aß and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aß or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts. RESULTS: Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aß and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aß (estimate, 0.15; SE=0.07; P=0.02) and tau tangle burden (estimate, 0.13; SE=0.06; P=0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aß (estimate, 0.27; SE=0.07; P<0.001) and tangle burden (estimate, 0.16; SE=0.06; P=0.005). CONCLUSIONS: These findings suggest that in the presence of elevated Aß or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Infarto Encefálico/metabolismo , Doenças Vasculares/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Arteriosclerose/metabolismo , Encéfalo/fisiopatologia , Infarto Encefálico/fisiopatologia , Angiopatia Amiloide Cerebral , Feminino , Humanos , Imuno-Histoquímica , Masculino , Análise de Regressão , Doenças Vasculares/fisiopatologiaRESUMO
AIMS: Brain mural cells (BMC), smooth muscle cells and pericytes, interact closely with endothelial cells and modulate numerous cerebrovascular functions. A loss of BMC function is suspected to play a role in the pathophysiology of Alzheimer's Disease (AD). METHODS: BMC markers, namely smooth muscle alpha actin (α-SMA) for smooth muscle cells, as well as platelet-derived growth factor receptor ß (PDGFRß) and aminopeptidase N (ANPEP or CD13) for pericytes, were assessed by Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders study, with ages at death ranging from 75 to 98 years old. RESULTS: Participants clinically diagnosed with AD had lower vascular levels of α-SMA, PDGFRß and CD13. These reductions were correlated with lower cognitive scores for global cognition, episodic and semantic memory, perceptual speed and visuospatial ability. In addition, α-SMA, PDGFRß and CD13 were negatively correlated with vascular Aß40 concentrations. Vascular levels of BMC markers were also inversely correlated with insoluble cleaved phosphorylated transactive response DNA binding protein 43 (TDP-43) (25 kDa) and positively correlated with soluble cleaved phosphorylated TDP-43 (35 kDa) in cortical homogenates, suggesting strong association between BMC loss and cleaved phosphorylated TDP-43 aggregation. CONCLUSIONS: The results of this study highlight a loss of BMC in AD. The associations between α-SMA, PDGFRß and CD13 vascular levels with cognitive scores, TDP-43 aggregation and cerebrovascular accumulation of Aß in the parietal cortex suggest that BMC loss contributes to both AD symptoms and pathology, further strengthening the link between cerebrovascular defects and dementia.
Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Miócitos de Músculo Liso/patologia , Lobo Parietal/patologia , Pericitos/patologia , Proteinopatias TDP-43/patologia , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Animais , Disfunção Cognitiva/etiologia , Feminino , Humanos , Masculino , CamundongosRESUMO
Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid ß plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid ß plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.
Assuntos
Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/patologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Idoso , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neuropatologia/métodos , Placa Amiloide/metabolismo , Estudos Prospectivos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Tauopatias/metabolismo , Proteínas tau/metabolismoRESUMO
The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer's disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [18F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) phases GO/2 (n=678). Near genome-wide significant interaction effect was observed for rs73069071 within the IAPP (amylin) and SLCO1A2 genes (P=6.2 × 10-8). Congruent results were found using data from participants followed up from ADNI-1 (Pone-tailed=0.028, n=165). Meta-analysis across ADNI-GO/2 and ADNI-1 revealed a genome-wide significant interaction effect (P=1.1 × 10-8). Our results were further supported by similar interaction effects on temporal lobe cortical thickness (whole-brain voxelwise analysis: familywise error corrected P=0.013) and longitudinal changes in ADAS-cog score and left middle temporal thickness and amygdalar volume (Pone-tailed=0.026, 0.019 and 0.003, respectively). Using postmortem beta-amyloid immunohistochemistry data from 243 AD participants in the Religious Orders Study and Memory and Aging Project, we also observed similar rs73069071-by-beta-amyloid deposition interaction effect on global cognitive function (Pone-tailed=0.005). Our findings provide insight into the complexity of the relationship between beta-amyloid burden and AD-related cognitive impairment. Although functional studies are required to elucidate the role of rs73069071 in AD pathophysiology, our results support the recently growing evidence on the role of amylin in AD.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/fisiologia , Transtornos Cognitivos/patologia , Idoso , Peptídeos beta-Amiloides/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Disfunção Cognitiva , Demência/metabolismo , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Masculino , Neuroimagem , Testes Neuropsicológicos , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Lobo TemporalRESUMO
