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1.
J Arthroplasty ; 39(8): 2147-2152.e1, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38452861

RESUMO

BACKGROUND: Total hip arthroplasty (THA) has become a common intervention for human immunodeficiency virus (HIV)-positive patients who have osteonecrosis of the femoral head. This paper provides a systematic review to assess survivorships, patient-reported outcomes (PROMs), infection rates, other complications, and immune competence for patients who had THAs who did and did not have HIV. METHODS: A comprehensive and systematic review of published studies investigating the outcomes of THA in HIV-positive patients (osteonecrosis and non-osteonecrosis patients) was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 10 studies with 9,534 HIV-positive patients fulfilled the inclusion and exclusion criteria. Manuscript quality was assessed on 2 scales: the Coleman Methodology Score and the level of evidence derived from Center for Evidence-Based Medicine criteria. Data were extracted from studies in the 5 key areas of interest: survivorships, PROMs, infection rates, complications, and clusters of differentiation-4 (CD4+) counts and viral loads. RESULTS: Implant survivorship was between 95% and 100%. Postoperative Harris Hip Scores were significantly improved from preoperative values in HIV-positive patients. Postoperative PROMs and infections did not appear to be different between HIV-positive and HIV-negative patients. Many of the cohort studies demonstrate comparable complication rates to matched controls. Where described (7 reports), mean CD4+ counts ranged from 425 to 646 cells/mm3, with low viral loads (3 reports) and variations not found to influence outcomes. CONCLUSIONS: THA is an effective treatment for HIV-positive patients, many of whom suffer from osteonecrosis of the femoral head. The results demonstrate excellent implant survivorship, improved quality of life, and a low risk of infections and complications.


Assuntos
Artroplastia de Quadril , Necrose da Cabeça do Fêmur , Humanos , Necrose da Cabeça do Fêmur/cirurgia , Infecções por HIV/complicações , Medidas de Resultados Relatados pelo Paciente , Complicações Pós-Operatórias/epidemiologia , Resultado do Tratamento
2.
Physiol Mol Biol Plants ; 30(3): 497-511, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38633271

RESUMO

Ziziphus nummularia an elite heat-stress tolerant shrub, grows in arid regions of desert. However, its molecular mechanism responsible for heat stress tolerance is unexplored. Therefore, we analysed whole transcriptome of Jaisalmer (heat tolerant) and Godhra (heat sensitive) genotypes of Z. nummularia to understand its molecular mechanism responsible for heat stress tolerance. De novo assembly of 16,22,25,052 clean reads yielded 276,029 transcripts. A total of 208,506 unigenes were identified which contains 4290 and 1043 differentially expressed genes (DEG) in TGO (treated Godhra at 42 °C) vs. CGO (control Godhra) and TJR (treated Jaisalmer at 42 °C) vs. CJR (control Jaisalmer), respectively. A total of 987 (67 highly enriched) and 754 (34 highly enriched) pathways were obsorved in CGO vs. TGO and CJR vs. TJR, respectively. Antioxidant pathways and TFs like Homeobox, HBP, ARR, PHD, GRAS, CPP, and E2FA were uniquely observed in Godhra genotype and SET domains were uniquely observed in Jaisalmer genotype. Further transposable elements were highly up-regulated in Godhra genotype but no activation in Jaisalmer genotype. A total of 43,093 and 39,278 simple sequence repeats were identified in the Godhra and Jaisalmer genotypes, respectively. A total of 10 DEGs linked to heat stress were validated in both genotypes for their expression under different heat stresses using quantitative real-time PCR. Comparing expression patterns of the selected DEGs identified ClpB1 as a potential candidate gene for heat tolerance in Z. nummularia. Here we present first characterized transcriptome of Z. nummularia in response to heat stress for the identification and characterization of heat stress-responsive genes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01431-y.

