RESUMO
Genomic data provides useful information for public health practice, particularly when combined with epidemiologic data. However, sampling bias is a concern because inferences from nonrandom data can be misleading. In March 2021, the Washington State Department of Health, USA, partnered with submitting and sequencing laboratories to establish sentinel surveillance for SARS-CoV-2 genomic data. We analyzed available genomic and epidemiologic data during presentinel and sentinel periods to assess representativeness and timeliness of availability. Genomic data during the presentinel period was largely unrepresentative of all COVID-19 cases. Data available during the sentinel period improved representativeness for age, death from COVID-19, outbreak association, long-term care facility-affiliated status, and geographic coverage; timeliness of data availability and captured viral diversity also improved. Hospitalized cases were underrepresented, indicating a need to increase inpatient sampling. Our analysis emphasizes the need to understand and quantify sampling bias in phylogenetic studies and continue evaluation and improvement of public health surveillance systems.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , Washington/epidemiologia , Vigilância de Evento Sentinela , Filogenia , GenômicaRESUMO
Brucellosis is a systemic bacterial zoonotic disease with potential endovascular complications including endocarditis, although multifocal vasculopathy is rare. Moreover, swine-associated human infections are less common since brucellosis was eradicated in commercial swine in U.S. states and territories. However, feral swine continue to serve as a reservoir for Brucella suis. We describe the case of a feral swine hunter who presented with fever and respiratory symptoms and was diagnosed with pulmonary embolus. Blood cultures revealed growth of Brucella, later confirmed as Brucella suis. Despite initial appropriate antimicrobial therapy, he maintained fever with worsening knee pain, and magnetic resonance imaging and two-dimensional echocardiography subsequently confirmed the presence of a thrombosed popliteal artery aneurysm and mitral valve vegetation, respectively. To our knowledge, this is the first report of contemporaneous venous and arterial thromboembolism attributable to B. suis infection.
RESUMO
Humanitarian policies aimed at welcoming forced migrants may yield unexpected economic dividends. This article focuses on the trade and investment links forged by refugees between their countries of resettlement and the origins they fled. We document how such immigrant-links differ in the case of refugees, focusing on why their opportunity sets might differ and the difficulties in establishing economic connections against a backdrop of civil conflict and political unrest. We conclude by discussing a range of policies aimed at engaging refugee diasporas to foster development at refugees' origins.
RESUMO
BACKGROUND: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-ß (Aß) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. OBJECTIVE: In the present study, we want to detail the interactions of inhalational anesthetics with Aß-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aß oligomerization and Aß-mediated neurotoxicity on processes related to cognition. METHODS: Oligomerization of Aß1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aß1-42, Aß1-40, pyroglutamate-modified amyloid-(AßpE3), and nitrated Aß (3NTyrAß), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aß plaque burden in transgenic AD mice (ArcAß) after anesthesia. RESULTS: Whereas isoflurane and sevoflurane did not affect Aß1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AßpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aß1-42-induced spine density attenuation. In the presence of Aß1-40 and AßpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aß1-42 or 3NTyrAß, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAß mice. CONCLUSION: None of the anesthetics aggravated Aß-derived AD pathology in vivo. However, Aß and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aß1-42 aggregation, LTP, and spine density.
Assuntos
Doença de Alzheimer/fisiopatologia , Anestésicos Inalatórios/administração & dosagem , Isoflurano/administração & dosagem , Placa Amiloide/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Xenônio/administração & dosagemRESUMO
Soil organic matter (SOM) is known to exert a major control on the mobility and bioavailability of cationic nutrients. However, the role of SOM in the fate of anionic nutrients, especially phosphorus (P), is less well characterized. The objectives of this study were to (1) compare the formation of binary complexes of calcium (Ca) with humic acids (HA) extracted from two contrasting soils, and (2) determine if binary HA-Ca complexes could incorporate P by forming ternary HA-Ca-P complexes. The Ca binding capacities of the HA extracted from an agricultural organic soil (AOS) and a pristine riparian soil (RS) were measured via potentiometric titrations; the formation of ternary complexes was analyzed by size fractionation using MWCO tubes. Proton and Ca binding capacities of RS-HA were higher than AOS-HA, and pH had a weaker effect on Ca binding to RS-HA. These differences are consistent with lower proportions of aromatic groups, and a higher proportion of alkyl groups derived from 13C NMR spectroscopy. Together, the NMR, titration and MWCO data indicate that Ca binds to RS-HA through monodentate complexes and electrostatic attraction that are capable of binding P producing ternary complexes. In contrast, at pH 8.5 Ca forms bidentate complexes with AOS-HA, which do not provide bridging positions to incorporate P. Overall, our results imply that the formation of HA-Ca and HA-Ca-P complexes depend on the structure of the HA, and that complexation to HA may play an important role in the fate of P in terrestrial and aquatic environments.
