RESUMO
OBJECTIVE: Subthreshold perceptual abnormalities are commonly used to identify individuals at clinical high risk (CHR) for developing a psychotic disorder. Predictive validity for modality-specific perceptual abnormality severity on psychosis risk is unknown. METHODS: We examined prospectively collected data from 164 individuals age 12-35 meeting criteria for CHR followed for 6-24 months or until conversion to psychosis. Using intake interview notes, baseline perceptual abnormality scores were split into auditory, visual, somatic/tactile, and olfactory/gustatory components, and auditory scores were further split into those for verbal vs non-verbal content. Relationships between perceptual abnormality characteristics and conversion were assessed with Cox proportional hazards regression and logistic regression. RESULTS: Unusual thought content and paranoia were predictive of conversion, but no modality-specific perceptual abnormality score predicted conversion status or days to conversion. However, when auditory perceptual abnormalities were further categorized as verbal vs non-verbal, the severity of verbal experiences was predictive of conversion to psychosis (P = 0.007). CONCLUSIONS: Perceptual abnormality scores failed to meaningfully predict conversion to psychosis in either direction in this CHR sample. However, verbal auditory experiences may identify a group of CHR individuals at elevated risk of conversion. Further exploration of the relationship between phenomenological aspects of perceptual abnormalities and conversion risk is warranted.
Assuntos
Alucinações/psicologia , Percepção/fisiologia , Transtornos da Percepção/psicologia , Transtornos Psicóticos/psicologia , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Alucinações/complicações , Humanos , Masculino , Transtornos Paranoides/diagnóstico , Transtornos Paranoides/psicologia , Valor Preditivo dos Testes , Sintomas Prodrômicos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/etnologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE: Predicting risk of posttraumatic stress disorder (PTSD) in the acute care setting is challenging given the pace and acute care demands in the emergency department (ED) and the infeasibility of using time-consuming assessments. Currently, no accurate brief screening for long-term PTSD risk is routinely used in the ED. One instrument widely used in the ED is the 27-item Immediate Stress Reaction Checklist (ISRC). The aim of this study was to develop a short screener using a machine learning approach and to investigate whether accurate PTSD prediction in the ED can be achieved with substantially fewer items than the IRSC. METHOD: This prospective longitudinal cohort study examined the development and validation of a brief screening instrument in two independent samples, a model development sample (N = 253) and an external validation sample (N = 93). We used a feature selection algorithm to identify a minimal subset of features of the ISRC and tested this subset in a predictive model to investigate if we can accurately predict long-term PTSD outcomes. RESULTS: We were able to identify a reduced subset of 5 highly predictive features of the ISRC in the model development sample (AUC = 0.80), and we were able to validate those findings in the external validation sample (AUC = 0.84) to discriminate non-remitting vs. resilient trajectories. CONCLUSION: This study developed and validated a brief 5-item screener in the ED setting, which may help to improve the diagnostic process of PTSD in the acute care setting and help ED clinicians plan follow-up care when patients are still in contact with the healthcare system. This could reduce the burden on patients and decrease the risk of chronic PTSD.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Estudos Prospectivos , Estudos Longitudinais , Serviço Hospitalar de EmergênciaRESUMO
AIMS/HYPOTHESIS: Our understanding of the transcription factors that control the development and function of rodent islet beta cells is advancing rapidly, yet less is known of the role they play in similar processes in human islets. METHODS: To characterise the abundance and regulation of key proteins involved in glucose-regulated insulin secretion in human islets, we examined the expression of MAFA, MAFB, GLUT2 (also known as SLC2A2), ßGK (also known as GCK) and PDX1 in isolated, highly purified human islets with an intact insulin secretory pattern. We also assessed these features in islets from two different mouse strains (C57BL/6J and FVB). RESULTS: Compared with mouse islets, human islets secreted more insulin at baseline glucose (5.6 mmol/l), but less upon stimulation with high glucose (16.7 mmol/l) or high glucose plus 3-isobutyl-1-methyl-xanthine. Human islets had relatively more MAFB than PDX1 mRNA, while mouse islets had relatively more Pdx1 than Mafb mRNA. However, v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) B protein was found in human islet alpha and beta cells. This is unusual as this regulator is only produced in islet alpha cells in adult mice. The expression of insulin, MAFA, ßGK and PDX1 was not glucose-regulated in human islets with an intact insulin secretory pattern. CONCLUSIONS/INTERPRETATION: Our results suggest that human islets have a distinctive distribution and function of key regulators of the glucose-stimulated insulin secretion pathway, emphasising the urgent need to understand the processes that regulate human islet beta cell function.