3.
J Evol Biol ; 36(2): 399-411, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36511814

RESUMO

The concept of ecomorphs, whereby species with similar ecologies have similar phenotypes regardless of their phylogenetic relatedness, is often central to discussions regarding the relationship between ecology and phenotype. However, some aspects of the concept have been questioned, and sometimes species have been grouped as ecomorphs based on phenotypic similarity without demonstrating ecological similarity. Within snakes, similar head shapes have convergently evolved in species living in comparable environments and/or with similar diets. Therefore, ecomorphs could exist in some snake lineages, but this assertion has rarely been tested for a wide-ranging group within a single framework. Natricine snakes (Natricinae) are ecomorphologically diverse and currently distributed in Asia, Africa, Europe and north-central America. They are primarily semiaquatic or ground-dwelling terrestrial snakes, but some are aquatic, burrowing or aquatic and burrowing in habit and may be generalist or specialist in diet. Thus, natricines present an interesting system to test whether snakes from different major habit categories represent ecomorphs. We quantify morphological similarity and disparity in head shape among 191 of the ca. 250 currently recognized natricine species and apply phylogenetic comparative methods to test for convergence. Natricine head shape is largely correlated with habit, but in some burrowers is better explained by dietary specialism. Convergence in head shape is especially strong for aquatic burrowing, semiaquatic and terrestrial ecomorphs and less strong for aquatic and burrowing ecomorphs. The ecomorph concept is useful for understanding natricine diversity and evolution, though would benefit from further refinement, especially for aquatic and burrowing taxa.


Assuntos
Colubridae , Serpentes , Animais , Filogenia , Serpentes/anatomia & histologia , Colubridae/anatomia & histologia , Dieta , Fenótipo , Europa (Continente) , Evolução Biológica
4.
Wilderness Environ Med ; 34(1): 96-99, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36400648

RESUMO

Pectoralis major tendon ruptures are rare injuries. We present a case of a pectoralis major tendon rupture incurred while bouldering that required surgical repair. The diagnosis of pectoralis major tendon rupture relies predominantly on clinical examination. Among athletes, outcomes after surgical repair are superior to those after nonoperative therapy in most cases of complete tendon rupture. Although infrequent, pectoralis major tendon ruptures can occur while climbing, and early recognition and expedited surgical treatment are paramount to maximize functional recovery.


Assuntos
Músculos Peitorais , Traumatismos dos Tendões , Humanos , Músculos Peitorais/cirurgia , Músculos Peitorais/lesões , Tendões , Traumatismos dos Tendões/diagnóstico , Traumatismos dos Tendões/etiologia , Traumatismos dos Tendões/cirurgia , Ruptura/cirurgia
5.
Environ Geochem Health ; 45(12): 8851-8865, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36700995

RESUMO

Weed infestation is a major biotic limitations in wheat cultivation; thus, various herbicides are being applied to control these weeds. Therefore, this study was undertaken for two successive years to assess degradation behaviours, persistence and residue risk imposed by carfentrazone, fenoxaprop-p-ethyl and pinoxaden sprayed as post-emergence herbicides in the wheat crop for management of weeds. Soil and crop samples were collected at periodically at after two hour of herbicide application till harvest of wheat crop and analysed by a high-performance liquid chromatograph. Degradation of carfentrazone, pinoxaden and fenoxaprop-p-ethyl, in the soil of wheat field occurred rapid to moderately with the mean half-life 9.92, 11.7 and 11.8 days, respectively. Persistence was found to be dependent on the weather parameters as well as physicochemical properties of the soil and herbicides. Half-life of studied herbicides was found to be negatively correlated with persistence (R2 0.38, p = 0.05, n = 3) and vapour pressure (R2 0.99, p = 0.05, n = 3). Principal component analysis revealed that the first two Principal Components (PCs) had eigenvalues more than 1, and the first and second PCs contributed 77.4 and 22.6% in herbicide residues and different parameters variation, respectively. Terminal residues of carfentrazone, pinoxaden and fenoxaprop-p-ethyl in the wheat straw, grains and soil were found below the maximum residue limits. Owing to the moderate persistence under wheat field conditions, carfentrazone, pinoxaden and fenoxaprop-p-ethyl are supposed to be safe for control of weeds in wheat crop and hence, suspected risk on the human and environment or crop produce under evaluated doses is negligible.


