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1.
Environ Res ; 216(Pt 2): 114636, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36283440

RESUMO

BACKGROUND: The physical environmental risk factors for psychotic disorders are poorly understood. This study aimed to examine the associations between exposure to ambient air pollution, climate measures and risk of hospitalization for psychotic disorders and uncover potential disparities by demographic, community factors. METHODS: Using Health Cost and Utilization Project (HCUP) State Inpatient Databases (SIDs), we applied zero-inflated negative binomial regression to obtain relative risks of hospitalization due to psychotic disorders associated with increases in residential exposure to ambient air pollution (fine particulate matter, PM2.5; nitrogen dioxide, NO2), temperature and cumulative precipitation. The analysis covered all-age residents in eight U.S. states over the period of 2002-2016. We additionally investigated modification by age, sex and area-level poverty, percent of blacks and Hispanics. RESULTS: Over the study period and among the covered areas, we identified 1,211,100 admissions due to psychotic disorders. For each interquartile (IQR) increase in exposure to PM2.5 and NO2, we observed a relative risk (RR) of 1.11 (95% confidence interval (CI) = 1.09, 1.13) and 1.27 (95% CI = 1.24, 1.31), respectively. For each 1 °C increase of temperature, the RR was 1.03 (95% CI = 1.03, 1.04). Males were more affected by NO2. Older age residents (≥30 yrs) were more sensitive to PM2.5 and temperature. Population living in economically disadvantaged areas were more affected by air pollution. CONCLUSIONS: The study suggests that living in areas with higher levels of air pollutants and ambient temperature could contribute to additional risk of inpatient care for individuals with psychotic disorders.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Transtornos Psicóticos , Masculino , Humanos , Dióxido de Nitrogênio/análise , Poluição do Ar/análise , Poluentes Atmosféricos/análise , Material Particulado/análise , Hospitalização , Transtornos Psicóticos/epidemiologia , Hospitais , Exposição Ambiental/análise
2.
Pathogens ; 11(12)2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36558732

RESUMO

BACKGROUND: Emphysematous pyelonephritis (EPN) is a necrotizing infection of the kidney and surrounding tissues with significant mortality. We aimed to assess the clinical factors and their influence on prognosis in patients being managed for EPN with and without ESBL-producing bacteria and to identify if those with EPN due to ESBL infections fared any different. METHODS: A retrospective analysis was performed on patients with EPN diagnosis from 22 centers across 11 countries (between 2013 and 2020). Demographics, clinical presentation, biochemical parameters, radiological features, microbiological characteristics, and therapeutic management were assessed. Univariable and multivariable analyses were performed to determine the independent variables associated with ESBL pathogens. A comparison of ESBL and non-ESBL mortality was performed evaluating treatment modality. RESULTS: A total of 570 patients were included. Median (IQR) age was 57 (47-65) years. Among urine cultures, the most common isolated pathogen was Escherichia coli (62.2%). ESBL-producing agents were present in 291/556 urine cultures (52.3%). In multivariable analysis, thrombocytopenia (OR 1.616 95% CI 1.081-2.413, p = 0.019), and Huang-Tseng type 4 (OR 1.948 95% CI 1.005-3.778, p= 0.048) were independent predictors of ESBL pathogens. Patients with Huang-Tseng Scale type 1 had 55% less chance of having ESBL-producing pathogens (OR 1.616 95% CI 1.081-2.413, p = 0.019). Early nephrectomy (OR 2.3, p = 0.029) and delayed nephrectomy (OR 2.4, p = 0.015) were associated with increased mortality in patients with ESBL infections. Conservative/minimally invasive management reported an inverse association with mortality (OR 0.314, p = 0.001). CONCLUSIONS: ESBL bacteria in EPN were not significantly associated with mortality in EPN. However, ESBL infections were associated with poor prognosis when patients underwent nephrectomy compared conservative/minimally invasive management.