Assuntos
Regulação da Expressão Gênica , Hiperglicemia/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Via Secretória , Adolescente , Adulto , Animais , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Fator de Transcrição MafB/genética , Fator de Transcrição MafB/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/farmacologia , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/metabolismo , Via Secretória/efeitos dos fármacos , Especificidade da Espécie , Técnicas de Cultura de Tecidos , Transativadores/genética , Transativadores/metabolismo , Adulto JovemRESUMO
The mosquito fauna in many areas of western Uganda has never been studied and is currently unknown. One area, Bwamba County, has been previously studied and documented but the species lists have not been updated for >40 yr. This paucity of data makes it difficult to determine which arthropod-borne viruses pose a risk to human or animal populations. Using CO2 baited-light traps, from 2008 through 2010, 67,731 mosquitoes were captured at five locations in western Uganda including Mweya, Sempaya, Maramagambo, Bwindi (BINP), and Kibale (KNP). Overall, 88 mosquito species, 7 subspecies, and 7 species groups in 10 genera were collected. The largest number of species was collected at Sempaya (65 species), followed by Maramagambo (45), Mweya (34), BINP (33), and KNP (22). However, species diversity was highest in BINP (Simpson's Diversity Index 1-D = 0.85), followed by KNP (0.80), Maramagambo (0.79), Sempaya (0.67), and Mweya (0.56). Only six species Aedes (Aedimorphus) cumminsii (Theobald), Aedes (Neomelaniconion) circumluteolus (Theobald), Culex (Culex) antennatus (Becker), Culex (Culex) decens group, Culex (Lutzia) tigripes De Grandpre and De Charmoy, and Culex (Oculeomyia) annulioris (Theobald), were collected from all five sites suggesting large differences in species composition among sites. Four species (Aedes (Stegomyia) metallicus (Edwards), Anopheles (Cellia) rivulorum Leeson, Uranotaenia (Uranotaenia) chorleyi (Edwards), and Uranotaenia (Uranotaenia) pallidocephala (Theobald) and one subspecies (Aedes (Stegomyia) aegypti formosus (Walker)) were collected in Bwamba County for the first time. This study represents the first description of the mosquito species composition of Mweya, Maramagambo, BINP, and KNP. A number of morphological variations were noted regarding the postspiracular scales, hind tibia, and sternites that make Culex (Culex) neavei (Theobald) challenging to identify. At least 50 species collected in this study have previously been implicated in the transmission of arboviruses of public health importance suggesting a high potential for maintenance and transmission of a wide variety of arboviruses in western Uganda.
Assuntos
Biodiversidade , Culicidae , Animais , Insetos Vetores , UgandaRESUMO
AIMS/HYPOTHESIS: Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro. METHODS: We assessed insulin sensitivity and insulin secretion in aldosterone synthase-deficient (As [also known as Cyp11b2](-/-)) and wild-type mice using euglycaemic-hyperinsulinaemic and hyperglycaemic clamps, respectively. We also conducted studies during high sodium intake to normalise renin activity and potassium concentration in As (-/-) mice. We subsequently assessed the effect of aldosterone on insulin secretion in vitro in the presence or absence of mineralocorticoid receptor antagonists in isolated C57BL/6J islets and in the MIN6 beta cell line. RESULTS: Fasting glucose concentrations were reduced in As (-/-) mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentrations increased to a greater extent in As (-/-) than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As (-/-) mice even during high sodium intake. There was no difference in insulin sensitivity between As (-/-) and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose- and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol. CONCLUSIONS/INTERPRETATION: We demonstrated that aldosterone deficiency or excess modulates insulin secretion in vivo and in vitro via reactive oxygen species and in a manner that is independent of mineralocorticoid receptors. These findings provide insight into the mechanism of glucose intolerance in conditions of relative aldosterone excess.
Assuntos
Aldosterona/metabolismo , Aldosterona/farmacologia , Glucose/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Animais , Glicemia/efeitos dos fármacos , Linhagem Celular , Citocromo P-450 CYP11B2/deficiência , Citocromo P-450 CYP11B2/genética , Técnicas In Vitro , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
A 2-month-old male Holstein calf was presented for evaluation of a continuous systolic murmur. A grade V/VI left basilar continuous murmur and a grade IV/VI right basilar continuous murmur was auscultated upon evaluation with increased respiratory effort, wheezes, and crackles. Multimodality diagnostics were performed on this patient for further workup and included transthoracic and transesophageal echocardiography, fluoroscopy guided angiography, and gross necropsy with histopathology. An aortopulmonary window with continuous left-to-right shunting was identified at the level of the left aortic sinus of Valsalva with a severely dilated left coronary artery and left-sided congestive heart failure. This case report outlines the diagnostic workup of a rare congenital heart defect and secondary cardiac abnormalities not previously identified in veterinary literature.
