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1.
Gastroenterology ; 166(1): 139-154, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37739089

RESUMO

BACKGROUND & AIMS: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. METHODS: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signaling pathway. RESULTS: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. CONCLUSIONS: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Proteínas que Contêm Bromodomínio , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Gencitabina , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína Smad2/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Arch Virol ; 169(3): 62, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38446223

RESUMO

Sampled ticks were screened for Crimean-Congo haemorrhagic fever virus (CCHFV) using an assay that targets the nucleoprotein gene region of the S segment, a conserved region of the CCHFV genome. Minimum infection rates of 0.34% and 0.10% were obtained when testing pools of Hyalomma rufipes and Amblyomma variegatum, respectively. Next-generation sequencing and phylogenetic analysis showed that the S and L segments of the CCHFV isolate clustered with those of similar isolates of genotype III. However, analysis of the M segment showed that reassortment had occurred, causing this segment to cluster with those of isolates of genotype I, providing the first evidence of such an occurrence in Ghana.


Assuntos
Amblyomma , Vírus da Febre Hemorrágica da Crimeia-Congo , Animais , Vírus da Febre Hemorrágica da Crimeia-Congo/genética , Gana , Filogenia , Bioensaio
3.
Blood ; 138(5): 370-381, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-33786580

RESUMO

Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Mutação com Perda de Função , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Proteína 2 de Ligação ao Retinoblastoma/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Camundongos , Proteínas de Neoplasias/genética , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Arch Microbiol ; 205(3): 92, 2023 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-36795247

RESUMO

Tick-borne pathogens harm livestock production and pose a significant risk to public health. To combat these effects, it is necessary to identify the circulating pathogens to create effective control measures. This study identified Anaplasma and Ehrlichia species in ticks collected from livestock in the Kassena-Nankana Districts between February 2020 and December 2020. A total of 1550 ticks were collected from cattle, sheep and goats. The ticks were morphologically identified, pooled and screened for pathogens using primers that amplify a 345 bp fragment of the 16SrRNA gene and Sanger sequencing. The predominant tick species collected was Amblyomma variegatum (62.98%). From the 491 tick pools screened, 34 (6.92%) were positive for Ehrlichia and Anaplasma. The pathogens identified were Ehrlichia canis (4.28%), Ehrlichia minasensis (1.63%), Anaplasma capra (0.81%) and Anaplasma marginale (0.20%). This study reports the first molecular identification of the above-mentioned Ehrlichia and Anaplasma species in ticks from Ghana. With the association of human infections with the zoonotic pathogen A. capra, livestock owners are at risk of infections, calling for the development of effective control measures.


Assuntos
Carrapatos , Animais , Bovinos , Ovinos , Humanos , Gado , Gana , Ehrlichia/genética , Anaplasma/genética , Cabras
5.
Med Vet Entomol ; 37(4): 878-882, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37589253

RESUMO

Ticks are efficient vectors for transmitting pathogens that negatively affect livestock production and pose a risk to public health. In this study, Babesia and Theileria species were identified in ticks collected from cattle, sheep and goats from the Kassena-Nankana Districts of Ghana between February and December 2020. A total of 1550 ticks were collected, morphologically identified, pooled and screened for pathogens using primers that amplify a 560 bp fragment of the ssrRNA gene and Sanger sequencing. Amblyomma variegatum (62.98%) was the predominant tick species. From the 491 tick pools screened, 12/15 (2.44%) positive pools were successfully sequenced. The pathogen DNA identified were Theileria ovis in eight (15.38%) pools of Rhipicephalus evertsi evertsi, Theileria velifera in two (0.78%) pools of A. variegatum and Babesia occultans and Babesia sp. Xinjiang in one (1.72%) pool each of Hyalomma truncatum. It was further observed that T. ovis occurred in ticks collected from only sheep (p < 0.001) which were females (p = 0.023) and < =1 year old (p = 0.040). This study reports the first identification of these pathogens in ticks within Kassena-Nankana. With the constant trade of livestock, there is a need for effective tick control measures to prevent infection spread.


