RESUMO
Single electron spins bound to multi-phosphorus nuclear spin registers in silicon have demonstrated fast (0.8 ns) two-qubit SWAP gates and long spin relaxation times (~30 s). In these spin registers, when the donors are ionized, the nuclear spins remain weakly coupled to their environment, allowing exceptionally long coherence times. When the electron is present, the hyperfine interaction allows coupling of the spin and charge degrees of freedom for fast qubit operation and control. Here we demonstrate the use of the hyperfine interaction to enact electric dipole spin resonance to realize high-fidelity ( F = 10 0 - 6 + 0 %) initialization of all the nuclear spins within a four-qubit nuclear spin register. By controllably initializing the nuclear spins to â â â , we achieve single-electron qubit gate fidelities of F = 99.78 ± 0.07% (Clifford gate fidelities of 99.58 ± 0.14%), above the fault-tolerant threshold for the surface code with a coherence time of T 2 * = 12 µ s .
RESUMO
BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disorder that may involve natural killer (NK) cells. Although NK cells are part of the innate immune system, they also influence adaptive immune responses. Double-filtration plasmapheresis (DFP) is an effective therapy for MG crisis. Thus, we examined the effects of DFP on the cytotoxicity of NK cells. METHODS: A total of 20 patients with MG and 16 healthy controls were recruited for the study. Ficoll-Paque-isolated peripheral blood mononuclear cells (PBMCs) and K562 cells were used as the effector and target cells, respectively. NK cell cytotoxicity was analyzed using flow cytometry immediately before and after DFP and upon course completion. RESULTS: Double-filtration plasmapheresis treatment decreased significantly the NK cell cytotoxicity in patients with MG, especially in good responders, those who were positive for acetylcholine receptor (AChR) antibodies, and those receiving immunosuppressants. CONCLUSIONS: The decrease in NK cell cytotoxicity after DFP and the decline of AChR antibody titer were observed in good responders indicating that this could benefit patients with MG.
Assuntos
Testes Imunológicos de Citotoxicidade/métodos , Células Matadoras Naturais/imunologia , Miastenia Gravis/terapia , Plasmaferese/métodos , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Feminino , Citometria de Fluxo/métodos , Humanos , Células K562 , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Miastenia Gravis/patologia , Linfócitos T Citotóxicos/patologia , Resultado do Tratamento , Adulto JovemRESUMO
The molecular mechanisms underlying the organization of ion channels and signaling molecules at the synaptic junction are largely unknown. Recently, members of the PSD-95/SAP90 family of synaptic MAGUK (membrane-associated guanylate kinase) proteins have been shown to interact, via their NH2-terminal PDZ domains, with certain ion channels (NMDA receptors and K+ channels), thereby promoting the clustering of these proteins. Although the function of the NH2-terminal PDZ domains is relatively well characterized, the function of the Src homology 3 (SH3) domain and the guanylate kinase-like (GK) domain in the COOH-terminal half of PSD-95 has remained obscure. We now report the isolation of a novel synaptic protein, termed GKAP for guanylate kinase-associated protein, that binds directly to the GK domain of the four known members of the mammalian PSD-95 family. GKAP shows a unique domain structure and appears to be a major constituent of the postsynaptic density. GKAP colocalizes and coimmunoprecipitates with PSD-95 in vivo, and coclusters with PSD-95 and K+ channels/NMDA receptors in heterologous cells. Given their apparent lack of guanylate kinase enzymatic activity, the fact that the GK domain can act as a site for protein-protein interaction has implications for the function of diverse GK-containing proteins (such as p55, ZO-1, and LIN-2/CASK).