Assuntos
Herbicidas , Triticum , Humanos , Triticum/química , Solo/química , Herbicidas/análise , Herbicidas/metabolismo
6.
PLoS Pathog ; 16(2): e1008287, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32032366

RESUMO

Our inability to predict which mutations could result in antibiotic resistance has made it difficult to rapidly identify the emergence of resistance, identify pre-existing resistant populations, and manage our use of antibiotics to effectively treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is essential for emergence from hypoxia, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid and delamanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, before being exposed to the drug. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias , Farmacorresistência Bacteriana , Mutação , Mycobacterium tuberculosis , Nitroimidazóis/farmacologia , Nitrorredutases , Oxazóis/farmacologia , Engenharia de Proteínas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Nitrorredutases/genética , Nitrorredutases/metabolismo , Polimorfismo Genético
7.
Br J Sports Med ; 56(9): 515-520, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35144918

RESUMO

OBJECTIVE: To examine the current evidence regarding return-to-play (RTP) and performance after Achilles tendon rupture in elite athletes treated with operative intervention. DESIGN: Scoping review. DATA SOURCES: Published sources identified through a PubMed search of elite athletes, defined as professional or division one collegiate athletes in baseball, basketball, American football or soccer. METHODS: Our search yielded a total of 2402 studies, with 13 studies fulfilling the study criteria of reporting elite athletes with objective measures of their athletic performance. A total of 709 elite athletes were included from the NBA, NFL, Major League Baseball (MLB), National Collegiate Athletic Association (NCAA) football and professional soccer. RESULTS AND DISCUSSION: Overall, 61%-100% of elite male athletes RTP after Achilles tendon rupture and operative repair. NBA players had inferior performance compared with their preoperative status as well as controls of non-injured players. Studies did not show significantly different performance after Achilles injury for MLB players. Professional soccer, NFL and NCAA football studies reported varying performance after injury. CONCLUSIONS: Evidence suggests that sports with explosive plantarflexion demands, such as basketball, may be associated with a greater decrease in performance despite operative intervention after Achilles rupture.


Assuntos
Tendão do Calcâneo , Traumatismos do Tornozelo , Traumatismos em Atletas , Basquetebol , Futebol , Traumatismos dos Tendões , Humanos , Masculino , Tendão do Calcâneo/lesões , Tendão do Calcâneo/cirurgia , Atletas , Traumatismos em Atletas/cirurgia , Basquetebol/lesões , Volta ao Esporte , Traumatismos dos Tendões/cirurgia
8.
J Shoulder Elbow Surg ; 31(8): 1563-1570, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35351655

RESUMO

BACKGROUND: Ulnar collateral ligament (UCL) tears are prevalent in Major League Baseball (MLB) pitchers and can cause significant loss of time with varying reports of impact on performance. Revision UCL reconstruction (UCLR) is becoming increasingly common, with little known about the effects on fastball (FB) velocity and usage (FB%) in this setting. HYPOTHESIS/PURPOSE: The purpose was to evaluate the effect of revision UCLR on MLB pitchers with respect to postoperative FB velocity and FB% at 1 and 2 years after return to play. The hypothesis was postoperative FB velocity and FB% would significantly decrease vs. prerevision levels, and that revision UCLRs would result in significantly decreased FB velocity and FB% in comparison to a matched group of MLB pitchers after primary UCLR. METHODS: Twenty-one pitchers who underwent revision UCLR and returned to MLB play were identified from public records from 2008-2021. The PITCHf(x) system collected FB velocity for 4-seam (4FB) and 2-seam (2FB) fastballs and total FB% for pitchers in the prerevision year as well as the 2 years after return. A matched control group of pitchers who underwent primary UCLR was used for comparison. RESULTS: There were no significant differences in FB velocity between prerevision levels (4FB 92.9 mph, 2FB 91.4 mph) and years 1 (4FB 92.5 mph, 2FB 91.2 mph) and 2 (4FB 93.4 mph, 2FB 91.1 mph) after revision UCLR. FB% decreased from the prerevision season (60.1) and the first (56.2, P = .036) and second years (52.5, P = .002) after return. There were no significant differences between FB velocity and FB% or between the revision and primary UCLR groups. CONCLUSION: Pitchers returning to the MLB level after revision UCLR can expect similar FB velocity to their prerevision FB velocity and to pitchers undergoing primary UCLR; however, they do demonstrate a decrease in FB%, which may suggest less confidence in their FB after RTP.