3.
Int J Surg Case Rep ; 101: 107799, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36434876

RESUMO

INTRODUCTION: The most common causes of hematuria are lower urinary tract infections, especially of the bladder, urolithiasis, urogenital tumors or benign prostatic hyperplasia; consequently, this condition presents the greatest clinical challenge due to its broad clinical spectrum, hematuria is an atypical form of presentation of testicular tumors, with very few cases reported in the literature, reaffirming the importance of a complete examination when approaching hematuria in the emergency department. CASE PRESENTATION: We present a case of a 31-year-old patient who presented to the emergency department with macroscopic hematuria of 5 weeks of evolution, showing on examination a mass in the left testicle. Imaging studies showed bilateral pulmonary metastatic lesions and retroperitoneal lymph node activity with a retrocaval conglomerate infiltrating the left ureter, for which a radical left orchiectomy and multiple procedures were performed to resolve the hematuria. DISCUSSION: Macroscopic hematuria in adolescents or young adults is an infrequent cause of admission to the Emergency Department with a large list of differential diagnoses both benign and malignant so it is necessary to perform exhaustive studies in its approach, when young patients present with a painless testicular mass, it is important to keep testicular cancer within the differential diagnoses, metastatic disease is a rare form of presentation in this type of tumors. The relevance of this clinical case lies in the fact that hematuria was the main symptom that brought the patient to the emergency department, so we must not forget that macroscopic hematuria should be extensively studied. CONCLUSION: When approaching a patient with macroscopic hematuria, the clinical history and physical examination is extremely important to provide the best possible care and focus the treatment properly.

4.
Environ Int ; 170: 107594, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36283157

RESUMO

BACKGROUND & AIM: Numerous studies have linked air pollution with cardiovascular diseases. Fewer studies examined the associations at low concentration levels or assessed potential modifiers. Some investigations only examined hospitalizations, which can miss incident cases. This study aims to address these gaps through a nationwide cohort study of Medicare enrollees. METHODS: Our study cohort comprise all Medicare enrollees (≥65 years old) continuously enrolled in the fee-for-service program and both Medicare part A and B across the contiguous U.S. from 2000 to 2016. We examined the associations of population-weighted ZIP code-level annual average PM2.5, NO2, and warm-season O3 (May-October), with the first diagnoses of atrial fibrillation (AF), congestive heart failure (CHF), and stroke. We fit multi-pollutant Cox proportional hazards models adjusted for individual demographic characteristics and area-level covariates. We further examined these associations at low pollutant concentration levels and the potential effect modifications by race/ethnicity and comorbidities (diabetes, hypertension, hyperlipidemia). RESULTS: Elevated PM2.5 and NO2 levels were associated with increased incidence of AF, CHF, and stroke. For each 1 µg/m3 increase in annual PM2.5, hazard ratios (HRs) were 1.0059 (95%CI: 1.0054-1.0064), 1.0260 (95%CI: 1.0256-1.0264), and 1.0279 (95%CI: 1.0274-1.0284), respectively. For each1 ppb increase in annual NO2, HRs are 1.0057 (95%CI: 1.0056-1.0059), 1.0112 (95%CI: 1.0110-1.0113), and 1.0095 (95%CI: 1.0093-1.0096), respectively. For warm-season O3, each 1 ppb increase was associated with increased incidence of CHF (HR=1.0035, 95%CI: 1.0033-1.0037) and stroke (HR=1.0026, 95%CI: 1.0023-1.0028). Larger magnitudes of HRs were observed when restricted to pollutants levels lower than NAAQS standards. Generally higher risks were observed for Black people and diabetics. CONCLUSIONS: Long-term exposure to PM2.5, NO2, and warm-season O3 were associated with increased incidence of cardiovascular diseases, even at low pollutant concentration levels. Black people and people with diabetes were found to be vulnerable populations.