Assuntos
Babesia , Doenças dos Bovinos , Parasitos , Rhipicephalus , Theileria , Feminino , Animais , Bovinos , Ovinos , Masculino , Gana , Doenças dos Bovinos/parasitologia
6.
Exp Appl Acarol ; 90(1-2): 137-153, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37322233

RESUMO

Ticks are arthropods of veterinary and medical importance which spread zoonotic pathogens that link animal and human health. In this study, ticks were collected from 448 livestock between February and December 2020 in the Kassena-Nankana Districts of Ghana and screened for the presence of zoonotic pathogens DNA using PCR and sequencing approaches. In total, 1550 ticks were collected and morphologically identified. Three tick genera were identified with Amblyomma variegatum (63%) as the predominant tick species collected. DNA was extracted from 491 tick pools and screened for the presence of DNA of Rickettsia spp. based on the 115 bp fragment of the 17 kDa surface protein and 639 bp of the Outer membrane protein A (ompA) gene and the 295 bp fragment of the transposase gene of Coxiella burnetii IS1111a element. From the 491 pools screened, the DNA of Rickettsia spp. and C. burnetii was detected in 56.8 and 3.7%, respectively. Coinfections were identified in 2.4% of the tick pools. Characterization of the Rickettsia spp. in this study based on the ompA gene showed that the DNA of Rickettsia africae and Rickettsia aeschlimannii accounted for 39.7 and 14.7%, respectively, and were 100% similar to sequences in GenBank. Most R. africae and C. burnetii infections occurred in ticks collected in the wet season, whereas R. aeschlimannii occurred mostly in the dry season. These pathogens are potential public health threats, thus there is a need to implement control measures to reduce the risk of infections in vulnerable populations.


Assuntos
Coxiella burnetii , Ixodidae , Rickettsia , Carrapatos , Animais , Humanos , Coxiella burnetii/genética , Gana/epidemiologia , Rickettsia/genética , Ixodidae/microbiologia
7.
Ann Neurol ; 88(2): 332-347, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32403198

RESUMO

OBJECTIVE: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. METHODS: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. RESULTS: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. INTERPRETATION: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332-347.


Assuntos
Dimetilaliltranstransferase/genética , Farnesiltranstransferase/genética , Geraniltranstransferase/genética , Perda Auditiva/genética , Distrofias Musculares/genética , Mutação/genética , Insuficiência Ovariana Primária/genética , Adolescente , Adulto , Animais , Feminino , Técnicas de Introdução de Genes/métodos , Perda Auditiva/diagnóstico por imagem , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico por imagem , Linhagem , Insuficiência Ovariana Primária/diagnóstico por imagem , Estrutura Secundária de Proteína , Análise de Sequência de DNA/métodos , Sequenciamento do Exoma/métodos , Adulto Jovem
8.
Nat Chem Biol ; 15(5): 519-528, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962627

RESUMO

Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.


Assuntos
Benzimidazóis/farmacologia , Proteína de Ligação a CREB/antagonistas & inibidores , Reprogramação Celular/efeitos dos fármacos , Proteína p300 Associada a E1A/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Isoxazóis/farmacologia , Oxazepinas/farmacologia , Piperidinas/farmacologia , Benzimidazóis/química , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Inibidores Enzimáticos/química , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Isoxazóis/química , Estrutura Molecular , Oxazepinas/química , Piperidinas/química , Domínios Proteicos/efeitos dos fármacos
9.
N Engl J Med ; 374(18): 1711-22, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27043165

RESUMO

BACKGROUND: Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. METHODS: In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. RESULTS: In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. CONCLUSIONS: Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).