There is growing evidence suggesting that vascular pathologies and dysfunction play a critical role in cognitive impairment, clinical Alzheimer's disease, and dementia. Vascular pathologies such as macroinfarcts, microinfarcts, microbleeds, small and large vessel cerebrovascular disease, and white matter disease are common especially in the brains of older persons where they contribute to cognitive impairment and lower the dementia threshold. Vascular dysfunction resulting in decreased cerebral blood flow, and abnormalities in the blood brain barrier may also contribute to the Alzheimer's disease (AD) pathophysiologic process and AD dementia. This review provides a clinical-pathological perspective on the role of vessel disease, vascular brain injury, alterations of the neurovascular unit, and mixed pathologies in the Alzheimer's disease pathophysiologic process and Alzheimer's dementia. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
Assuntos
Doença de Alzheimer/etiologia , Transtornos Cerebrovasculares/complicações , Disfunção Cognitiva/etiologia , Demência/etiologia , Fatores Etários , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cerebrovasculares/patologia , Transtornos Cerebrovasculares/fisiopatologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Demência/patologia , Demência/fisiopatologia , Humanos , Fatores de RiscoRESUMO
Mass incarceration of young Black men has a significant impact on their network composition and stability that, in turn, may have major implications for health and well-being. A sub-group of young Black men with criminal justice involvement (CJI) identify as gay, bisexual or are non-identified men who have sex with men (hereafter MSM). This paper focuses on the potential effects of CJI on the composition of Black MSM social and sexual networks, their stability over time, and concomitant health and social outcomes. We use data from the UConnect study, a population-based cohort of young Black MSM 16-29 years of age (n=618) selected using respondent-driven sampling in Chicago from 2013-2016. Both confidant and sexual network name generators and interpreters were administered at 9-month intervals over three waves of data collection. Ego and dyadic-level data were collected on behaviors prevalent among MSM and including factors associated with network CJI, network stability, and health outcomes. Generalized Structural Equation Models (GSEM) were utilized to determine the relationship between CJI network composition, network stability and behaviors prevalent among young Black MSM and their networks. In the UConnect cohort, 46% had at least once been detained, arrested or spent time in jail or prison. In addition, 20% of participants reported incident CJI over the study period. Respondents with a history of CJI were significantly more likely to have CJI homophily in their confidant and sexual networks. Multivariate analyses demonstrate that the association between one's history of CJI, housing instability and drug use is partially explained by one's network CJI. In addition, a higher prevalence of network CJI is associated with increased turnover in the confidant network, and this network instability is also related to important health and social outcomes. This analysis describes the networks of criminal justice involved men among a representative sample of young Black MSM and demonstrates the relationship between CJI network homophily, network stability and their impact on several key health and social outcomes relevant to this population.
RESUMO
Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Predisposição Genética para Doença , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Doença de Alzheimer/patologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Criança , Pré-Escolar , Imagem de Tensor de Difusão , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
Rising rates of HIV infection among younger black men who have sex with men (YBMSM) in the USA have generated a public health emergency. Living with HIV requires deep and persistent social support often available only from close confidants. Enlisting endogenous support network members into the care of HIV-infected YBMSM may help shape sustainable supportive environments, leading to long-term improvements in mental and HIV-specific health outcomes. The present study examined trends in support network change over time after new HIV diagnoses among 14 YBMSM. Participants completed a social network survey that utilized sociograms to record support confidants (SCs) preceding HIV diagnosis and at one and nine months postdiagnosis. Reported SCs included family of origin, friends, sex partners, and other associates. Analysis revealed three distinct patterns of change: high gain, high turnover, and stable networks. These patterns offer valuable insights into the social support of YBMSM during the period following diagnosis. This research underscores a growing movement to embrace key support figures in the lives of YBMSM, who may be critical to promoting overall health and adherence to HIV-care.