5.
Environ Health ; 21(1): 96, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36221093

RESUMO

BACKGROUND: Numerous studies have documented PM2.5's links with adverse health outcomes. Comparatively fewer studies have evaluated specific PM2.5 components. The lack of exposure measurements and high correlation among different PM2.5 components are two limitations. METHODS: We applied a novel exposure prediction model to obtain annual Census tract-level concentrations of 15 PM2.5 components (Zn, V, Si, Pb, Ni, K, Fe, Cu, Ca, Br, SO42-, NO3-, NH4+, OC, EC) in Massachusetts from 2000 to 2015, to which we matched geocoded deaths. All non-accidental mortality, cardiovascular mortality, and respiratory mortality were examined for the population aged 18 or over. Weighted quantile sum (WQS) regression models were used to examine the cumulative associations between PM2.5 components mixture and outcomes and each component's contributions to the cumulative associations. We have fit WQS models on 15 PM2.5 components and a priori identified source groups (heavy fuel oil combustion, biomass burning, crustal matter, non-tailpipe traffic source, tailpipe traffic source, secondary particles from power plants, secondary particles from agriculture, unclear source) for the 15 PM2.5 components. Total PM2.5 mass analysis and single component associations were also conducted through quasi-Poisson regression models. RESULTS: Positive cumulative associations between the components mixture and all three outcomes were observed from the WQS models. Components with large contribution to the cumulative associations included K, OC, and Fe. Biomass burning, traffic emissions, and secondary particles from power plants were identified as important source contributing to the cumulative associations. Mortality rate ratios for cardiovascular mortality were of greater magnitude than all non-accidental mortality and respiratory mortality, which is also observed in cumulative associations estimated from WQS, total PM2.5 mass analysis, and single component associations. CONCLUSION: We have found positive associations between the mixture of 15 PM2.5 components and all non-accidental mortality, cardiovascular mortality, and respiratory mortality. Among these components, Fe, K, and OC have been identified as having important contribution to the cumulative associations. The WQS results also suggests potential source effects from biomass burning, traffic emissions, and secondary particles from power plants.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Doenças Cardiovasculares , Óleos Combustíveis , Doenças Respiratórias , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Doenças Cardiovasculares/induzido quimicamente , Monitoramento Ambiental , Óleos Combustíveis/análise , Humanos , Chumbo/análise , Material Particulado/análise , Doenças Respiratórias/epidemiologia
6.
Biochimie ; 202: 226-236, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36057372

RESUMO

The most enigmatic group of rattlesnakes is the long-tailed rattlesnake group, consisting of three species: Crotalus ericsmithi, Crotalus lannomi and Crotalus stejnegeri. These species have been the least studied rattlesnakes in all aspects, and no study on the characterization of their venoms has been carried out to date. Our main objective was to investigate the proteomic composition, as well as some of the biochemical and toxic activities of these venoms, and their neutralization by commercial antivenom. The venom proteome of C. ericsmithi mainly contains metalloproteinases (SVMP; 49.3%), phospholipases A2 (PLA2; 26.2%), disintegrins (Dis; 12.6%), and snake venom serine proteases (SVSP; 6.8%), while C. lannomi venom mainly consists of SVMP (47.1%), PLA2 (19.3%), Dis (18.9%), SVSP (6%) and l-amino acid oxidase (LAAO; 2.6%). For these venoms high lethality was recorded in mice, the most potent being that of C. lannomi (LD50 of 0.99 µg/g body weight), followed by C. ericsmithi (1.30 µg/g) and finally C. stejnegeri (1.79 µg/g). The antivenoms Antivipmyn® from SILANES and Fabotherapic polyvalent antiviperin® from BIRMEX neutralized the lethal activity of the three venoms. Although this group of snakes is phylogenetically related to the C. viridis group, no neurotoxic components (crotoxin or crotoxin-like proteins) common in rattlesnakes were found in their venoms. This study expands current knowledge on the venoms of understudied snake species of the Mexican herpetofauna.


Assuntos
Crotalus , Crotoxina , Animais , Camundongos , Peçonhas , Proteômica , Proteoma
7.
Toxins (Basel) ; 14(8)2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-36006194

RESUMO

Biochemical and biological differences in the venom of Crotalus durissus cumanensis from three ecoregions of Colombia were evaluated. Rattlesnakes were collected from the geographic areas of Magdalena Medio (MM), Caribe (CA) and Orinoquía (OR). All three regionally distributed venoms contain proteases, PLA2s and the basic subunit of crotoxin. However, only crotamine was detected in the CA venom. The highest lethality, coagulant, phospholipase A2 and hyaluronidase activities were found in the MM venom. Also, some differences, observed by western blot and immunoaffinity, were found in all three venoms when using commercial antivenoms. Furthermore, all three eco-regional venoms showed intraspecific variability, considering the differences in the abundance and intensity of their components, in addition to the activity and response to commercial antivenoms.