Assuntos
Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Lidocaína/uso terapêutico , Parada Cardíaca Extra-Hospitalar/tratamento farmacológico , Adulto , Idoso , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Reanimação Cardiopulmonar/métodos , Doenças do Sistema Nervoso Central/epidemiologia , Terapia Combinada , Método Duplo-Cego , Cardioversão Elétrica , Serviços Médicos de Emergência , Feminino , Humanos , Análise de Intenção de Tratamento , Lidocaína/efeitos adversos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Alta do Paciente , Taxa de Sobrevida , Taquicardia Ventricular/complicações , Fibrilação Ventricular/complicações , Fibrilação Ventricular/terapia
10.
Prehosp Emerg Care ; 23(4): 560-565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30285520

RESUMO

Background: Left ventricular assist devices (LVADs) are used with increasing frequency and left in place for longer periods of time. Prior publications have focused on the mechanics of troubleshooting the device itself. We aim to describe the epidemiology of LVAD patient presentations to emergency medical services (EMS), prehospital assessments and interventions, and hospital outcomes. Methods: This is a retrospective chart review of known LVAD patients that belong to a single academic center's heart failure program who activated the 9-1-1 system and were transported by an urban EMS system to one of the center's 2 emergency departments between January 2012 and December 2015. Identifying demographics were used to query the electronic medical record of the responding city fire agency and contracted transporting ambulance service. Two reviewers abstracted prehospital chief complaint, vital signs, assessments, and interventions. Emergency department and hospital outcomes were retrieved separately. Results: From January 2012 to December 2015, 15 LVAD patients were transported 16 times. The most common prehospital chief complaint was weakness (7/16), followed by chest pain (3/16). Of the 7 patients presenting with weakness, one was diagnosed with a stroke in the emergency department. Another patient was diagnosed with subarachnoid hemorrhage and expired during hospital admission. This was the only death in the cohort. The most common hospital diagnosis was GI bleed (3/16). The overall admission rate was 87.5% (14/16). Conclusions: EMS interactions with LVAD patients are infrequent but have high rates of admission and incidence of life-threatening diagnoses. The most common prehospital presenting symptoms were weakness and chest pain, and most prehospital interactions did not require LVAD-specific interventions. In addition to acquiring technical knowledge regarding LVADs, EMS providers should be aware of non-device-related complications including intracranial and GI bleeding and take this into account during their assessment.


Assuntos
Serviços Médicos de Emergência , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/terapia , Coração Auxiliar , Serviços Urbanos de Saúde , Adulto , Idoso , Feminino , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Angew Chem Int Ed Engl ; 58(2): 515-519, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30431220

RESUMO

Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.

12.
Circulation ; 136(22): 2119-2131, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-28904070

RESUMO

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) commonly presents with nonshockable rhythms (asystole and pulseless electric activity). It is unknown whether antiarrhythmic drugs are safe and effective when nonshockable rhythms evolve to shockable rhythms (ventricular fibrillation/pulseless ventricular tachycardia [VF/VT]) during resuscitation. METHODS: Adults with nontraumatic OHCA, vascular access, and VF/VT anytime after ≥1 shock(s) were prospectively randomized, double-blind, to receive amiodarone, lidocaine, or placebo by paramedics. Patients presenting with initial shock-refractory VF/VT were previously reported. The current study was a prespecified analysis in a separate cohort that initially presented with nonshockable OHCA and was randomized on subsequently developing shock-refractory VF/VT. The primary outcome was survival to hospital discharge. Secondary outcomes included discharge functional status and adverse drug-related effects. RESULTS: Of 37 889 patients with OHCA, 3026 with initial VF/VT and 1063 with initial nonshockable-turned-shockable rhythms were treatment-eligible, were randomized, and received their assigned drug. Baseline characteristics among patients with nonshockable-turned-shockable rhythms were balanced across treatment arms, except that recipients of a placebo included fewer men and were less likely to receive bystander cardiopulmonary resuscitation. Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug, and ancillary antiarrhythmic drugs than recipients of a placebo (P<0.05). In all, 16 (4.1%) amiodarone, 11 (3.1%) lidocaine, and 6 (1.9%) placebo-treated patients survived to hospital discharge (P=0.24). No significant interaction between treatment assignment and discharge survival occurred with the initiating OHCA rhythm (asystole, pulseless electric activity, or VF/VT). Survival in each of these categories was consistently higher with active drugs, although the trends were not statistically significant. Adjusted absolute differences (95% confidence interval) in survival from nonshockable-turned-shockable arrhythmias with amiodarone versus placebo were 2.3% (-0.3, 4.8), P=0.08, and for lidocaine versus placebo 1.2% (-1.1, 3.6), P=0.30. More than 50% of these survivors were functionally independent or required minimal assistance. Drug-related adverse effects were infrequent. CONCLUSIONS: Outcome from nonshockable-turned-shockable OHCA is poor but not invariably fatal. Although not statistically significant, point estimates for survival were greater after amiodarone or lidocaine than placebo, without increased risk of adverse effects or disability and consistent with previously observed favorable trends from treatment of initial shock-refractory VF/VT with these drugs. Together the findings may signal a clinical benefit that invites further investigation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01401647.