Assuntos
Cálcio/química , Fósforo/análise , Poluentes do Solo/análise , Ânions , Cálcio da Dieta , Cátions , Substâncias Húmicas/análise , Minerais , Solo/química , Poluentes do Solo/químicaRESUMO
Treatment of postsurgical iatrogenic ventricular septal defects (VSDs) remains a challenge. Surgical closure is associated with significant morbidity and mortality. A peripheral accessed percutaneous approach is faced with difficulties of gaining adequate access and complex positioning in a beating heart. We report a case of using a hybrid approach to treat iatrogenic VSD with surgical right atriotomy and delivery of an Amplatzer system under direct visualization and transesophageal echocardiography guidance.
Assuntos
Ecocardiografia Transesofagiana/métodos , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/cirurgia , Dispositivo para Oclusão Septal , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Septo Interventricular/diagnóstico por imagem , Septo Interventricular/cirurgiaRESUMO
Campylobacter species are common causes of diarrheal illness following consumption of contaminated food or unpasteurized dairy products, but subsequent dissemination and joint space infections are rare. We describe a patient who consumed undercooked chicken wings, with subsequent development of a febrile gastrointestinal illness marked by copious, watery stool output. This was followed by acute onset of pain and inability to bear weight on his right hip and leg where he had undergone prior arthroplasty. Synovial fluid cultures revealed Campylobacter coli, identified utilizing matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The patient made a full recovery following hip joint space debridement with prosthesis retention, coupled with sequential intravenous and oral ciprofloxacin therapy. This case highlights both the potential for prosthetic joint infection with Campylobacter coli following diarrheal illness, as well as challenges in reducing Campylobacter contamination within commercially distributed chicken wings.
RESUMO
IMPORTANCE: Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. OBJECTIVE: The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. DESIGN, SETTING, AND PARTICIPANTS: Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/µL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. INTERVENTIONS: Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. MAIN OUTCOMES AND MEASURES: Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. RESULTS: Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/µL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. CONCLUSIONS AND RELEVANCE: Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/µL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02595866.
Assuntos
Cisto Broncogênico/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Ecocardiografia Transesofagiana/métodos , Veia Cava Superior/diagnóstico por imagem , Veia Cava Superior/fisiopatologia , Adulto , Cisto Broncogênico/fisiopatologia , Humanos , MasculinoRESUMO
BACKGROUND: It is controversially discussed whether general anaesthesia increases the risk of Alzheimer's disease (AD) or accelerates its progression. One important factor in AD pathogenesis is the accumulation of soluble amyloid beta (Aß) oligomers which affect N-methyl-d-aspartate (NMDA) receptor function and abolish hippocampal long-term potentiation (LTP). NMDA receptor antagonists, at concentrations allowing physiological activation, can prevent Aß-induced deficits in LTP. The anaesthetics xenon and S-ketamine both act as NMDA receptor antagonists and have been reported to be neuroprotective. In this study, we investigated the effects of subanaesthetic concentrations of these drugs on LTP deficits induced by different Aß oligomers and compared them to the effects of radiprodil, a NMDA subunit 2B (GluN2B)-selective antagonist. METHODS: We applied different Aß oligomers to murine brain slices and recorded excitatory postsynaptic field potentials before and after high-frequency stimulation in the CA1 region of hippocampus. Radiprodil, xenon and S-ketamine were added and recordings evoked from a second input were measured. RESULTS: Xenon and radiprodil, applied at low concentrations, partially restored the LTP deficit induced by pre-incubated Aß1-42. S-ketamine showed no effect. None of the drugs tested were able to ameliorate Aß1-40-induced LTP-deficits. CONCLUSIONS: Xenon administered at subanaesthetic concentrations partially restored Aß1-42-induced impairment of LTP, presumably via its weak NMDA receptor antagonism. The effects were in a similar range than those obtained with the NMDA-GluN2B antagonist radiprodil. Our results point to protective properties of xenon in the context of pathological distorted synaptic physiology which might be a meaningful alternative for anaesthesia in AD patients.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Anestésicos/administração & dosagem , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Xenônio/administração & dosagem , Acetamidas/administração & dosagem , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Camundongos , Piperidinas/administração & dosagemRESUMO