Assuntos
Negro ou Afro-Americano , Infecções por HIV/etnologia , Homossexualidade Masculina/etnologia , Apoio Social , Adulto , População Negra , Infecções por HIV/psicologia , Homossexualidade Masculina/psicologia , Humanos , Masculino , Estados Unidos , Adulto JovemRESUMO
Lewy bodies are common in the ageing brain and often co-occur with Alzheimer's disease pathology. There is little known regarding the independent role of Lewy body pathology in cognition impairment, decline and fluctuations in community-dwelling older persons. We examined the contribution of Lewy body pathology to dementia, global cognition, cognitive domains, cognitive decline and fluctuations in 872 autopsied subjects (mean age = 87.9 years) from the Rush Religious Order Study (n = 491) and Memory and Aging Project (n = 381) longitudinal community-based clinical-pathological studies. Dementia was based on a clinical evaluation; annual cognitive performance tests were used to create a measure of global cognition and five cognitive domains. Lewy body type was determined by using α-synuclein immunostained sections of substantia nigra, limbic and neocortical regions. Statistical models included multiple regression models for dementia and cognition and mixed effects models for decline. Cognitive fluctuations were estimated by comparing standard deviations of individual residuals from mean trajectories of decline in those with and without Lewy bodies. All models controlled for age, sex, education, Alzheimer's disease pathology and infarcts. One hundred and fifty-seven subjects (18%) exhibited Lewy body pathology (76 neocortical-type, 54 limbic-type and 27 nigra-predominant). One hundred and three (66%) subjects with Lewy body pathology had a pathologic diagnosis of Alzheimer's disease. Neocortical-type, but not nigral-predominant or limbic-type Lewy body pathology was related to an increased odds of dementia (odds ratio = 3.21; 95% confidence interval = 1.78-5.81) and lower cognition (P < 0.001) including episodic memory function (P < 0.001) proximate to death. Neocortical-type Lewy body pathology was also related to a faster decline in global cognition (P < 0.001), decline in all five specific cognitive domains (all P-values < 0.001), and to fluctuations in decline of working and semantic memory (P-values < 0.001). Limbic-type Lewy body pathology was related to lower and faster decline in visuospatial skills (P = 0.042). The relationship of Lewy body pathology to cognition and dementia was not modified by Alzheimer's disease pathology. Neocortical-type Lewy body pathology is associated with increased odds of dementia; lower and more rapid decline in all cognitive domains including episodic memory and fluctuations in decline in semantic and working memory. Limbic-type Lewy body pathology is specifically associated with lower and more rapid decline in visuospatial skills. The effect of Lewy body pathology on cognition appears to be independent of Alzheimer's disease pathology.
Assuntos
Doença de Alzheimer/patologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/patologia , Corpos de Lewy/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Comorbidade , Feminino , Humanos , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/patologia , Estudos Longitudinais , Masculino , Testes NeuropsicológicosRESUMO
Reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemic heart disease, Alzheimer disease, Parkinson disease and aging. ROS are generated by mitochondria as the toxic by-products of oxidative phosphorylation, their energy generating pathway. Genetic inactivation of the mitochondrial form of superoxide dismutase in mice results in dilated cardiomyopathy, hepatic lipid accumulation and early neonatal death. We report that treatment with the superoxide dismutase (SOD) mimetic Manganese 5, 10, 15, 20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) rescues these Sod2tm1Cje(-/-) mutant mice from this systemic pathology and dramatically prolongs their survival. The animals instead develop a pronounced movement disorder progressing to total debilitation by three weeks of age. Neuropathologic evaluation reveals a striking spongiform degeneration of the cortex and specific brain stem nuclei associated with gliosis and intramyelinic vacuolization similar to that observed in cytotoxic edema and disorders associated with mitochondrial abnormalities such as Leighs disease and Canavans disease. We believe that due to the failure of MnTBAP to cross the blood brain barrier progressive neuropathology is caused by excessive mitochondrial production of ROS. Consequently, MnTBAP-treated Sod2tm1Cje(-/-) mice may provide an excellent model for examining the relationship between free radicals and neurodegenerative diseases and for screening new drugs to treat these disorders.