Assuntos
Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Reanimação Cardiopulmonar , Cardioversão Elétrica , Lidocaína/uso terapêutico , Parada Cardíaca Extra-Hospitalar/terapia , Taquicardia Ventricular/terapia , Fibrilação Ventricular/terapia , Idoso , Idoso de 80 Anos ou mais , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Reanimação Cardiopulmonar/efeitos adversos , Reanimação Cardiopulmonar/mortalidade , Método Duplo-Cego , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Lidocaína/efeitos adversos , Masculino , Pessoa de Meia-Idade , América do Norte , Parada Cardíaca Extra-Hospitalar/diagnóstico , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Alta do Paciente , Estudos Prospectivos , Recuperação de Função Fisiológica , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/mortalidade , Fibrilação Ventricular/fisiopatologia
13.
Emerg Infect Dis ; 24(9): 1765-1767, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30124422

RESUMO

Spondweni virus (SPONV) and Zika virus cause similar diseases in humans. We detected SPONV outside of Africa from a pool of Culex mosquitoes collected in Haiti in 2016. This finding raises questions about the role of SPONV as a human pathogen in Haiti and other Caribbean countries.


Assuntos
Culex/virologia , Infecções por Flavivirus/transmissão , Flavivirus/isolamento & purificação , Insetos Vetores/virologia , Animais , Infecções por Flavivirus/prevenção & controle , Haiti , Humanos
14.
Malar J ; 17(1): 94, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29471881

RESUMO

BACKGROUND: In this semi-field study, a new polymer-enhanced deltamethrin formulation, K-Othrine® PolyZone, was compared to a standard deltamethrin product for residual activity against a susceptible strain of laboratory-reared Anopheles gambiae using standard WHO cone bioassays. METHODS: Residual insecticide efficacy was recorded after exposure to metal, cement and wood panels maintained in experimental huts in sub-tropical environmental conditions in north central Florida, USA, and panels stored in a climate controlled chamber located at the Centers for Disease Control and Prevention, Georgia, USA. CONCLUSIONS: K-Othrine® PolyZone demonstrated 100% control on metal and cement panels 1 year post application and > 80% control on wood panels up to 6 mo. The new formulation should be considered for use in indoor residual spray programmes requiring long-term control of malaria vectors.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/crescimento & desenvolvimento , Materiais de Construção , Inseticidas/farmacologia , Nitrilas/farmacologia , Piretrinas/farmacologia , Animais , Bioensaio , Interações Medicamentosas , Florida , Georgia , Análise de Sobrevida
15.
J Emerg Med ; 55(1): 71-77, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29731285