Assuntos
Proteínas de Transporte/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Células COS , Proteínas de Transporte/metabolismo , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Canais Iônicos , Proteínas de Membrana , Dados de Sequência Molecular , Núcleosídeo-Fosfato Quinase/metabolismo , Proteínas/genética , Ratos , Proteínas Associadas SAP90-PSD95 , Sinapses/metabolismoRESUMO
Mechanisms of ion channel clustering by cytoplasmic membrane-associated guanylate kinases such as postsynaptic density 95 (PSD-95) and synapse-associated protein 97 (SAP97) are poorly understood. Here, we investigated the interaction of PSD-95 and SAP97 with voltage-gated or Kv K(+) channels. Using Kv channels with different surface expression properties, we found that clustering by PSD-95 depended on channel cell surface expression. Moreover, PSD-95-induced clusters of Kv1 K(+) channels were present on the cell surface. This was most dramatically demonstrated for Kv1.2 K(+) channels, where surface expression and clustering by PSD-95 were coincidentally promoted by coexpression with cytoplasmic Kvbeta subunits. Consistent with a mechanism of plasma membrane channel-PSD-95 binding, coexpression with PSD-95 did not affect the intrinsic surface expression characteristics of the different Kv channels. In contrast, the interaction of Kv1 channels with SAP97 was independent of Kv1 surface expression, occurred intracellularly, and prevented further biosynthetic trafficking of Kv1 channels. As such, SAP97 binding caused an intracellular accumulation of each Kv1 channel tested, through the accretion of SAP97 channel clusters in large (3-5 microm) ER-derived intracellular membrane vesicles. Together, these data show that ion channel clustering by PSD-95 and SAP97 occurs by distinct mechanisms, and suggests that these channel-clustering proteins may play diverse roles in regulating the abundance and distribution of channels at synapses and other neuronal membrane specializations.
Assuntos
Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Células COS , Membrana Celular/metabolismo , Proteína 1 Homóloga a Discs-Large , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Canal de Potássio Kv1.1 , Canal de Potássio Kv1.2 , Canal de Potássio Kv1.4 , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Canais de Potássio/biossíntese , Frações SubcelularesRESUMO
CASK, the rat homolog of a gene (LIN-2) required for vulval differentiation in Caenorhabditis elegans, is expressed in mammalian brain, but its function in neurons is unknown. CASK is distributed in a punctate somatodendritic pattern in neurons. By immunogold EM, CASK protein is concentrated in synapses, but is also present at nonsynaptic membranes and in intracellular compartments. This immunolocalization is consistent with biochemical studies showing the presence of CASK in soluble and synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a specific interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate proteoglycan (HSPG). The interaction was confirmed by coimmunoprecipitation from heterologous cells. In brain, syndecan-2 localizes specifically at synaptic junctions where it shows overlapping distribution with CASK, consistent with an interaction between these proteins in synapses. Cell surface HSPGs can bind to extracellular matrix proteins, and are required for the action of various heparin-binding polypeptide growth/differentiation factors. The synaptic localization of CASK and syndecan suggests a potential role for these proteins in adhesion and signaling at neuronal synapses.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina , Proteoglicanas de Heparan Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Neurônios/metabolismo , Núcleosídeo-Fosfato Quinase/metabolismo , Proteoglicanas/metabolismo , Sinapses/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Encéfalo/metabolismo , Células COS , Técnica Indireta de Fluorescência para Anticorpo , Guanilato Quinases , Proteínas de Helminto , Glicoproteínas de Membrana/genética , Proteínas de Membrana , Microscopia Imunoeletrônica , Dados de Sequência Molecular , Núcleosídeo-Fosfato Quinase/genética , Proteoglicanas/genética , Coelhos , Ratos , Frações Subcelulares , Sindecana-2RESUMO
The PSD-95/SAP90 family of PDZ-containing proteins is directly involved in the clustering of specific ion channels at synapses. We report that channel clustering depends on a conserved N-terminal domain of PSD-95 that mediates multimerization and disulfide linkage of PSD-95 protomers. This N-terminal multimerization domain confers channel clustering activity on a single PDZ domain. Thus, channel clustering depends on aggregation of PDZ domains achieved by head-to-head multimerization of PSD-95, rather than by concatenation of PDZ domains in PSD-95 monomers. This mechanism predicts that PSD-95 can organize heterogeneous membrane protein clusters via differential binding specificities of its three PDZ domains. PSD-95 and its relative chapsyn-110 exist as disulfide-linked complexes in rat brain, consistent with head-to-head multimerization of these proteins in vivo.