Assuntos
DNA Mitocondrial/genética , Metaloporfirinas/farmacologia , Doenças Neurodegenerativas/genética , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Animais , Encéfalo/patologia , Tronco Encefálico/patologia , Tronco Encefálico/ultraestrutura , Córtex Cerebral/patologia , Córtex Cerebral/ultraestrutura , Sequestradores de Radicais Livres/farmacologia , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/enzimologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Taxa de Sobrevida , Núcleos do Trigêmeo/patologia , Núcleos do Trigêmeo/ultraestrutura , Vacúolos/patologia , Vacúolos/ultraestruturaRESUMO
The amphibian tetradecapeptide, bombesin, and structurally related peptides caused a marked increase in ouabain-sensitive 86Rb+ uptake (a measure of Na+/K+ pump activity) in quiescent Swiss 3T3 cells. This effect occurred within seconds after the addition of the peptide and appeared to be mediated by an increase in Na+ entry into the cells. The effect of bombesin on Na+ entry and Na+/K+ pump activity was concentration dependent with half-maximal stimulation occurring at 0.3-0.4 nM. The structurally related peptides litorin, gastrin-releasing peptide, and neuromedin B also stimulated ouabain-sensitive 86Rb+ uptake; the relative potencies of these peptides in stimulating the Na+/K+ pump were comparable to their potencies in increasing DNA synthesis (Zachary, I., and E. Rozengurt, 1985, Proc. Natl. Acad. Sci. USA., 82:7616-7620). Bombesin increased Na+ influx, at least in part, through an Na+/H+ antiport. The peptide augmented intracellular pH and this effect was abolished in the absence of extracellular Na+. In addition to monovalent ion transport, bombesin and the structurally related peptides rapidly increased the efflux of 45Ca2+ from quiescent Swiss 3T3 cells. This Ca2+ came from an intracellular pool and the efflux was associated with a 50% decrease in total intracellular Ca2+. The peptides also caused a rapid increase in cytosolic free calcium concentration. Prolonged pretreatment of Swiss 3T3 cells with phorbol dibutyrate, which causes a loss of protein kinase C activity (Rodriguez-Pena, A., and E. Rozengurt, 1984, Biochem. Biophys. Res. Commun., 120:1053-1059), greatly decreased the stimulation of 86Rb+ uptake and Na+ entry by bombesin implicating this phosphotransferase system in the mediation of part of these responses to bombesin. Since some activation of monovalent ion transport by bombesin was seen in phorbol dibutyrate-pretreated cells, it is likely that the peptide also stimulates monovalent ion transport by a second mechanism.
Assuntos
Líquidos Corporais/efeitos dos fármacos , Bombesina/farmacologia , Cálcio/metabolismo , Líquido Intracelular/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Potássio/metabolismo , Sódio/metabolismo , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Linhagem Celular , Concentração de Íons de Hidrogênio , Interfase/efeitos dos fármacos , Líquido Intracelular/metabolismo , Canais Iônicos/metabolismo , Cinética , Camundongos , Oligopeptídeos/farmacologia , Dibutirato de 12,13-Forbol , Ésteres de Forbol/farmacologia , Radioisótopos/metabolismo , Rubídio/metabolismoRESUMO
The 100-fold increase in free cystine content characteristic of cultured skin fibroblasts from patients with nephropathic cystinosis was decreased more than 50 percent by addition of L-ascorbic acid to the culture medium at concentrations of 0.29 to 2.9 millimolar. Fresh ascorbic acid must be added to the culture medium daily to produce a progressive decrease of the free cystine content of the cells over a 3-day period. Upon removal of ascorbic acid from the medium, the free cystine content returns to its initial value.
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Ácido Ascórbico/farmacologia , Cistina/metabolismo , Cistinose/metabolismo , Ácido Ascórbico/uso terapêutico , Células Cultivadas , Cistinose/tratamento farmacológico , Ditiotreitol/farmacologiaRESUMO
In patients with cystinosis, the concentration of free cystine in leukocytes was 80 times greater than normal, and six times the normal content for their parents. This is the first demonstration of an abnormality in heterozygotes for this rare inherited disease of childhood. Three-quarters of the cystine was recovered in the granular fraction of cystinotic leukocytes.
Assuntos
Cistina/sangue , Cistinose/genética , Leucócitos/análise , Fosfatase Ácida/análise , Núcleo Celular , Cisteína/sangue , Grânulos Citoplasmáticos , Etilmaleimida/farmacologia , Humanos , Leucócitos/citologia , Leucócitos/enzimologia , Biologia MolecularRESUMO
Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.