Assuntos
Venenos de Crotalídeos , Crotoxina , Animais , Antivenenos , Colômbia , Crotalus , Fosfolipases A2
8.
Toxins (Basel) ; 14(8)2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35893753

RESUMO

Within Neotropical pit-vipers, the Mexican/Central-American clade consisting of Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium is a wide-ranging, morphologically and ecologically diverse group of snakes. Despite their prevalence, little is known of the functional aspects of their venoms. This study aimed to fill the knowledge gap regarding coagulotoxic effects and to examine the potential of different therapeutic approaches. As a general trait, the venoms were shown to be anticoagulant but were underpinned by diverse biochemical actions. Pseudo-procoagulant activity (i.e., thrombin-like), characterized by the direct cleavage of fibrinogen to form weak fibrin clots, was evident for Atropoides picadoi, Cerrophidiontzotzilorum, Metlapilcoatlus mexicanus, M. nummifer, M. occiduus, M. olmec, and Porthidium porrasi. In contrast, other venoms cleaved fibrinogen in a destructive (non-clotting) manner, with C. godmani and C. wilsoni being the most potent. In addition to actions on fibrinogen, clotting enzymes were also inhibited. FXa was only weakly inhibited by most species, but Cerrophidion godmani and C. wilsoni were extremely strong in their inhibitory action. Other clotting enzymes were more widely inhibited by diverse species spanning the full taxonomical range, but in each case, there were species that had these traits notably amplified relatively to the others. C. godmani and C. wilsoni were the most potent amongst those that inhibited the formation of the prothrombinase complex and were also amongst the most potent inhibitors of Factor XIa. While most species displayed only low levels of thrombin inhibition, Porthidium dunni potently inhibited this clotting factor. The regional polyvalent antivenom produced by Instituto Picado Clodomiro was tested and was shown to be effective against the diverse anticoagulant pathophysiological effects. In contrast to the anticoagulant activities of the other species, Porthidium volcanicum was uniquely procoagulant through the activation of Factor VII and Factor XII. This viperid species is the first snake outside of the Oxyuranus/Pseudonaja elapid snake clade to be shown to activate FVII and the first snake venom of any kind to activate FXII. Interestingly, while small-molecule metalloprotease inhibitors prinomastat and marimastat demonstrated the ability to prevent the procoagulant toxicity of P. volcanicum, neither ICP antivenom nor inhibitor DMPS showed this effect. The extreme variation among the snakes here studied underscores how venom is a dynamic trait and how this can shape clinical outcomes and influence evolving treatment strategies.


Assuntos
Venenos de Crotalídeos , Crotalinae , Viperidae , Animais , Anticoagulantes/farmacologia , Antivenenos/farmacologia , Venenos de Crotalídeos/química , Venenos Elapídicos , Elapidae , Fibrinogênio , Venenos de Serpentes , Trombina
9.
Biochimie ; 201: 55-62, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35781049

RESUMO

Alpha-latrotoxin (ɑLTx) is the component responsible for causing the pathophysiology in patients bitten by spiders from the genus Latrodectus, commonly known as black widow spiders. The current antivenom used to treat these envenomations in Mexico is produced using the venom of thousands of spiders, obtained through electrical stimulation. This work aimed to produce this protein as well as two of its fragments in a bacterial model, to evaluate their use as immunogens to produce neutralizing hyperimmune sera, in rabbits. ɑLTx is a 130 kDa protein which has not yet been obtained in a soluble active form using bacterial models. In the present work, ɑLTx and two of its fragments, ankyrin domain and amino terminal domain (LTxAnk and LTxNT) were produced in bacteria and solubilized from inclusion bodies using N-lauroyl sarcosine. These three proteins were used for hyperimmunization in order to evaluate their potential as immunogens for the production of neutralizing hyperimmune sera against the complete venom of Latrodectus mactans. The hyperimmune sera obtained using the complete ɑLTx as well as the LTxNT, was capable of preventing death of mice envenomated with 3 LD50s of venom, both in preincubation and rescue experiments. Conversely, the serum obtained using the LTxAnk fragment, generated only partial protection and a delay in the time of death, even with a maximum dose of 450 µL. We therefore conclude that the produced proteins show great potential for their use as immunogens and should be further tested in large animals, such as horses.


Assuntos
Viúva Negra , Venenos de Aranha , Animais , Anquirinas , Antivenenos/farmacologia , Antivenenos/uso terapêutico , Cavalos , Camundongos , Coelhos
10.
Sci Data ; 9(1): 330, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35725848

RESUMO

A pandemic, like other disasters, changes how systems work. In order to support research on how the COVID-19 pandemic impacted the dynamics of a single metropolitan area and the communities therein, we developed and made publicly available a "data-support system" for the city of Boston. We actively gathered data from multiple administrative (e.g., 911 and 311 dispatches, building permits) and internet sources (e.g., Yelp, Craigslist), capturing aspects of housing and land use, crime and disorder, and commercial activity and institutions. All the data were linked spatially through BARI's Geographical Infrastructure, enabling conjoint analysis. We curated the base records and aggregated them to construct ecometric measures (i.e., descriptors of a place) at various geographic scales, all of which were also published as part of the database. The datasets were published in an open repository, each accompanied by a detailed documentation of methods and variables. We anticipate updating the database annually to maintain the tracking of the records and associated measures.