Assuntos
Dissulfetos/química , Proteínas do Tecido Nervoso/fisiologia , Canais de Potássio/química , Canais de Potássio/metabolismo , Animais , Células COS/química , Células COS/fisiologia , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/metabolismo , Proteína 4 Homóloga a Disks-Large , Dissulfetos/metabolismo , Deleção de Genes , Guanilato Quinases , Peptídeos e Proteínas de Sinalização Intracelular , Ligantes , Proteínas de Membrana , Dados de Sequência Molecular , Mutagênese/fisiologia , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Núcleosídeo-Fosfato Quinase/genética , Núcleosídeo-Fosfato Quinase/metabolismo , Testes de Precipitina , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína , Ratos , Homologia de Sequência de Aminoácidos , Superfamília Shaker de Canais de Potássio , Transfecção , Proteínas Supressoras de TumorRESUMO
During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.
Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Ligação a DNA/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camadas Germinativas/metabolismo , Neocórtex/embriologia , Animais , Morte Celular , Movimento Celular/fisiologia , Proteínas de Ligação a DNA/genética , Óperon Lac/fisiologia , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Mutação , Neocórtex/anormalidades , Neocórtex/crescimento & desenvolvimento , Proteínas do Tecido Nervoso , Vias Neurais/fisiologia , Neurônios/metabolismo , Proteína Reelina , Serina Endopeptidases , Transmissão Sináptica , Proteínas com Domínio TRESUMO
The Omp85 proteins form a large membrane protein family in bacteria and eukaryotes. Omp85 proteins are composed of a C-terminal ß-barrel-shaped membrane domain and one or more N-terminal polypeptide transport-associated (POTRA) domains. However, Arabidopsis thaliana contains two genes coding for Omp85 proteins without a POTRA domain. One gene is designated P39, according to the molecular weight of the encoded protein. The protein is targeted to plastids and it was established that p39 has electrophysiological properties similar to other Omp85 family members, particularly to that designated as Toc75V/Oep80. We analysed expression of the gene and characterised two T-DNA insertion mutants, focusing on alterations in photosynthetic activity, plastid ultrastructure, global expression profile and metabolome. We observed pronounced expression of P39, especially in veins. Mutants of P39 show growth aberrations, reduced photosynthetic activity and changes in plastid ultrastructure, particularly in the leaf tip. Further, they display global alteration of gene expression and metabolite content in leaves of mature plants. We conclude that the function of the plastid-localised and vein-specific Omp85 family protein p39 is important, but not essential, for maintenance of metabolic homeostasis of full-grown A. thaliana plants. Further, the function of p39 in veins influences the functionality of other plant tissues. The link connecting p39 function with metabolic regulation in mature A. thaliana is discussed.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas de Membrana/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Genes de Plantas/genética , Homeostase/genética , Proteínas de Membrana/genética , Folhas de Planta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tilacoides/metabolismoRESUMO
The objectives of this study were to perform an economic evaluation of a targeted school-based dental checkup program in northern metropolitan Melbourne, Victoria. A 12-mo retrospective case-control cohort analysis using the decision tree method evaluated the incremental cost-utility and cost-effectiveness ratio (ICUR/ICER) for passive standard care dental services and an outreach pilot intervention completed in 2013. A societal perspective was adopted. A total of 273 children ( n = 273) aged between 3 and 12 y met the inclusion/exclusion criteria: 128 in the standard care group and 145 in the intervention group. The total society costs included health sector costs, patient/family costs, and productivity