We investigated the impacts of resource access roads on soil enzyme activities in contrasting forested boreal peatlands (bog and fen). In August 2016, a total of 72 peat samples were collected from twelve 20â¯m long transects perpendicular to access roads, with a further six samples collected from undisturbed reference areas. Sampling locations represent a range in three variables associated with roads: 1) side of the road (upstream/downstream), 2) distance to a culvert (longitudinal; <2 and >20â¯m), and 3) distance from the road (lateral; 2, 6, and 20â¯m). Phenol oxidase and hydrolase (glucosidase, sulfatase, xylosidase, glucosaminidase, and phosphatase) enzyme activities were determined for each sample, in addition to water table depth, phenolic concentration, pH, and peat temperature. The average hydrolase activities in the fen were ~four times higher than in the bog. At the bog, the water table depth, phenolic concentration, pH and the activities of phenol oxidase, sulfatase, glucosidase, xylosidase and glucosaminidase were all significantly influenced by one or more road associated factors. The highest enzyme activities in the bog occurred on the downstream side of the road at plots located far from the culvert. In contrast, the flow of water in the fen was not perpendicular to the road. Consequently, no significant variations in water table depth, phenolic concentration, pH or enzyme activity were found with respect to road associated factors. Results indicate that road crossings in boreal peatlands can indirectly alter enzyme activities, likely as part of a causal chain following changes to hydrology and redox conditions. Two of six investigated enzymes had significantly higher activities in the road disturbed areas compared to undisturbed areas, suggesting ultimately that roads may enhance organic matter decomposition rates. However, adequate hydrologic connections through culverts and road construction parallel to the water flow can minimize the road-induced impacts.
RESUMO
A livestock farmer with a history of arthropathy presented with unilateral olecranon bursal swelling and tenderness. Multiple wound and intraoperative cultures revealed growth of Trueperella bernardiae, a Gram-positive coccobacillus, with symptom resolution following appropriate antimicrobial therapy. To our knowledge, this is the first case report of olecranon bursitis caused by this organism. Coryneform bacteria are often regarded as contaminants in clinical cultures, but advanced techniques for species identification may reveal expanded pathogenic potential of individual species like T. bernardiae and elucidate epidemiologic clues for osteoarticular infections in these cases.
RESUMO
BACKGROUND: Biliary atresia is a life-threatening disease characterised by progressive destruction of both intra- and extra-hepatic biliary ducts. The mainstay of treatment is Kasai portoenterostomy, as soon as the disease has been confirmed. Glucocorticosteroids are steroid hormones which act on the glucocorticoid receptor and have a range of metabolic and immunomodulatory effects. Glucocorticosteroids are used to improve the postoperative outcomes in infants who have undergone Kasai portoenterostomy. OBJECTIVES: To assess the beneficial and harmful effects of glucocorticosteroid administration versus placebo or no intervention following Kasai portoenterostomy in infants with biliary atresia. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded (Web of Science), and online trial registries (last search: 20 December 2017) for randomised controlled trials. SELECTION CRITERIA: We included randomised clinical trials which assessed glucocorticosteroids for infants who have undergone Kasai portoenterostomy. For harm, we also considered quasi-randomised studies, observational studies, and case-control studies that were identified amongst the search results. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed the risk of bias for each trial according to prespecified domains. We analysed data using both random-effects and fixed-effect models. We performed the analyses using Review Manager 5.3 and Trial Sequental Analysis software. We considered a P value of 0.025 or less, two-tailed, as statistically significant. We planned to calculate risk ratios (RRs) for dichotomous outcomes, and the mean difference (MD) for continuous outcomes. For all association measures, we planned to use 95% confidence intervals (CIs) as well as Trial Sequential Analysis-adjusted CIs. We used Trial Sequential Analyisis to control the risks of random errors; however, we were often unable to implement this beyond calculating the required information size as there were few trials