Assuntos
Beisebol , Ligamento Colateral Ulnar , Articulação do Cotovelo , Reconstrução do Ligamento Colateral Ulnar , Ligamento Colateral Ulnar/cirurgia , Articulação do Cotovelo/cirurgia , Humanos , Período Pós-Operatório , Reconstrução do Ligamento Colateral Ulnar/métodos
9.
Chin J Traumatol ; 25(6): 395-399, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35450804

RESUMO

Subcutaneous emphysema is commonly associated with infection caused by gas-producing organisms. In this case report, we describe a rare instance of traumatic subcutaneous emphysema of the hand and forearm caused by a puncture injury to the first web space of the hand. Our objective is to increase awareness of the potential for seemingly minor trauma to cause entrapment of significant air in subcutaneous tissues, thereby decreasing the likelihood that a clinically benign-appearing patient will be started down an unnecessarily aggressive treatment pathway. A 16-year-old, otherwise healthy white female, presented to the pediatric emergency room with an impressive amount of subcutaneous emphysema that developed over a 12-h period after sustaining an accidental laceration to the first web space of her right hand. She appeared nontoxic and had a clinically benign presentation. A comprehensive work-up was performed. She was splinted by the orthopedic surgery resident on call, and was admitted to the Pediatric Intensive Care Unit for overnight monitoring. She received tetanus vaccination and broad-spectrum antibiotics. The patient was discharged 2 days after admittance, with a splint applied to her right hand and forearm. She undertook home-based physical and occupational therapy. She had a pain-free range-of-motion in the right wrist, elbow and shoulder. The swelling in the right hand subsided completely. Although initially alarming, traumatic subcutaneous emphysema in an otherwise healthy patient from minor wounds (as featured in this case) does not necessarily mean one ought to proceed down an aggressive treatment algorithm. Careful evaluation of the patient's history, clinical examination findings, and determination of the Laboratory Risk Indicator for Necrotizing Fasciitis score can help guide physicians in the management of traumatic subcutaneous emphysema and potentially avoid unnecessary and costly interventions.


Assuntos
Enfisema Subcutâneo , Ferimentos Penetrantes , Humanos , Criança , Feminino , Adolescente , Antebraço , Enfisema Subcutâneo/etiologia , Enfisema Subcutâneo/terapia , Enfisema Subcutâneo/diagnóstico , Extremidade Superior , Antibacterianos/uso terapêutico , Ferimentos Penetrantes/cirurgia
10.
Antimicrob Agents Chemother ; 65(11): e0141821, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34460302

RESUMO

Telacebec (Q203) is a new antituberculosis drug in clinical development that has extremely potent activity against Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU). The potency of Q203 has prompted investigation of its potential role in ultrashort, even single-dose, treatment regimens for BU in mouse models. However, the relationships of Q203 dose, dose schedule, duration, and host immune status to treatment outcomes remain unclear, as does the risk of emergence of drug resistance with Q203 monotherapy. Here, we used mouse footpad infection models in immunocompetent BALB/c and immunocompromised SCID-beige mice to compare different Q203 doses, different dosing schedules, and treatment durations ranging from 1 day to 2 weeks, on long-term outcomes. We also tested whether combining Q203 with a second drug can increase efficacy. Overall, efficacy depended on total dose more than on duration. Total doses of 5 to 20 mg/kg rendered nearly all BALB/c mice culture negative by 13 to 14 weeks posttreatment, without selection of Q203-resistant bacteria. Addition of a second drug did not significantly increase efficacy. Although less potent in SCID-beige mice, Q203 still rendered the majority of footpads culture negative at total doses of 10 to 20 mg/kg. Q203 resistance was identified in relapse isolates from some SCID-beige mice receiving monotherapy but not in isolates from those receiving Q203 combined with bedaquiline or clofazimine. Overall, these results support the potential of Q203 monotherapy for single-dose or other ultrashort therapy for BU, although highly immunocompromised hosts may require higher doses or durations and/or combination therapy.