losses in 2014 Australian dollars. Outcome measures were evaluated using quality-adjusted tooth years (QATY) and the combined deciduous and permanent decayed, missing, and filled teeth prevented (DMFT-prevented). A generic outcome variable was created to determine the impact of the intervention to reach underserved populations based on government concession eligibility (cardholder status). Uncertainties were incorporated using 95% confidence intervals. The mean total society cost per child is $463 and $291 ( P = 0.002), QATY utility difference is 0.283 and 0.293 ( P = 0.937), effectiveness difference is 0.16 and 0.10 ( P = 0.756), and cardholder status is 50.0% and 66.2% ( P = 0.007), respectively, for the standard care and intervention groups. On average per child, there was a cost saving of $172 and improvement of 0.01 QATY, with an additional proportion of 16.2% of cardholder children reached. The calculated ICER was $3,252 per DMFT-prevented. The intervention dominates standard care for QATY and per 1% cardholder reached outcome measures. Our study found the pilot checkup program was largely less costly and more effective compared with the current standard care. Further research is needed to quantify the value of outreach interventions to prevent dental caries development and progression in populations from low socioeconomic status. Knowledge Transfer Statement: The findings of this research demonstrated that an outreach dental program can be less costly and more effective than standard models of dental care. It showed that a school-based dental checkup program is beneficial despite other opinions that dental screening is ineffective as a method to improve public dental health. There is fiscal economic evidence to support broader expansion of similar programs locally and internationally to reduce dental caries for children from low-income families.
RESUMO
In order to elucidate the dose-response relationship between ingested inorganic arsenic and internal cancers, a total of 263 patients with blackfoot disease and 2293 healthy residents in the endemic area of arseniasis were recruited and followed up for 7 years. The information on consumption of high-arsenic artesian well water, sociodemographic characteristics, life-style and dietary habits, and personal and family history of cancers was obtained through standardized interviews. The occurrence of internal cancers among study subjects was determined through annual health examinations, home visit personal interviews, household registration data checks, and national death certification and cancer registry profile linkages. A dose-response relationship was observed between the long-term arsenic exposure from drinking artesian well water and the incidence of lung cancer, bladder cancer, and cancers of all sites combined after adjustment for age, sex, and cigarette smoking through Cox's proportional hazards regression analysis. Blackfoot disease patients had a significantly increased cancer incidence after adjustment for cumulative arsenic exposure.
Assuntos
Arsênio/toxicidade , Neoplasias/epidemiologia , Poluentes Químicos da Água/toxicidade , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Pulmonares/induzido quimicamente , Masculino , Neoplasias/induzido quimicamente , Doenças Vasculares Periféricas/induzido quimicamente , Taiwan/epidemiologia , Fatores de Tempo , Neoplasias da Bexiga Urinária/induzido quimicamenteRESUMO
The syndecan family of cell surface heparan sulfate proteoglycans interacts via their cytoplasmic C-terminal tail with the PDZ domain of CASK/LIN-2, a membrane-associated guanylate kinase homolog. The syndecan-CASK interaction may be involved in intercellular signaling and/or cell adhesion. Here we show that syndecan-1 to syndecan-4 have distinctive mRNA distributions in adult rat brain by in situ hybridization, with syndecan-2 and -3 being the major syndecans expressed in neurons of the forebrain. At the protein level, syndecan-2 and -3 are differentially localized within neurons; syndecan-3 is concentrated in