Assuntos
Variação Genética , Haplótipos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Alelos , Animais , Povo Asiático/genética , População Negra/genética , Fosfatos de Dinucleosídeos/genética , Evolução Molecular , Feminino , Heterozigoto , Hispânico ou Latino/genética , Humanos , Masculino , Mutação , Pan troglodytes/genética , População Branca/genética , Cromossomo X/genéticaRESUMO
The relationships between hygiene, sexual behaviour and HIV infection are poorly understood. We examine these relationships in Indian truck drivers, a group at high risk for HIV infection. Truck drivers (n = 189) were recruited into an integrated HIV and hygiene Information Motivation (IM) programme. Sociodemographic characteristics, sexual and hygiene behaviour and HIV prevalence were determined. Multivariate logistic regression and linear generalized estimating equation models were utilized. At baseline, 2.1% of drivers were HIV infected and 34% who reported having contact with female sex workers (FSWs) had contact within the previous six months. Those who washed their hands postdefecation were less likely to report genital symptoms (OR 0.02; P = 0.01) and have sex with an FSW (OR [odds ratio] 0.21; P = 0.05). After an IM intervention, there were no changes in sexual risk-taking behaviour (coefficient -0.15 to -0.02; P = 0.13-0.75); however, hygiene behaviour improved from baseline (coefficient 0.09-0.31; P < 0.01 to P = 0.03). Personal hygiene habits, like handwashing, seem to be a modifiable behaviour after a modest intervention, whereas HIV risk-taking behaviour was not. The association between hygiene and HIV risk-taking suggests the need for further evaluation of the relationship and that of other hygiene practices in high-risk men in India.
Assuntos
Infecções por HIV/epidemiologia , Higiene , Assunção de Riscos , Comportamento Sexual , Meios de Transporte , Adulto , Feminino , Infecções por HIV/prevenção & controle , HIV-1 , Desinfecção das Mãos/métodos , Conhecimentos, Atitudes e Prática em Saúde , Inquéritos Epidemiológicos , Humanos , Índia , Entrevistas como Assunto , Masculino , Prevalência , Recursos HumanosRESUMO
Certain aminothiols rapidly deplete cultured cystinotic skin fibroblasts of their abnormally high free (nonprotein) cystine pool. The free cystine content of these cells if reduced by over 90% in 1 h with 0.1 mM cysteamine. This is more rapid than previously known methods of removing free cystine from cystinotic fibroblasts. The disulfide, cystamine, is also able to deplete cystinotic cells of free cystine. A patient with nephropathic cystinosis and end-stage renal disease was treated with cysteamine, both intravenously and orally. Both methods of administration rapidly lowered the free cystine content of the patient's peripheral leukocytes. Study of the patient's urinary sulfur excretion did not conclusively determine the effect of this therapy on the total body cystine pool. Her renal status remained at end stage after 1 mo of oral cysteamine, when an episode of grand mal seizures prompted cessation of the study. Determination of the proper place of aminothiol therapy in this disease will depend upon further clinical trial with patients whose kidney function has not deteriorated to the point of irreversible change, accompanied by careful monitoring of plasma aminothiol levels.
Assuntos
Cisteamina/análogos & derivados , Cistina/deficiência , Cistinose/tratamento farmacológico , Criança , Cistamina/uso terapêutico , Cisteamina/metabolismo , Cisteamina/uso terapêutico , Cistina/metabolismo , Feminino , Fibroblastos/metabolismo , Glutationa/metabolismo , Glutationa/uso terapêutico , Humanos , Leucócitos/metabolismo , Modelos Biológicos , OxirreduçãoRESUMO
BACKGROUND: Olfactory dysfunction is common in old age, but its basis is uncertain. OBJECTIVE: To test the hypothesis that difficulty in identifying odours in old age is related to the accumulation of Alzheimer's disease pathology. METHODS: As part of the Rush Memory and Aging Project, participants completed the 12-item Brief Smell Identification Test, a standard measure of odour identification. During a mean (standard deviation (SD)) of 2.2 (1.2) years of follow-up (range 0.2-4.9), 166 people died, with brain autopsies performed on 129 (77.7%) people and neuropathological examinations completed on 77 (mean (SD) age at death 87.5 (5.9) years; median postmortem interval 6.1 h). From a uniform postmortem examination of multiple brain regions, summary measures of plaque and tangle pathology were derived on the basis of silver staining, and those of amyloid beta burden, tangle density and Lewy bodies on the basis of immunohistochemistry. RESULTS: Odour identification performance ranged from 0 to 12 correct (mean (SD) 8.0 (2.6)). In analyses adjusted for age, sex and education, a composite measure of plaques and tangles accounted for >12% of the variation in odour identification. The association remained after controlling for dementia or semantic memory. Density of tau tangles was inversely related to odour identification. A similar effect for amyloid burden was attenuated after controlling for tangles. The association with odour identification was robust for tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites. Lewy bodies, identified in 12.5%, were not related to odour identification, probably partly due to to their relative infrequency. CONCLUSION: The results suggest that difficulty in identifying familiar odours in old age is partly due to the accumulation of neurofibrillar pathology in central olfactory regions.