Assuntos
Úlcera de Buruli , Mycobacterium ulcerans , Animais , Úlcera de Buruli/tratamento farmacológico , Imidazóis , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Piperidinas , Piridinas
11.
Mol Phylogenet Evol ; 161: 107152, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33741534

RESUMO

Phylogenetic relationships of sub-Saharan African natricine snakes are understudied and poorly understood, which in turn has precluded analyses of the historical biogeography of the Seychelles endemic Lycognathophis seychellensis. We inferred the phylogenetic relationships of Seychelles and mainland sub-Saharan natricines by analysing a multilocus DNA sequence dataset for three mitochondrial (mt) and four nuclear (nu) genes. The mainland sub-Saharan natricines and L. seychellensis comprise a well-supported clade. Two maximally supported sets of relationships within this clade are (Limnophis,Natriciteres) and (Afronatrix,(Hydraethiops,Helophis)). The relationships of L. seychellensis with respect to these two lineages are not clearly resolved by analysing concatenated mt and nu data. Analysed separately, nu data best support a sister relationship of L. seychellensis with (Afronatrix,(Hydraethiops,Helophis)) and mt data best support a sister relationship with all mainland sub-Saharan natricines. Methods designed to cope with incomplete lineage sorting strongly favour the former hypothesis. Genetic variation among up to 33 L. seychellensis from five Seychelles islands is low. Fossil calibrated divergence time estimates support an overseas dispersal of the L. seychellensis lineage to the Seychelles from mainland Africa ca. 43-25 million years before present (Ma), rather than this taxon being a Gondwanan relic.


Assuntos
Colubridae/genética , Evolução Molecular , Filogenia , Filogeografia , África Subsaariana , Animais , Análise de Sequência de DNA , Seicheles
12.
Artigo em Inglês | MEDLINE | ID: mdl-32205344

RESUMO

Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to ≤ 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.


Assuntos
Úlcera de Buruli , Mycobacterium ulcerans , Animais , Antibacterianos/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Quimioterapia Combinada , Imidazóis , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas , Piridinas
13.
J Surg Oncol ; 121(7): 1104-1114, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32153042

RESUMO

BACKGROUND AND OBJECTIVES: Acetabular reconstruction with a coned-stem prosthesis has been one of the reliable procedures following pelvic tumor resections but is associated with a risk of complications and postoperative morbidity. We investigated whether navigated reconstruction could decrease the complication rate and optimize outcomes. METHODS: A retrospective study was conducted on 33 patients who underwent acetabular resection and reconstruction with ice-cream cone prostheses; outcomes were compared between the navigated and nonnavigated groups. RESULTS: A clear margin was obtained in 91% and 82% of the navigated and nonnavigated groups, respectively. The local recurrence (LR) rate was 12%, and all LRs occurred in the nonnavigated group. The rate of major complications requiring surgical intervention was significantly lower in the navigated group (9%) than in the nonnavigated group (50%; P = .024). Two implant failures occurred in the nonnavigated group. Functional outcomes were significantly correlated with the occurrence of major complications (P = .010) and the use of navigation (P = .043); superior functional scores were observed in the navigated group (Musculoskeletal Tumor Society, 73% vs 55%; Toronto Extremity Salvage Score, 73% vs 56%). CONCLUSION: Ice-cream cone prosthesis is an acceptable reconstruction modality following periacetabular tumor resections, and computer navigation are useful to facilitate proper resection margins and implant position.


Assuntos
Acetábulo/cirurgia , Neoplasias Ósseas/cirurgia , Prótese de Quadril , Neoplasias Pélvicas/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Pélvicas/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Implantação de Prótese/efeitos adversos , Implantação de Prótese/instrumentação , Implantação de Prótese/métodos , Procedimentos de Cirurgia Plástica/efeitos adversos , Procedimentos de Cirurgia Plástica/instrumentação , Estudos Retrospectivos , Cirurgia Assistida por Computador/efeitos adversos , Cirurgia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X , Adulto Jovem
14.
Artigo em Inglês | MEDLINE | ID: mdl-31036687

RESUMO

Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc1:aa3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidase-deficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 µg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.