axons, whereas syndecan-2 is localized in synapses. The synaptic accumulation of syndecan-2 occurs late in synapse development. CASK is a cytoplasmic-binding partner for syndecans, and its subcellular distribution changes strikingly during development, shifting from a primarily axonal distribution in the first 2 postnatal weeks to a somatodendritic distribution in adult brain. This change in CASK distribution correlates temporally and spatially with the expression patterns of syndecan-3 and -2, consistent with the association of both of these syndecans with CASK in vivo. In support of this, we were able to coimmunoprecipitate a complex of CASK and syndecan-3 from brain extracts. Our results indicate that specific syndecans are differentially expressed in various cell types of the brain and are targeted to distinct subcellular compartments in neurons, where they may serve specialized functions. Moreover, CASK is appropriately expressed and localized to interact with both syndecan-2 and -3 in different compartments of the neuron throughout postnatal development.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteoglicanas de Heparan Sulfato/genética , Glicoproteínas de Membrana/genética , Neurônios/metabolismo , Proteoglicanas/genética , Sequência de Aminoácidos , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Células COS , Desenvolvimento Embrionário e Fetal , Imuno-Histoquímica , Glicoproteínas de Membrana/química , Dados de Sequência Molecular , Proteoglicanas/química , RNA Mensageiro/genética , Ratos , Proteínas Recombinantes/biossíntese , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Frações Subcelulares/metabolismo , Sinapses/metabolismo , Sindecana-1 , Sindecana-2 , Sindecana-3 , Sindecana-4 , Sindecanas , Transcrição Gênica , TransfecçãoRESUMO
Members of the postsynaptic density-95 (PSD-95)/SAP90 family of membrane-associated guanylate kinase (MAGUK) proteins function as multimodular scaffolds that organize protein-signaling complexes at neuronal synapses. MAGUK proteins contain PDZ, Src homology 3 (SH3), and guanylate kinase (GK)-like domains, all of which can function as sites for specific protein-protein interactions. We report here a direct protein-protein interaction between the SH3 domain and the GK region in the PSD-95 family of MAGUKs. The SH3 domain of the PSD-95 family appears to have an atypical binding specificity, because the classical SH3 binding (-P-X-X-P-) motif is absent from the GK domain. Although SH3-GK binding can occur in either an intramolecular or intermolecular manner, the intramolecular mode is preferred, possibly because of additional tertiary interactions available when the SH3 and GK domains are adjacent in the same polypeptide. Mutations disrupting the intramolecular SH3-GK interaction do not interfere with PSD-95 association with the K(+) channel Kv1.4 or with the GK domain-binding protein GKAP. The same mutations, however, inhibit the clustering of Kv1.4 by PSD-95, suggesting that the intramolecular SH3-GK interaction may modulate the clustering activity of PSD-95.
Assuntos
Proteínas do Tecido Nervoso/metabolismo , Núcleosídeo-Fosfato Quinase/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Domínios de Homologia de src/genética , Animais , Sítios de Ligação/fisiologia , Células COS , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Guanilato Quinases , Canal de Potássio Kv1.4 , Mutagênese/fisiologia , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Núcleosídeo-Fosfato Quinase/química , Núcleosídeo-Fosfato Quinase/genética , Mutação Puntual , Proteínas Associadas SAP90-PSD95 , Sinapses/química , Sinapses/enzimologia , Técnicas do Sistema de Duplo-Híbrido , Quinases da Família src/metabolismoRESUMO