Assuntos
COVID-19 , Bases de Dados Factuais , Boston/epidemiologia , COVID-19/epidemiologia , Gerenciamento de Dados , Humanos , Pandemias
11.
Nanomaterials (Basel) ; 12(6)2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35335836

RESUMO

Resonant tunneling diode photodetectors appear to be promising architectures with a simple design for mid-infrared sensing operations at room temperature. We fabricated resonant tunneling devices with GaInAsSb absorbers that allow operation in the 2-4 µm range with significant electrical responsivity of 0.97 A/W at 2004 nm to optical readout. This paper characterizes the photosensor response contrasting different operational regimes and offering a comprehensive theoretical analysis of the main physical ingredients that rule the sensor functionalities and affect its performance. We demonstrate how the drift, accumulation, and escape efficiencies of photogenerated carriers influence the electrostatic modulation of the sensor's electrical response and how they allow controlling the device's sensing abilities.

12.
Toxicon ; 211: 44-49, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35317994

RESUMO

Mexico is home to an extreme diversity of herpetofauna, with venomous snakes imposing a significant burden upon public health. However, little is known about the pathophysiological venom actions of a number of potentially medically important species, including those from the genera Mixcoatlus and Ophryacus. Our study aimed to fill this knowledge gap by ascertaining the effects of Mixcoatlus melanurus, Ophryacus smaragdinus and Ophryacus sphenophrys venoms upon the coagulation cascade utilising a series of well-validated coagulation assays. While M. melanurus venom exhibited no significant coagulotoxic activities, both O. smaragdinus and O. sphenophrys venoms exerted multiple coagulotoxic activities upon the coagulation cascade which would be contributing towards a net anticoagulant venom activity. O. sphenophrys significantly inhibited the spontaneous clotting of plasma but O. smaragdinus did not. They differed in that O. sphenophrys inhibited the clotting enzymes factor IXa and factor XIa. However, O. smaragdinus was able to inhibit factor Xa in isolation-assays. Both O. smaragdinus and O. sphenophrys degraded fibrinogen, with O. smaragdinus venom causing a significantly weaker fibrinogen clot than O. sphenophrys. In vitro antivenom efficacy assays were undertaken to ascertain the efficacy of Antivipmyn-Tri antivenom (which is made using Bothrops, Crotalus, and Lachesis venoms). This antivenom was chosen due to the phylogenetic uncertain position of the Ophryacus, but with some molecular genetics' studies placing it as sister to Lachesis. Despite the complexity of the antivenom immunising mixture, the anticoagulant activity of O. sphenophrys venom was relatively poorly neutralised by the antivenom. This work contributes to the understanding of the functional activity of Mixcoatlus and Ophryacus venoms, laying a foundation for future work investigating the coagulotoxins present within Ophryacus venoms in addition to providing data useful for the evidence-based design of clinical management strategies for the envenomed patient.


Assuntos
Crotalinae , Viperidae , Animais , Anticoagulantes/farmacologia , Antivenenos/farmacologia , Humanos , Filogenia
13.
Toxicon ; 207: 43-47, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35007607

RESUMO

Here we report, for the first time, a natural hybrid between Crotalus atrox and C. mictlantecuhtli based on intermediate characteristics of the external morphology and venom. Morphologically, the individual had characteristics of both parent species. The hybrid's venom exhibited an intermediate composition including the presence of crotoxin which has never been documented in C. atrox but is well documented in C. mictlantecuhtli. The hybrid's venom was highly toxic and showed an intermediate proteolytic activity between the parental species. The two Mexican antivenoms were able to neutralize the hybrid's venom's lethality.