RESUMO

BACKGROUND: A significant increase in false positive ST-elevation myocardial infarction (STEMI) electrocardiogram interpretations was noted after replacement of all of the City of San Diego's 110 monitor-defibrillator units with a new brand. These concerns were brought to the manufacturer and a revised interpretive algorithm was implemented. OBJECTIVES: This study evaluated the effects of a revised interpretation algorithm to identify STEMI when used by San Diego paramedics. METHODS: Data were reviewed 6 months before and 6 months after the introduction of a revised interpretation algorithm. True-positive and false-positive interpretations were identified. Factors contributing to an incorrect interpretation were assessed and patient demographics were collected. RESULTS: A total of 372 (234 preimplementation, 138 postimplementation) cases met inclusion criteria. There was a significant reduction in false positive STEMI (150 preimplementation, 40 postimplementation; p < 0.001) after implementation. The most common factors resulting in false positive before implementation were right bundle branch block, left bundle branch block, and atrial fibrillation. The new algorithm corrected for these misinterpretations with most postimplementation false positives attributed to benign early repolarization and poor data quality. Subsequent follow-up at 10 months showed maintenance of the observed reduction in false positives. CONCLUSIONS: This study shows that introducing a revised 12-lead interpretive algorithm resulted in a significant reduction in the number of false positive STEMI electrocardiogram interpretations in a large urban emergency medical services system. Rigorous testing and standardization of new interpretative software is recommended before introduction into a clinical setting to prevent issues resulting from inappropriate cardiac catheterization laboratory activations.


Assuntos
Algoritmos , Serviços Médicos de Emergência/normas , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , California , Eletrocardiografia/métodos , Serviços Médicos de Emergência/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Design de Software , Fatores de Tempo
16.
Bioconjug Chem ; 27(2): 329-40, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26646666

RESUMO

A bone imaging toolkit of 21 fluorescent probes with variable spectroscopic properties, bone mineral binding affinities, and antiprenylation activities has been created, including a novel linking strategy. The linking chemistry allows attachment of a diverse selection of dyes fluorescent in the visible to near-infrared range to any of the three clinically important heterocyclic bisphosphonate bone drugs (risedronate, zoledronate, and minodronate or their analogues). The resultant suite of conjugates offers multiple options to "mix and match" parent drug structure, fluorescence emission wavelength, relative bone affinity, and presence or absence of antiprenylation activity, for bone-related imaging applications.


Assuntos
Doenças Ósseas/diagnóstico , Osso e Ossos/patologia , Difosfonatos/química , Corantes Fluorescentes/química , Imagem Óptica/métodos , Animais , Linhagem Celular , Humanos , Masculino , Ratos Sprague-Dawley
18.
Prehosp Emerg Care ; 19(2): 328-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25291381

RESUMO

BACKGROUND: Inadvertent hyperventilation is associated with poor outcomes from traumatic brain injury (TBI). Hypocapnic cerebral vasoconstriction is well described and causes an immediate and profound decrease in cerebral perfusion. The hemodynamic effects of positive-pressure ventilation (PPV) remain incompletely understood but may be equally important, particularly in the hypovolemic patient with TBI. OBJECTIVE: Preliminary report on the application of a previously described mathematical model of perfusion and ventilation to prehospital data to predict intrathoracic pressure. METHODS: Ventilation data from 108 TBI patients (76 ground transported, 32 helicopter transported) were used for this analysis. Ventilation rate (VR) and end-tidal carbon dioxide (PetCO2) values were used to estimate tidal volume (VT). The values for VR and estimated VT were then applied to a previously described mathematical model of perfusion and ventilation. This model allows input of various lung parameters to define a pressure-volume relationship, then derives mean intrathoracic pressure (MITP) for various VT and VR values. For this analysis, normal lung parameters were utilized. Separate analyses were performed assuming either fixed or variable PaCO2-PetCO2 differences. Ground and air medical patients were compared with regard to VR, PetCO2, estimated VT, and predicted MITP. RESULTS: A total of 10,647 measurements were included from the 108 TBI patients, representing about 13 minutes of ventilation per patient. Mean VR values were higher for ground patients versus air patients (21.6 vs. 19.7 breaths/min; p < 0.01). Estimated VT values were similar for ground and air patients (399 mL vs. 392 mL; p = NS) in the fixed model but not the variable (636 vs. 688 mL, respectively; p < 0.01). Mean PetCO2 values were lower for ground versus air patients (30.6 vs. 33.8 mmHg; p < 0.01). Predicted MITP values were higher for ground versus air patients, assuming either fixed (9.0 vs. 8.1 mmHg; p < 0.01) or variable (10.9 vs. 9.7 mmHg; p < 0.01) PaCO2-PetCO2 differences. CONCLUSIONS: Predicted MITP values increased with ventilation rates. Future studies to externally validate this model are warranted.