The neurofibromatosis type 1 (NF1) gene encodes a large tumor suppressor protein (neurofibromin). Although it is known to possess Ras GTPase-activating protein (GAP) activity, the cellular role of neurofibromin remains unclear. Here we used yeast two-hybrid screening to identify neurofibromin-interacting proteins. Syndecan-2, a transmembrane heparan sulfate proteoglycan (HSPG), was isolated as a binding partner for two distinct regions of the neurofibromin protein. We subsequently found that neurofibromin can bind all four mammalian syndecans. NF1 interaction requires the transmembrane domain and a membrane-proximal region of the cytoplasmic tail of syndecan, but not the C terminus of syndecan known to bind to CASK, a membrane-associated guanylate kinase (MAGUK). Neurofibromin, syndecans, and CASK have overlapping subcellular distributions in axons and synapses of neurons, as shown by biochemical fractionation and immunostaining. Moreover, neurofibromin exists in a complex with syndecan and CASK in vivo, as evidenced by their coimmunoprecipitation from rat brain. Our findings suggest that interaction with different members of the syndecan family may be a mechanism for localizing neurofibromin to specialized domains of the plasma membrane.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina , Proteoglicanas de Heparan Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteoglicanas/metabolismo , Animais , Encéfalo/metabolismo , Química Encefálica , Guanilato Quinases , Humanos , Substâncias Macromoleculares , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Neurofibromatose 1/genética , Neurofibromina 1 , Núcleosídeo-Fosfato Quinase/metabolismo , Testes de Precipitina , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína/fisiologia , Proteoglicanas/genética , Ratos , Saccharomyces/genética , Frações Subcelulares/química , Frações Subcelulares/metabolismo , Sindecana-2 , Sindecana-3 , Sindecanas , Técnicas do Sistema de Duplo-HíbridoRESUMO
Zn-doped TiO2 nanotubes were fabricated by nanolaminated packing of alternating layers of TiO2 and ZnO by atomic layer deposition (ALD) using a polycarbonate (PC) membrane as a template. With 400 cycles of ALD, the nanotubes with a thickness of 28 nm and an outer diameter of 220 nm were obtained after removing the PC membrane by annealing at 450 °C. The doping concentration of ZnO in TiO2 depends on the precursor cycle ratio of ZnO to TiO2. With the precursor cycle ratio of ZnO : TiO2 at 0.04, a uniform bulk solubility of â¼8 at% is obtained, and the surface concentration of Zn is even higher, â¼16 at%. From the depth profiles measured by secondary ion mass spectrometry, Zn is uniformly distributed across the thickness, which is further confirmed by analyses of X-ray photoelectron spectroscopy, X-ray diffraction, and Raman spectroscopy. Additionally, from the transmission electron microscopic observation, the highly doped anatase TiO2 exhibits some regions of severe deformation that results in localized solid-state amorphization.
RESUMO
To examine the association between long-term exposure to inorganic arsenic and the prevalence of hypertension, we studied a total of 382 men and 516 women residing in villages where arseniasis was hyperendemic. Hypertension was defined as a systolic blood pressure of 160 mm Hg or greater, a diastolic blood pressure of 95 mm Hg or greater, or a history of hypertension treated regularly with antihypertensive drugs. The long-term arsenic exposure was calculated from the history of artesian well water consumption obtained through standardized interviews based on a structured questionnaire and the measured arsenic concentration in well water. Residents in villages where long-term arseniasis was hyperendemic had a 1.5-fold increase in age- and sex-adjusted prevalence of hypertension compared with residents in nonendemic areas. Duration of artesian well water consumption, average arsenic concentration in drinking water, and cumulative arsenic exposure were all significantly associated with hypertension prevalence. The higher the cumulative arsenic exposure, the higher the prevalence of hypertension. This dose-response relation remained significant after adjustment for age, sex, diabetes mellitus, proteinuria, body mass index, and serum triglyceride level. The results suggest that long-term arsenic exposure may induce hypertension in humans.