Assuntos
Venenos de Crotalídeos , Crotoxina , Animais , Antivenenos , Venenos de Crotalídeos/toxicidade , Crotalus , México
14.
Biochimie ; 192: 111-124, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34656669

RESUMO

Intraspecific variation in snake venoms has been widely documented worldwide. However, there are few studies on this subject in Mexico. Venom characterization studies provide important data used to predict clinical syndromes, to evaluate the efficacy of antivenoms and, in some cases, to improve immunogenic mixtures in the production of antivenoms. In the present work, we evaluated the intraspecific venom variation of Crotalus basiliscus, a rattlesnake of medical importance and whose venom is used in the immunization of horses to produce one of the Mexican antivenoms. Our results demonstrate that there is variation in biological and biochemical activities among adult venoms and that there is an ontogenetic change from juvenile to adult venoms. Juvenile venoms were more lethal and had higher percentages of crotamine and crotoxin, while adult venoms had higher percentages of snake venom metalloproteases (SVMPs). Additionally, we documented crotoxin-like PLA2 variation in which specimens from Zacatecas, Sinaloa and Michoacán (except 1) lacked the neurotoxin, while the rest of the venoms had it. Finally, we evaluated the efficacy of three lots of Birmex antivenom and all three were able to neutralize the lethality of four representative venoms but were not able to neutralize crotamine. We also observed significant differences in the LD50 values neutralized per vial among the different lots. Based on these results, we recommend including venoms containing crotamine in the production of antivenom for a better immunogenic mixture and to improve the homogeneity of lots.


Assuntos
Antivenenos/química , Crotalus , Crotoxina/química , Animais , Humanos , México , Camundongos , Especificidade da Espécie
15.
Toxins (Basel) ; 13(8)2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34437453

RESUMO

The Baja California Peninsula has over 250 islands and islets with many endemic species. Among them, rattlesnakes are the most numerous but also one of the least studied groups. The study of island rattlesnake venom could guide us to a better understanding of evolutionary processes and the description of novel toxins. Crotalus helleri caliginis venom samples were analyzed to determine possible ontogenetic variation with SDS-PAGE in one and two dimensions and with RP-HPLC. Western Blot, ELISA, and amino-terminal sequencing were used to determine the main components of the venom. The biological and biochemical activities demonstrate the similarity of C. helleri caliginis venom to the continental species C. helleri helleri, with both having low proteolytic and phospholipase A2 (PLA2) activity but differing due to the absence of neurotoxin (crotoxin-like) in the insular species. The main components of the snake venom were metalloproteases, serine proteases, and crotamine, which was the most abundant toxin group (30-35% of full venom). The crotamine was isolated using size-exclusion chromatography where its functional effects were tested on mouse phrenic nerve-hemidiaphragm preparations in which a significant reduction in muscle twitch contractions were observed. The two Mexican antivenoms could neutralize the lethality of C. helleri caliginis venom but not the crotamine effects.


Assuntos
Antivenenos/uso terapêutico , Crotalus , Crotoxina/química , Crotoxina/genética , Crotoxina/toxicidade , Paralisia/induzido quimicamente , Paralisia/tratamento farmacológico , Mordeduras de Serpentes/tratamento farmacológico , Animais , Ontologias Biológicas , Variação Genética , México
16.
J Chem Ecol ; 47(10-11): 907-914, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34165686

RESUMO

The use of venom in predation exerts a corresponding selection pressure for the evolution of venom resistance. One of the mechanisms related to venom resistance in animals (predators or prey of snakes) is the presence of molecules in the blood that can bind venom toxins, and inhibit their pharmacological effects. One such toxin type are venom phospholipase A2s (PLA2s), which have diverse effects including anticoagulant, myotoxic, and neurotoxic activities. BoaγPLI isolated from the blood of Boa constrictor has been previously shown to inhibit venom PLA2s that induced myotoxic and edematogenic activities. Recently, in addition to its previously described and very potent neurotoxic effect, the venoms of American coral snakes (Micrurus species) have been shown to have anticoagulant activity via PLA2 toxins. As coral snakes eat other snakes as a major part of their diet, neonate Boas could be susceptible to predation by this sympatric species. Thus, this work aimed to ascertain if BoaγPLI provided a protective effect against the anticoagulant toxicity of venom from the model species Micrurus laticollaris in addition to its ability shown previously against other toxin types. Using a STA R Max coagulation analyser robot to measure the effect upon clotting time, and TEG5000 thromboelastographers to measure the effect upon clot strength, we evaluated the ability of BoaγPLI to inhibit M. laticollaris venom. Our results indicate that BoaγPLI is efficient at inhibiting the M. laticollaris anticoagulant effect, reducing the time of coagulation (restoring them closer to non-venom control values) and increasing the clot strength (restoring them closer to non-venom control values). These findings demonstrate that endogenous PLA2 inhibitors in the blood of non-venomous snakes are multi-functional and provide broad resistance against a myriad of venom PLA2-driven toxic effects including coagulotoxicity, myotoxicity, and neurotoxicity. This novel form of resistance could be evidence of selective pressures caused by predation from venomous snakes and stresses the need for field-based research aimed to expand our understanding of the evolutionary dynamics of such chemical arms race.