Assuntos
Aneurisma , Cardiopatias Congênitas , Seio Aórtico , Aneurisma/veterinária , Animais , Valva Aórtica , Vasos Coronários , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/veterinária , Masculino , Imagem MultimodalRESUMO
BACKGROUND AND PURPOSE: SWI is an advanced imaging modality that is especially useful in cerebral microhemorrhage detection. Such microhemorrhages have been identified in adult contact sport athletes, and the sequelae of these focal bleeds are thought to contribute to neurodegeneration. The purpose of this study was to utilize SWI to determine whether the prevalence and incidence of microhemorrhages in adolescent football players are significantly greater than those of adolescent noncontact athletes. MATERIALS AND METHODS: Preseason and postseason SWI was performed and evaluated on 78 adolescent football players. SWI was also performed on 27 adolescent athletes who reported no contact sport history. Two separate one-tailed Fisher exact tests were performed to determine whether the prevalence and incidence of microhemorrhages in adolescent football players are greater than those of noncontact athlete controls. RESULTS: Microhemorrhages were observed in 12 football players. No microhemorrhages were observed in any controls. Adolescent football players demonstrated a significantly greater prevalence of microhemorrhages than adolescent noncontact controls (P = .02). Although 2 football players developed new microhemorrhages during the season, microhemorrhage incidence during 1 football season was not statistically greater in the football population than in noncontact control athletes (P = .55). CONCLUSIONS: Adolescent football players have a greater prevalence of microhemorrhages compared with adolescent athletes who have never engaged in contact sports. While microhemorrhage incidence during 1 season is not significantly greater in adolescent football players compared to adolescent controls, there is a temporal association between playing football and the appearance of new microhemorrhages.
Assuntos
Hemorragia Cerebral Traumática/diagnóstico por imagem , Hemorragia Cerebral Traumática/etiologia , Futebol Americano/lesões , Neuroimagem/métodos , Adolescente , Atletas , Humanos , Incidência , Imageamento por Ressonância Magnética/métodos , Masculino , PrevalênciaRESUMO
Horseradish peroxidase (HRP) in the presence of specific immunoglobulin G antibody to HRP is selectively absorbed from the gut lumen and transferred by intestinal epithelial cells to the lamina propria in newborn rats. The HRP is not transferred in detectable amounts in the absence of the antibody. Transport of maternally derived antigen via antigen-antibody complexes may have important influences on the developing immune system in young mammals.
Assuntos
Animais Recém-Nascidos/imunologia , Complexo Antígeno-Anticorpo , Antígenos , Absorção Intestinal , Jejuno/imunologia , Animais , Transporte Biológico Ativo , Feminino , Peroxidase do Rábano Silvestre/imunologia , Fragmentos Fab das Imunoglobulinas , Fragmentos Fc das Imunoglobulinas , Jejuno/metabolismo , Masculino , RatosRESUMO
Retention in the pigeon and in the goldfish was measured 1 day or 2 weeks after the mastery of each of a series of color discrimination. The amount of forgetting in the pigeon increased with the number of prior problems and increased more rapidly at the longer than at the shorter interval. the amount of forgetting in the goldfish was independent, at both intervals, of the number of prior problems. These results point to the operation of different memory mechanisms in the two animals.
Assuntos
Percepção de Cores , Columbidae , Peixes , Memória , Animais , Aprendizagem por Discriminação , TempoRESUMO
The control of arthropod-borne virus diseases such as dengue may ultimately require the genetic manipulation of mosquito vectors to disrupt virus transmission to human populations. To reduce the ability of mosquitoes to transmit dengue viruses, a recombinant Sindbis virus was used to transduce female Aedes aegypti with a 567-base antisense RNA targeted to the premembrane coding region of dengue type 2 (DEN-2) virus. The transduced mosquitoes were unable to support replication of DEN-2 virus in their salivary glands and therefore were not able to transmit the virus.