Assuntos
Arsênio/efeitos adversos , Hipertensão/epidemiologia , Poluentes Químicos da Água/efeitos adversos , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores SexuaisRESUMO
To elucidate the associations of arsenic-induced skin cancer with serum beta-carotene level and arsenic methylation capability, a total of 654 residents of age 30 or older were recruited from three arseniasis-hyperendemic villages in Taiwan and regularly examined for skin lesions during the follow-up period. There were 33 cases affected with newly diagnosed skin cancer during the follow-up, giving an incidence of 14.74 per 1000 person-years. Although most study subjects had stopped consuming high-arsenic artesian well water more than 20 years ago, the risk of skin cancer was found to increase significantly with cumulative arsenic exposure before the cessation of drinking artesian well water in a dose-response relationship. Frozen serum samples collected at the recruitment from newly developed skin cancer cases and matched controls were tested for beta-carotene levels by high-performance liquid chromatography. Frozen urine samples of these subjects were examined by high-performance liquid chromatography to speciate arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMA), and dimethylarsinic acid and then quantitated by hydride generator combined with atomic absorption spectrometry. Skin cancer cases had a significantly lower serum level of beta-carotene than matched healthy controls. Although the primary methylation capability indexed by the ratio of MMA/(AsIII + AsV) was greater in cases than in controls, the secondary methylation capability indexed by the ratio of dimethylarsinic acid/MMA was lower in cases than in controls. An elevated proportion of MMA in total urinary arsenic level was associated with an increased risk of skin cancer. Subjects with a cumulative arsenic exposure of > or = 20.0 mg/liter-year and a proportion of MMA in total urinary arsenic level >26.7% had a multivariate-adjusted odds ratio of developing skin cancer as high as 20.91 (95% confidence interval, 2.63-166.5) compared wih those who had a cumulative arsenic exposure of <20.0 mg/liter-year and a MMA percentage of < or = 26.7%. Whether the association with capability of inorganic methylation is also applied to cancers of internal organs, including lung, liver, and urinary bladder, remains to be elucidated.
Assuntos
Arsênio/efeitos adversos , Arsenicais/farmacocinética , Neoplasias Cutâneas/induzido quimicamente , Teratogênicos/farmacocinética , Poluentes Químicos da Água/efeitos adversos , beta Caroteno/sangue , Adulto , Idoso , Arsênio/farmacocinética , Arsenicais/efeitos adversos , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Metilação , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/epidemiologia , Relação Estrutura-Atividade , Taiwan/epidemiologia , Poluentes Químicos da Água/farmacocinéticaRESUMO
To elucidate the association between arsenic-related ischemic heart disease (ISHD) and serum antioxidant micronutrient level, residents aged 30 or older living in arseniasis-hyperendemic villages in Taiwan were recruited in a community-based health survey. A structured questionnaire was used to obtain a history of long-term exposure to arsenic through consuming artesian well water and fasting serum samples were also collected at the recruitment. A total of 74 patients affected with ISHD, who were diagnosed through both electrocardiography and Rose questionnaire interview, and 193 age-sex-matched healthy controls were selected for the examination of serum levels of micronutrients by high performance liquid chromatography (HPLC). There was a significant biological gradient between the risk of ISHD and the duration of consuming high-arsenic artesian well water. A significant reverse dose-response relationship with arsenic-related ISHD was observed for serum level of alpha- and beta-carotene, but not for serum levels of retinol, lycopene and alpha-tocopherol. Multivariate analysis showed a synergistic interaction on arsenic-related ISHD between duration of consuming artesian well water and low serum carotene level. An increased risk of arsenic-related ISHD was also associated with hypertension and elevated body mass index, but not with serum lipid profile, cigarette smoking and alcohol drinking. The findings seem to suggest that arsenic-related ISHD has a pathogenic mechanism which is at least partially different from that of ISHD unrelated to long-term exposure to arsenic.