Assuntos
Lesões Encefálicas/terapia , Pulmão/fisiopatologia , Respiração com Pressão Positiva/métodos , Adulto , Humanos , Modelos Teóricos
19.
Am J Emerg Med ; 33(1): 56-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25455049

RESUMO

OBJECTIVE: We studied the complications and timing implications of prehospital activated charcoal (PAC). Appropriateness of PAC administration was also evaluated. METHODS: We retrospectively reviewed prehospital records over 32 months for overdose cases, where PAC was administered. Cases were assessed for amount and type of ingestant, clinical findings, timing of PAC, timing of transport and arrival into the emergency department (ED), and complications. Encounter duration in cases of PAC was compared with that, for all cases during the study period, where an overdose patient who did not receive activated charcoal was transported. RESULTS: Two thousand eight hundred forty-five total cases were identified. In 441 cases, PAC was given; and complications could be assessed. Two hundred eighty-one of these had complete information regarding timing of ingestion, activated charcoal administration, and transport. The average time between overdose and PAC was 49.8 minutes (range, 7-199 minutes; median, 41.0 minutes; SD, 30.4 minutes). Complications included emesis (7%), declining mental status (4%), declining blood pressure (0.4%), and declining oxygen saturation (0.4%). Four hundred seventeen cases of PAC had documentation of timing of emergency medical service (EMS) arrival on scene and arrival at the ED. Average EMS encounter time was 29 minutes (range, 10-53 minutes; median, 27.9 minutes). Two thousand forty-four poisoning patients were transported who did not receive PAC. The average EMS encounter time for this group was 28.1 minutes (range, 4-82 minutes; median, 27.3 minutes), not significantly different (P =.114). CONCLUSIONS: Prehospital activated charcoal did not appear to markedly delay transport or arrival of overdose patients into the ED and was generally safe.


Assuntos
Antídotos/uso terapêutico , Carvão Vegetal/uso terapêutico , Overdose de Drogas/tratamento farmacológico , Intoxicação/tratamento farmacológico , Serviços Médicos de Emergência , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
20.
J Am Mosq Control Assoc ; 31(3): 248-57, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26375906

RESUMO

Traditional sources of carbon dioxide (CO2), dry ice, and compressed gas, were tested against 3 combinations of food-grade reagents known to generate CO2using a compact, lightweight generator delivery system with Centers for Disease Control and Prevention light traps. Three 6 × 6 Latin square trials were completed near the Florida Gulf Coast in the Lower Suwannee Wildlife Refuge during the summer of 2013, collecting a total of 31,632 female mosquitoes. Treatments included dry ice, compressed CO2gas, a control trap (no CO2), citric acid + sodium bicarbonate, vinegar + sodium bicarbonate, and yeast + sugar. Decreasing order of trap collections (treatment mean number of mosquitoes per trap night ± standard error) were dry ice 773.5 (± 110.1) > compressed gas 440.7 (± 42.3) > citric acid + sodium bicarbonate 197.6 (± 30.4), yeast + sugar 153.6 (± 27.4) > vinegar + sodium bicarbonate 109.6 (± 16.2) > control 82.4 (± 14.0). A 2-way Kruskal-Wallis analysis by treatment, site, and treatment × site interaction identified significant differences between all treatments. Although dry ice and compressed CO2gas collected significantly more mosquitoes than other combinations (P < 0.05), use of citric acid and sodium bicarbonate or yeast and sugar greatly outperformed unbaited traps and offer a good alternative to dry ice and compressed gas in areas where these agents are not readily available or are difficult to obtain due to logistical constraints. An inexpensive, portable CO2generator for use with food-grade reagents is described.


Assuntos
Dióxido de Carbono/fisiologia , Culicidae/fisiologia , Controle de Mosquitos/métodos , Animais , Gelo-Seco , Feminino , Florida , Luz , Controle de Mosquitos/instrumentação , Saccharomyces cerevisiae/metabolismo
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