and data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We found two randomised controlled trials fulfilling the inclusion criteria of our review. The trials provided data for meta-analysis. We judged the two trials as trials at low risk of bias. The two trials randomised a total of 213 infants to glucocorticosteroids versus placebo. In our Trial Sequential Analysis, the required information size (that is, the meta-analytic sample size) was not reached for any outcome. Trials were funded by charities, public organisations, and received support from private sector companies, none of which seemed to have an interest in the outcome of the respective trials. The effect of glucocorticosteroids after Kasai portoenterostomy on all-cause mortality is uncertain; the confidence interval is consistent with appreciable benefit and harm (RR 1.00; 95% CI 0.14 to 6.90; low-certainty evidence). The results showed little or no difference in adverse effects between the use of glucocorticosteroids or placebo after Kasai portoenterostomy, however this analysis was based on a single trial and we have low certainty in the result (RR 1.02; 95% CI 0.87 to 1.20;). Available data suggest that the proportions of infants who do not clear their jaundice at six months is similar between the two groups (RR 0.89; 95% CI 0.67 to 1.17; low-certainty evidence). All-cause mortality or liver transplantation did not differ at two years between the two groups (RR 1.00; 95% CI 0.72 to 1.39; low-certainty evidence). There were no data regarding health-related quality of life.Our searches also yielded 19 observational studies, some of them containing limited information on harmful effects of glucocorticosteroid treatment. We presented the extracted information narratively. We identified one further ongoing trial with no currently available results. AUTHORS' CONCLUSIONS: The two meta-analysed randomised clinical trials present insufficient evidence to determine the effects of using glucocorticosteroids versus placebo after Kasai portoenterostomy in infants with biliary atresia on any of the primary or secondary review outcomes. There is insufficient evidence to support glucocorticosteroid use in the postoperative management of infants with biliary atresia for long-term outcomes of all-cause mortality or liver transplantation. It is also unclear if glucocorticosteroids are able to reduce the numbers of infants who did not clear their jaundice by six months. Further randomised, placebo-controlled trials are required to be able to determine if glucocorticosteroids may be of benefit in the postoperative management of infants with biliary atresia treated with Kasai portoenterostomy. Such trials need to be conducted as multicentre trials.
Assuntos
Atresia Biliar/tratamento farmacológico , Glucocorticoides/uso terapêutico , Portoenterostomia Hepática/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Atresia Biliar/etiologia , Atresia Biliar/mortalidade , Humanos , Lactente , Transplante de Fígado/estatística & dados numéricos , Portoenterostomia Hepática/métodos , Portoenterostomia Hepática/mortalidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVES: Trauma is a significant cause of morbidity and mortality worldwide. The literature on paediatric trauma epidemiology in low- and middle-income countries (LMICs) is limited. This study aims to gather epidemiological data on paediatric trauma. METHODS: This is a multicentre prospective cohort study of paediatric trauma admissions, over 1 month, from 15 paediatric surgery centres in 11 countries. Epidemiology, mechanism of injury, injuries sustained, management, morbidity and mortality data were recorded. Statistical analysis compared LMICs and high-income countries (HICs). RESULTS: There were 1377 paediatric trauma admissions over 31 days; 1295 admissions across ten LMIC centres and 84 admissions across five HIC centres. Median number of admissions per centre was 15 in HICs and 43 in LMICs. Mean age was 7 years, and 62% were boys. Common mechanisms included road traffic accidents (41%), falls (41%) and interpersonal violence (11%). Frequent injuries were lacerations, fractures, head injuries and burns. Intra-abdominal and intra-thoracic injuries accounted for 3 and 2% of injuries. The mechanisms and injuries sustained differed significantly between HICs and LMICs. Median length of stay was 1 day and 19% required an operative intervention; this did not differ significantly between HICs and LMICs. No mortality and morbidity was reported from HICs. In LMICs, in-hospital morbidity was 4.0% and mortality was 0.8%. CONCLUSION: The spectrum of paediatric trauma varies significantly, with different injury mechanisms and patterns in LMICs. Healthcare structure, access to paediatric surgery and trauma prevention strategies may account for these differences. Trauma registries are needed in LMICs for future research and to inform local policy.