Assuntos
Antioxidantes/metabolismo , Arsênio/efeitos adversos , Carotenoides/sangue , Isquemia Miocárdica/sangue , Isquemia Miocárdica/induzido quimicamente , Abastecimento de Água , Adulto , Consumo de Bebidas Alcoólicas , Cromatografia Líquida de Alta Pressão , Humanos , Licopeno , Análise Multivariada , Isquemia Miocárdica/epidemiologia , Fatores de Risco , Fumar , Fatores Socioeconômicos , Inquéritos e Questionários , Taiwan/epidemiologia , Fatores de Tempo , Vitamina A/sangue , Vitamina E/sangue , Abastecimento de Água/análise , beta Caroteno/sangueRESUMO
Arsenic is a notorious environmental toxicant known as both a carcinogen and an atherogen in human beings, but the pathogenic mechanisms are not completely understood. In cell culture studies, trivalent arsenic enhanced oxidative stress in a variety of mammalian cells, and this association may be closely associated with the development of arsenic-related diseases. To investigate the effect of arsenic exposure on oxidative stress in humans, we conducted a population study to determine the relationships of blood arsenic to reactive oxidants and antioxidant capacity at the individual level. We recruited 64 study subjects ages 42-75 years from residents of the Lanyang Basin on the northeast coast of Taiwan, where arsenic content in well water varies from 0 to > or = 3,000 microg/L. We used a chemiluminescence method, with lucigenin as an amplifier for measuring superoxide, to measure the plasma level of reactive oxidants. We used the azino-diethyl-benzthiazoline sulphate method to determine the antioxidant capacity level in plasma of each study subject. We determined arsenic concentration in whole blood by hydride formation with an atomic absorption spectrophotometer. The average arsenic concentration in whole blood of study subjects was 9.60 +/- 9.96 microg/L (+/- SD) with a range from 0 to 46.50 microg/L. The level of arsenic concentration in whole blood of study subjects showed a positive association with the level of reactive oxidants in plasma (r = +0.41, p = 0.001) and an inverse relationship with the level of plasma antioxidant capacity (r = -0.30, p = 0.014). However, we found no significant association (p = 0.266) between levels of plasma reactive oxidants and antioxidant capacity. Our results also show that the lower the primary arsenic methylation capability, the lower the level of plasma antioxidant capacity (p = 0.029). These results suggest that ingestion of arsenic-contaminated well water may cause deleterious effects by increasing the level of reactive oxidants and decreasing the level of antioxidant capacity in plasma of individuals. Persistent oxidative stress in peripheral blood may be a mechanism underlying the carcinogenesis and atherosclerosis induced by long-term arsenic exposure.
Assuntos
Antioxidantes/farmacologia , Arsênio/efeitos adversos , Arsênio/sangue , Poluentes Ambientais/efeitos adversos , Poluentes Ambientais/sangue , Estresse Oxidativo , Espécies Reativas de Oxigênio/sangue , Adulto , Idoso , Arteriosclerose/fisiopatologia , Feminino , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Neoplasias/fisiopatologia , TaiwanRESUMO
Diabetes prevalence in arseniasis-hyperendemic villages in Taiwan has been reported to be significantly higher than in the general population. The aim of this cohort study was to further evaluate the association between ingested inorganic arsenic and the incidence of non-insulin-dependent diabetes mellitus in these villages. A total of 446 nondiabetic residents in these villages were followed biannually by oral glucose tolerance test. Diabetes is defined as a fasting plasma glucose level > or = 7.8 mmol/L and/or a 2-hr post-load glucose level > or = 11.1 mmol/L. During the follow-up period of 1499.5 person-years, 41 cases developed diabetes, showing an overall incidence of 27.4/1,000 person-years. The incidence of diabetes correlated with age, body mass index, and cumulative arsenic exposure. The multivariate-adjusted relative risks were 1.6, 2.3, and 2.1 for age > or = 55 versus < 55 years, a body mass index ¿Greater/Equal to] 25 versus < 25 kg/m(2), and a cumulative arsenic exposure > or = 17 versus < 17 mg/L-years, respectively. The incidence density ratios (95% confidence intervals) between the hyperendemic villages and the two nonendemic control townships were 3.6 (3.5-3.6), 2.3 (1.1-4.9), 4.3 (2.4-7.7), and 5.5 (2.2-13.5), respectively, for the age groups of 35-44, 45-54, 55-64, and 65-74 years. The findings are consistent with our previous cross-sectional observation that ingested inorganic arsenic is diabetogenic in human beings.
Assuntos
Arsênio/efeitos adversos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Estudos de Coortes , Exposição Ambiental , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologiaRESUMO
The case of an infant with endocardial fibroelastosis and a coexistent anomalous right coronary artery that originated from the pulmonary trunk is presented. The causal relation between the two conditions is discussed.