Assuntos
Aedes/virologia , Vírus da Dengue/genética , Dengue/transmissão , Insetos Vetores/virologia , RNA Antissenso/genética , Aedes/genética , Animais , Vírus da Dengue/fisiologia , Sistema Digestório/virologia , Feminino , Engenharia Genética , Vetores Genéticos , Genoma Viral , Humanos , Insetos Vetores/genética , Glândulas Salivares/virologia , Sindbis virus/genética , Replicação ViralRESUMO
A new strain of Culex flavivirus (family Flaviviridae, genus Flavivirus, CxFV), an insect virus first described in Japan, was isolated from adult Culex quinquefasciatus Say (Diptera: Culicidae) collected in 2006 from Izabal Department on the Caribbean coast of Guatemala. Mosquito pools were assayed for flavivirus RNA by using flavivirus group-specific primers that amplified a 720-bp region of the nonstructural (NS) 5 gene by standard reverse transcriptase-polymerase chain reaction. From 210 pools (1,699 mosquitoes), eight tested positive, and six of these mosquito pools produced virus isolates in Aedes albopictus Skuse C6/36 cells. Nucleotide sequence comparison of the eight flavivirus RNA-positive pools showed that there was 100% identity among them, and phylogenetic analysis of the NS5 and envelope gene regions indicated that they represent a strain of the recently described CxFV from Japan. This is the first report of an insect flavivirus from Central America.
Assuntos
Culex/virologia , Flavivirus/isolamento & purificação , Animais , Feminino , Flavivirus/genética , Guatemala , Dados de Sequência Molecular , Filogenia , RNA Viral/genética , Alinhamento de Sequência , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genéticaRESUMO
Despite evidence of arbovirus activity in northwestern Uganda (West Nile Sub-region), there is very limited information on the mosquito fauna of this region. The only published study reported 52 mosquito species in northwestern Uganda but this study took place in 1950 and the information has not been updated for more than 60 yr. In January and June 2011, CO2 baited-light traps were used to collect 49,231 mosquitoes from four different locations, Paraa (9,487), Chobe (20,025), Sunguru (759), and Rhino Camp (18,960). Overall, 72 mosquito species representing 11 genera were collected. The largest number of distinct species was collected at Chobe (43 species), followed by Paraa (40), Sunguru (34), and Rhino Camp (25). Only eight of the 72 species (11.1%) were collected from all four sites: Aedes (Stegomyia) aegypti formosus (Walker), Anopheles (Cellia) funestus group, Culex (Culex) decens group, Cx. (Culex) neavei Theobald, Cx. (Culex) univittatus Theobald, Cx. (Culiciomyia) cinereus Theobald, Cx. (Oculeomyia) poicilipes (Theobald), and Mansonia (Mansonoides) uniformis (Theobald). Fifty-four species were detected in northwestern Uganda for the first time; however, these species have been detected elsewhere in Uganda and do not represent new introductions to the country. Thirty-three species collected during this study have previously been implicated in the transmission of arboviruses of public health importance.
Assuntos
Distribuição Animal , Culicidae/fisiologia , Animais , Culicidae/classificação , UgandaRESUMO
We have identified a novel 69-kD peptide autoantigen (ICA69) associated with insulin-dependent diabetes mellitus (IDDM) by screening a human islet lambda gt11 cDNA expression library with cytoplasmic islet cell antibody positive sera from relatives of IDDM patients who progressed to the overt disease. The deduced open reading frame of the ICA69 cDNA predicts a 483-amino acid protein. ICA69 shows no nucleotide or amino acid sequence relation to any known sequence in GenBank, except for two short regions of similarity with BSA. The ICA69 cDNA probe hybridizes with a 2-kb mRNA in poly(A+) RNA from human pancreas, brain, heart, thyroid, and kidney, but not with skeletal muscle, placenta, spleen, or ovary. Expression of ICA69 was also detected in beta cells and cell lines, as well as in tumoral tissue of islet cell origin. The native ICA69 molecule migrates to 69 kD in SDS-PAGE as detected with specific antibodies. Serum samples from relatives of IDDM patients specifically reacted with affinity-purified recombinant ICA69 on Western blotting. The structural gene for ICA69 was designated ICA1. A homologue in the mouse, designated Ica-1 was mapped to the proximal end of chromosome 6 (within 6 cM of the Met protooncogene). ICA69 adds a novel autoantigen to the family of identified islet target molecules, and by the manner of its identification and characterization large amounts of antigen are available for development of quantitative, convenient predictive assays for autoantibodies and analysis of the role of this molecule in diabetes autoimmunity, as well as its physiologic function.