Assuntos
Ferimentos e Lesões/epidemiologia , Acidentes por Quedas/estatística & dados numéricos , Acidentes de Trânsito/estatística & dados numéricos , Adolescente , Queimaduras/epidemiologia , Criança , Traumatismos Craniocerebrais/epidemiologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Sistema de Registros , Traumatismos Torácicos/epidemiologiaRESUMO
HIV-associated neurocognitive disorders (HAND) affects more than half of persons living with HIV-1/AIDS (PLWHA). Identification of biomarkers representing the cognitive status of PLWHA is a critical step for implementation of successful cognitive, behavioral and pharmacological strategies to prevent onset and progression of HAND. However, the presence of co-morbidity factors in PLWHA, the most common being substance abuse, can prevent the identification of such biomarkers. We have optimized a protocol to profile plasma miRNAs using quantitative RT-qPCR and found a miRNA signature with very good discriminatory ability to distinguish PLWHA with cognitive impairment from those without cognitive impairment. Here, we have evaluated this miRNA signature in PLWHA with alcohol use disorder (AUD) at LSU Health Sciences Center (LSUHSC). The results show that AUD is a potential confounding factor for the miRNAs associated with cognitive impairment in PLWHA. Furthermore, we have investigated the miRNA signature associated with cognitive impairment in an independent cohort of PLWHA using plasma samples from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) program. Despite differences between the two cohorts in socioeconomic status, AUD, and likely misuse of illicit or prescription drugs, we validated a miRNA signature for cognitive deficits found at LSUHSC in the CHARTER samples.
RESUMO
Hypothyroidism is a common comorbidity that on acute presentation is often overlooked. It can be an easily managed condition; however non-compliance can have severe consequences. In the presented case it was requirement for emergency surgery that resulted in stoma formation. This case is a first example of the need to include patient's decision making process with regards to medication adherence in the setting of chronic disease.
Assuntos
Constipação Intestinal/complicações , Hipotireoidismo/complicações , Perfuração Intestinal/etiologia , Constipação Intestinal/etiologia , Constipação Intestinal/cirurgia , Feminino , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Humanos , Perfuração Intestinal/cirurgia , Pessoa de Meia-Idade , Cooperação do PacienteRESUMO
BACKGROUND: Epstein-Barr Virus (EBV) is associated with hematopoietic malignancies, such as Burkitt's lymphoma, post-transplantation lymphoproliferative disorder, and diffuse large B-cell lymphoma. The current approach for EBV-associated lymphoma involves chemotherapy to eradicate cancer cells, however, normal cells may be injured and organ dysfunction may occur with currently employed regimens. This research is focused on employing arsenic trioxide (ATO) as EBV-specific cancer therapy takes advantage of the fact the EBV resides within the malignant cells. METHODS AND RESULTS: Our research reveals that low ATO inhibits EBV gene expression and genome replication. EBV spontaneous reactivation starts as early as 6 h after re-suspending EBV-positive Mutu cells in RPMI media in the absence of ATO, however this does not occur in Mutu cells cultured with ATO. ATO's inhibition of EBV spontaneous reactivation is dose dependent. The expression of the EBV immediate early gene Zta and early gene BMRF1 is blocked with low concentrations of ATO (0.5 nM - 2 nM) in EBV latency type I cells and EBV-infected PBMC cells. The combination of ATO and ganciclovir further diminishes EBV gene expression. ATO-mediated reduction of EBV gene expression can be rescued by co-treatment with the proteasome inhibitor MG132, indicating that ATO promotes ubiquitin conjugation and proteasomal degradation of EBV genes. Co-immunoprecipitation assays with antibodies against Zta pulls down more ubiquitin in ATO treated cell lysates. Furthermore, MG132 reverses the inhibitory effect of ATO on anti-IgM-, PMA- and TGF-ß-mediated EBV reactivation. Thus, mechanistically ATO's inhibition of EBV gene expression occurs via the ubiquitin pathway. Moreover, ATO treatment results in increased cell death in EBV-positive cells compared to EBV-negative cells, as demonstrated by both MTT and trypan blue assays. ATO-induced cell death in EBV-positive cells is dose dependent. ATO and ganciclovir in combination further enhances cell death specifically in EBV-positive cells. CONCLUSION: ATO-mediated inhibition of EBV lytic gene expression results in cell death selectively in EBV-positive lymphocytes, suggesting that ATO may potentially serve as a drug to treat EBV-related lymphomas in the clinical setting.