Assuntos
Boidae , Cobras Corais , Fosfolipases A2/toxicidade , Proteínas de Répteis/toxicidade , Venenos de Serpentes/química , Simpatria , Peçonhas/química , Animais , Fosfolipases A2/química , Comportamento Predatório , Proteínas de Répteis/química , Venenos de Serpentes/análise , Venenos de Serpentes/enzimologia , Peçonhas/análise , Peçonhas/enzimologia
17.
Toxicon ; 197: 70-78, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33894246

RESUMO

Crotamine is a paralyzing toxin (MW: ~5 kDa) found in different proportions in some rattlesnake venoms (up to 62%). Mexican pit viper antivenoms have shown low immunoreactivity against crotamine, which is an urgent quality to be improved. The objective of this work was to evaluate the ability of a novel recombinant fusion protein composed of sphingomyelinase D and crotamine, and two whole venoms from Crotalus molossus nigrescens and C. oreganus helleri to produce neutralizing antibodies against crotamine. These immunogens were separately used for immunization procedures in rabbits. Then, we generated three experimental antivenoms to test their cross-reactivity via western-blot against crotamine from 7 species (C. m. nigrescens, C. o. helleri, C. durissus terrificus, C. scutulatus salvini, C. basiliscus, C. culminatus and C. tzabcan). We also performed pre-incubation neutralization experiments in mice to measure the neutralizing potency of each antivenom against crotamine induced hind limb paralysis. Our antivenoms showed broad recognition across crotamine from most of the tested species. Also, neutralization against crotamine paralysis symptom was successfully achieved by our three antivenoms, albeit with different efficiencies. Our results highlight the use of crotamine enriched venoms and our novel recombinant fusion protein as promising immunogens to improve the neutralizing potency against crotamine for the improvement of Mexican antivenoms.


Assuntos
Venenos de Crotalídeos , Animais , Antivenenos/farmacologia , Crotalus , México , Camundongos , Testes de Neutralização , Coelhos , Proteínas Recombinantes de Fusão
18.
Front Immunol ; 12: 612846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815366

RESUMO

Rattlesnakes are a diverse clade of pit vipers (snake family Viperidae, subfamily Crotalinae) that consists of numerous medically significant species. We used validated in vitro assays measuring venom-induced clotting time and strength of any clots formed in human plasma and fibrinogen to assess the coagulotoxic activity of the four medically relevant Mexican rattlesnake species Crotalus culminatus, C. mictlantecuhtli, C. molossus, and C. tzabcan. We report the first evidence of true procoagulant activity by Neotropical rattlesnake venom in Crotalus culminatus. This species presented a strong ontogenetic coagulotoxicity dichotomy: neonates were strongly procoagulant via Factor X activation, whereas adults were pseudo-procoagulant in that they converted fibrinogen into weak, unstable fibrin clots that rapidly broke down, thereby likely contributing to net anticoagulation through fibrinogen depletion. The other species did not activate clotting factors or display an ontogenetic dichotomy, but depleted fibrinogen levels by cleaving fibrinogen either in a destructive (non-clotting) manner or via a pseudo-procoagulant mechanism. We also assessed the neutralization of these venoms by available antivenom and enzyme-inhibitors to provide knowledge for the design of evidence-based treatment strategies for envenomated patients. One of the most frequently used Mexican antivenoms (Bioclon Antivipmyn®) failed to neutralize the potent procoagulant toxic action of neonate C. culminatus venom, highlighting limitations in snakebite treatment for this species. However, the metalloprotease inhibitor Prinomastat substantially thwarted the procoagulant venom activity, while 2,3-dimercapto-1-propanesulfonic acid (DMPS) was much less effective. These results confirm that venom-induced Factor X activation (a procoagulant action) is driven by metalloproteases, while also suggesting Prinomastat as a more promising potential adjunct treatment than DMPS for this species (with the caveat that in vivo studies are necessary to confirm this potential clinical use). Conversely, the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) inhibited the direct fibrinogen cleaving actions of C. mictlantecuhtli venom, thereby revealing that the pseudo-procoagulant action is driven by kallikrein-type serine proteases. Thus, this differential ontogenetic variation in coagulotoxicity patterns poses intriguing questions. Our results underscore the need for further research into Mexican rattlesnake venom activity, and also highlights potential limitations of current antivenom treatments.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Venenos de Crotalídeos/toxicidade , Animais , Antivenenos/imunologia , Fatores de Coagulação Sanguínea/metabolismo , Testes de Coagulação Sanguínea/métodos , Transtornos de Proteínas de Coagulação/sangue , Transtornos de Proteínas de Coagulação/diagnóstico , Transtornos de Proteínas de Coagulação/etiologia , Crotalus/classificação , Crotalus/genética , México , Testes de Neutralização
19.
Artigo em Inglês | MEDLINE | ID: mdl-33766656