Assuntos
Autoantígenos/genética , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Sequência de Aminoácidos , Animais , Autoantígenos/química , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , Cricetinae , DNA/genética , Expressão Gênica , Ligação Genética , Humanos , Técnicas Imunoenzimáticas , Camundongos , Dados de Sequência Molecular , Peso Molecular , Oligodesoxirribonucleotídeos/química , RNA Mensageiro/genética , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , TransfecçãoRESUMO
A Xenopus oocyte expression system was used to examine how glucose transporters (GLUT 2 and GLUT 3) and glucokinase (GK) activity affect glucose utilization. Uninjected oocytes and low rates of both glucose transport and phosphorylation; expression of GLUT 2 or GLUT 3 increased glucose phosphorylation approximately 20-fold by a low Km, endogenous hexokinase at glucose concentrations < or = 1 mM, but not at higher glucose concentrations. Coexpression of functional GK isoforms with GLUT 2 or 3 increased glucose utilization approximately an additional two- to threefold primarily at the physiologic glucose concentrations of 5-20 mM. The Km for glucose of both the hepatic and beta cell isoforms of GK, determined in situ, was approximately 5-10 mM when coexpressed with either GLUT 2 or GLUT 3. The increase in glucose utilization by coexpression of GLUT 3 and GK was dependent upon glucose phosphorylation since two missense GK mutations linked with maturity-onset diabetes, 182: Val-->Met and 228:Thr-->Met, did not increase glucose utilization despite accumulation of both a similar amount of immunoreactive GK protein and glucose inside the cell. Coexpression of a mutant GK and a normal GK isoform did not interfere with the function of the normal GK enzyme. Since the coexpression of GK and a glucose transporter in oocytes resembles conditions in the hepatocyte and pancreatic beta cell, these results indicate that increases in glucose utilization at glucose concentrations > 1 mM depend upon both a functional glucose transporter and GK.
Assuntos
Glucoquinase/genética , Glucose/metabolismo , Proteínas de Transporte de Monossacarídeos/genética , Proteínas do Tecido Nervoso , Oócitos/metabolismo , Animais , Transporte Biológico , Feminino , Expressão Gênica , Glucoquinase/metabolismo , Transportador de Glucose Tipo 2 , Transportador de Glucose Tipo 3 , Humanos , Cinética , Proteínas de Transporte de Monossacarídeos/metabolismo , Fosforilação , Mutação Puntual/fisiologia , RNA Mensageiro , Xenopus laevisRESUMO
Over a thousand combinations of polyanions and polycations were tested to search for new polymer candidates that would be suitable for encapsulation of living cells. The combination of sodium alginate, cellulose sulfate, poly (methylene-co-guanidine) hydrochloride, calcium chloride, and sodium chloride was most promising. In parallel, a novel multiloop chamber reactor was developed to control the time of complex formation and to negate gravitational effects such as pancreatic islet sedimentation and droplet deformation during the encapsulation process. Encapsulated rat islets demonstrated glucose-stimulated insulin secretion in vitro, and reversed diabetes in mice. This new capsule formulation and encapsulation system allows independent adjustments of capsule size, wall thickness, mechanical strength, and permeability, which may offer distinct advantages for immunoisolating cells.
Assuntos
Materiais Biocompatíveis , Cultura em Câmaras de Difusão , Transplante das Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas/métodos , Polímeros , Animais , Biotecnologia , Cápsulas , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/cirurgia , Feminino , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Transplante das Ilhotas Pancreáticas/fisiologia , Masculino , Teste de Materiais , Membranas Artificiais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Permeabilidade , Coelhos , Ratos , Ratos Sprague-Dawley , Transplante HeterólogoRESUMO
Some people hear voices that others do not, but only some of those people seek treatment. Using a Pavlovian learning task, we induced conditioned hallucinations in four groups of people who differed orthogonally in their voice-hearing and treatment-seeking statuses. People who hear voices were significantly more susceptible to the effect. Using functional neuroimaging and computational modeling of perception, we identified processes that differentiated voice-hearers from non-voice-hearers and treatment-seekers from non-treatment-seekers and characterized a brain circuit that mediated the conditioned hallucinations. These data demonstrate the profound and sometimes pathological impact of top-down cognitive processes on perception and may represent an objective means to discern people with a need for treatment from those without.