Assuntos
Arsenicais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Herpesvirus Humano 4/fisiologia , Linfócitos/virologia , Óxidos/metabolismo , Ativação Viral/efeitos dos fármacos , Trióxido de Arsênio , Morte Celular , Linhagem Celular Tumoral , HumanosRESUMO
Combining unique, annual, bilateral data on labor flows of highly skilled immigrants for 10 OECD destinations between 2000 and 2012, with new databases comprising both unilateral and bilateral policy instruments, we present the first judicious cross-country assessment of policies aimed to attract and select high-skilled workers. Points-based systems are much more effective in attracting and selecting high-skilled migrants than requiring a job offer, labor market tests, and shortage lists. Offers of permanent residency, while attracting the highly skilled, overall reduce the human capital content of labor flows because they prove more attractive to non-high-skilled workers. Bilateral recognition of diploma and social security agreements foster greater flows of high-skilled workers and improve the skill selectivity of immigrant flows. Conversely, double taxation agreements deter high-skilled migrants, although they do not alter overall skill selectivity. Our results are robust to a variety of empirical specifications that account for destination-specific amenities, multilateral resistance to migration, and the endogeneity of immigration policies.
Assuntos
Emigração e Imigração/legislação & jurisprudência , Emprego/estatística & dados numéricos , Emprego/normas , Política Pública , Países Desenvolvidos , Humanos , Política , Fatores SocioeconômicosRESUMO
Human Immunodeficiency Virus (HIV)-infected individuals are at increased risk for developing neurocognitive disorders and depression. These conditions collectively affect more than 50% of people living with HIV/AIDS and adversely impact adherence to HIV therapy. Thus, identification of early markers of neurocognitive impairment could lead to interventions that improve psychosocial functioning and slow or reverse disease progression through improved treatment adherence. Evidence has accumulated for the role and function of microRNAs in normal and pathological conditions. We have optimized a protocol to profile microRNAs in body fluids. Using this methodology, we have profiled plasma microRNA expression for 30 age-matched, HIV-infected (HIV(+) ) patients and identified highly sensitive and specific microRNA signatures distinguishing HIV(+) patients with cognitive impairment from those without cognitive impairment. These results justify follow-on studies to determine whether plasma microRNA signatures can be used as a screening or prognostic tool for HIV(+) patients with neurocognitive impairment. J. Cell. Physiol. 231: 829-836, 2016. © 2015 Wiley Periodicals, Inc.
Assuntos
Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Infecções por HIV/sangue , Infecções por HIV/complicações , MicroRNAs/sangue , Adulto , Disfunção Cognitiva/genética , Demografia , Infecções por HIV/genética , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
More than 70,000 large dams have been built worldwide. With growing water stress and demand for energy, this number will continue to increase in the foreseeable future. Damming greatly modifies the ecological functioning of river systems. In particular, dam reservoirs sequester nutrient elements and, hence, reduce downstream transfer of nutrients to floodplains, lakes, wetlands, and coastal marine environments. Here, we quantify the global impact of dams on the riverine fluxes and speciation of the limiting nutrient phosphorus (P), using a mechanistic modeling approach that accounts for the in-reservoir biogeochemical transformations of P. According to the model calculations, the mass of total P (TP) trapped in reservoirs nearly doubled between 1970 and 2000, reaching 42 Gmol y(-1), or 12% of the global river TP load in 2000. Because of the current surge in dam building, we project that by 2030, about 17% of the global river TP load will be sequestered in reservoir sediments. The largest projected increases in TP and reactive P (RP) retention by damming will take place in Asia and South America, especially in the Yangtze, Mekong, and Amazon drainage basins. Despite the large P retention capacity of reservoirs, the export of RP from watersheds will continue to grow unless additional measures are taken to curb anthropogenic P emissions.