RESUMO

What factors influence the evolution of a heavily selected functional trait in a diverse clade? This study adopts rattlesnakes as a model group to investigate the evolutionary history of venom coagulotoxicity in the wider context of phylogenetics, natural history, and biology. Venom-induced clotting of human plasma and fibrinogen was determined and mapped onto the rattlesnake phylogenetic tree to reconstruct the evolution of coagulotoxicity across the group. Our results indicate that venom phenotype is often independent of phylogenetic relationships in rattlesnakes, suggesting the importance of diet and/or other environmental variables in driving venom evolution. Moreover, the striking inter- and intraspecific variability in venom activity on human blood highlights the considerable variability faced by physicians treating envenomation. This study is the most comprehensive effort to date to describe and characterize the evolutionary and biological aspects of coagulotoxins in rattlesnake venom. Further research at finer taxonomic levels is recommended to elucidate patterns of variation within species and lineages.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Venenos de Crotalídeos/toxicidade , Animais , Crotalus , Evolução Molecular , Fibrinogênio/química , Humanos , Especificidade da Espécie
20.
Toxins (Basel) ; 13(2)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499001

RESUMO

The toxin composition of snake venoms and, thus, their functional activity, can vary between and within species. Intraspecific venom variation across a species' geographic range is a major concern for antivenom treatment of envenomations, particularly for countries like French Guiana that lack a locally produced antivenom. Bothrops asper and Bothrops atrox are the most medically significant species of snakes in Latin America, both producing a variety of clinical manifestations, including systemic bleeding. These pathophysiological actions are due to the activation by the venom of the blood clotting factors Factor X and prothrombin, thereby causing severe consumptive coagulopathy. Both species are extremely wide-ranging, and previous studies have shown their venoms to exhibit regional venom variation. In this study, we investigate the differential coagulotoxic effects on human plasma of six venoms (four B. asper and two B. atrox samples) from different geographic locations, spanning from Mexico to Peru. We assessed how the venom variation of these venom samples affects neutralisation by five regionally available antivenoms: Antivipmyn, Antivipmyn-Tri, PoliVal-ICP, Bothrofav, and Soro Antibotrópico (SAB). The results revealed both inter- and intraspecific variations in the clotting activity of the venoms. These variations in turn resulted in significant variation in antivenom efficacy against the coagulotoxic effects of these venoms. Due to variations in the venoms used in the antivenom production process, antivenoms differed in their species-specific or geographical neutralisation capacity. Some antivenoms (PoliVal-ICP, Bothrofav, and SAB) showed species-specific patterns of neutralisation, while another antivenom (Antivipmyn) showed geographic-specific patterns of neutralisation. This study adds to current knowledge of Bothrops venoms and also illustrates the importance of considering evolutionary biology when developing antivenoms. Therefore, these results have tangible, real-world implications by aiding evidence-based design of antivenoms for treatment of the envenomed patient. We stress that these in vitro studies must be backed by future in vivo studies and clinical trials before therapeutic guidelines are issued regarding specific antivenom use in a clinical setting.


Assuntos
Anticorpos Neutralizantes/farmacologia , Antivenenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Bothrops , Venenos de Crotalídeos/antagonistas & inibidores , Hemorragia/tratamento farmacológico , Mordeduras de Serpentes/tratamento farmacológico , Animais , Especificidade de Anticorpos , Bothrops/imunologia , Bothrops/metabolismo , Reações Cruzadas , Venenos de Crotalídeos/imunologia , Venenos de Crotalídeos/metabolismo , Hemorragia/sangue , Hemorragia/imunologia , Humanos , Mordeduras de Serpentes/sangue , Mordeduras de Serpentes/imunologia , Especificidade da Espécie
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