Assuntos
Encéfalo/fisiologia , Condicionamento Clássico , Alucinações/psicologia , Percepção , Estimulação Acústica , Adulto , Simulação por Computador , Feminino , Alucinações/fisiopatologia , Audição , Humanos , Masculino , Modelos Neurológicos , Rede Nervosa , Neuroimagem , Estimulação Luminosa , Transtornos Psicóticos/fisiopatologia , Transtornos Psicóticos/psicologia , VozRESUMO
SV40 was first identified as a contaminant of poliovaccines used from 1955 until 1963. Recently, SV40 has been detected in several human tumors. The virus detected in human tumors often contained only one 72-bp enhancer in the regulatory region, in contrast to the SV40 originally isolated from poliovaccines, which contained two 72-bp enhancers. The origin of viruses with one 72-bp enhancer in humans was unknown, because it was thought that these viruses were not present in poliovaccines. It was also thought that all poliovaccine vials produced from 1955 until 1963 had been discarded, thus the possibility that one 72-bp virions contaminated those vials could not be tested. We unexpectedly obtained what appear to be the last available vials of poliovaccine produced in 1955. In these vials, we detected and sequenced SV40 containing only one 72-bp enhancer in the regulatory region. The tissue culture cytopathic test currently used in the United States to screen oral poliovaccines was designed to detect rapidly proliferating SV40 virions containing two 72-bp enhancers. We found that this test is not sensitive enough to detect low amounts of the slow-replicating SV40 virions containing one 72-bp enhancer. This virus was easily detected in the same cells by immunostaining and PCR. Twelve current vials of poliovaccines tested uniformly negative for SV40, suggesting that the precaution of preparing poliovaccines from kidneys obtained from monkeys bred in isolated colonies prevented SV40 contamination. Our data demonstrate that humans were exposed to SV40 viruses with both one 72-bp enhancer and two 72-bp enhancers SV40 through contaminated vaccines. Our data also suggest that instead of cytopathic tests, immunohistochemical and/or molecular studies should be used to screen poliovaccines for SV40 to completely eliminate the risk of occasional contamination.
Assuntos
Contaminação de Medicamentos , Vacina Antipólio de Vírus Inativado/genética , Vírus 40 dos Símios/isolamento & purificação , Animais , Sequência de Bases , Células Cultivadas , Chlorocebus aethiops , DNA Viral/análise , História do Século XX , Humanos , Dados de Sequência Molecular , Vacina Antipólio de Vírus Inativado/história , Homologia de Sequência do Ácido Nucleico , Vírus 40 dos Símios/classificação , Vírus 40 dos Símios/genéticaRESUMO
Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.
Assuntos
Asbesto Crocidolita/toxicidade , Mesotelioma/etiologia , Neoplasias Peritoneais/etiologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Animais , Asbesto Crocidolita/administração & dosagem , Líquido Ascítico/química , Quimiocinas/análise , Citocinas/análise , Relação Dose-Resposta a Droga , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Leucócitos/patologia , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/fisiologia , Masculino , Mesotelioma/genética , Camundongos , Camundongos Endogâmicos C57BL , Fibras Minerais/toxicidade , Neoplasias Peritoneais/genética , Peritonite/etiologia , Peritonite/genética , Distribuição Aleatória , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/fisiologiaRESUMO
BACKGROUND: Data regarding the viremia profile of chikungunya virus (CHIKV) infected patients especially during the pre-febrile period is limited. OBJECTIVE: To obtain virological kinetic data on CHIKV infections. STUDY DESIGN: A two-week community observation for dengue transmission was conducted in Bandung, Indonesia, from 2005 to 2009. Acute specimens from non-dengue febrile patients were screened by pan-alphavirus conventional RT-PCR. The positives were confirmed for CHIKV RNA by a specific RT-PCR followed by sequencing. Simultaneously these specimens were also cultured in Vero cells and tested for anti-CHIK IgM MAC-ELISA. All the available serial specimens,including the pre-febrile specimens, from confirmed CHIK cases, were tested by virus isolation, RT-PCR, qRT-PCR, and CHIK IgM ELISA. RESULTS: There were five laboratory confirmed CHIK cases identified and studied. Among these, viremia was determined to extend from as early as 6 days prior to until 13 days post fever onset. Quantitative RT-PCR showed viremia peaked at or near onset of illness. CONCLUSION: In this study, individuals were identified with viremia prior to fever onset and extending beyond the febrile phase. This extended viremic phase has the potential to impact transmission dynamics and thus the public health response to CHIK outbreaks.