Assuntos
Antibacterianos/farmacologia , Úlcera de Buruli/tratamento farmacológico , Mycobacterium ulcerans/efeitos dos fármacos , Animais , Carga Bacteriana , Úlcera de Buruli/microbiologia , Úlcera de Buruli/patologia , Claritromicina/farmacologia , Clofazimina/farmacologia , Modelos Animais de Doenças , Farmacorresistência Bacteriana/efeitos dos fármacos , Quimioterapia Combinada , Transporte de Elétrons/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium ulcerans/genética , Piperidinas/farmacologia , Piridinas/farmacologia , Rifampina/análogos & derivados , Rifampina/farmacologia , Estreptomicina/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-30559131

RESUMO

Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control regimens of RIF plus either streptomycin (STR) or CLR or test regimens of RIF plus either LZD (1 of 2 doses), SZD, or TZD for up to 8 weeks. All combination regimens reduced the swelling and bacterial burden in footpads after two weeks of treatment compared with RIF alone. RIF+SZD was the most active test regimen, while RIF+LZD was also no less active than RIF+CLR. After 4 and 6 weeks of treatment, neither CLR nor the oxazolidinones added significant bactericidal activity to RIF alone. By the end of 8 weeks of treatment, all regimens rendered footpads culture negative. We conclude that SZD and LZD warrant consideration as alternative companion agents to CLR in combination with RIF to treat BU, especially when CLR is contraindicated, intolerable, or unavailable. Further evaluation could prove SZD superior to CLR in this combination.


Assuntos
Antibacterianos/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Mycobacterium ulcerans/efeitos dos fármacos , Oxazolidinonas/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Claritromicina/uso terapêutico , Modelos Animais de Doenças , Feminino , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Oxazolidinonas/efeitos adversos , Rifampina/uso terapêutico , Tetrazóis/efeitos adversos
16.
Artigo em Inglês | MEDLINE | ID: mdl-30833432

RESUMO

Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined, and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in a 1-log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to that for BMZ treatment alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 versus 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to the level for BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.


Assuntos
Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Linezolida/uso terapêutico , Moxifloxacina/uso terapêutico , Nitroimidazóis/uso terapêutico , Pirazinamida/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Ribossômico 16S/genética , Tuberculose/tratamento farmacológico , Tuberculose/genética
17.
Opt Express ; 27(18): 26203-26217, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31510479

RESUMO

Silicon slot waveguide Bragg gratings have been designed, fabricated and the experimental data has been analyzed for its slow light properties. Slow light with a group index of 12.38 at a wavelength near 1555 nm and having a low propagation loss of 5.1 dB/mm has been determined for internally corrugated slot waveguide Bragg gratings on a silicon-on-insulator platform. The combination of slow light and low propagation loss make the internally corrugated slot waveguide Bragg gratings especially attractive as a phase shifter section for low drive voltage, high speed and compact electro-optic modulators.

18.
J Wound Care ; 28(12): 850-860, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31825775

RESUMO

OBJECTIVE: The objective of this study was to compare the ability of foam dressing-based and non-foam-based closed incision negative pressure therapy (ciNPT) systems to close isolated incisional deficits in a tissue model. METHODS: Similarly sized foam-based and non-foam-based absorbent ciNPT dressings were applied to ~36cm long, ~3mm and ~6mm wide simulated incisions in gel sheets covered with drape (n=6 dressings/group/experimental condition spread over three respective therapy units). Changes in incision widths were measured directly or with overlying solid gel sheeting (to mimic tissue resistance), at five equally spaced locations before, immediately upon and one hour after initiating negative pressure using associated therapy units. RESULTS: Foam-based ciNPT closed simulated incisions more often than non-foam-based ciNPT in all tested conditions (p<0.05). While foam-based ciNPT almost completely closed the ~3mm wide incisional spaces, unlike non-foam-based ciNPT, the biggest differences between the two groups were observed with the ~6mm incisional width, which allowed maximal inward-stretching of the appositional faces without complete closure. The additional gel layer blunted closure in both groups, but much more with non-foam-based ciNPT. There was minimal impact of negative pressure duration on these results. CONCLUSION: Foam-based ciNPT closed incisional widths in simulated tissue significantly more compared with non-foam-based ciNPT. Different ciNPT systems should not be considered necessarily equivalent in performance.


Assuntos
Modelos Anatômicos , Tratamento de Ferimentos com Pressão Negativa , Infecção da Ferida Cirúrgica/prevenção & controle , Humanos , Infecção da Ferida Cirúrgica/enfermagem , Cicatrização
19.
Curr Issues Mol Biol ; 27: 1-36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28885172

RESUMO

The history of DNA sequencing dates back to 1970s. During this period the two first generation nucleotide sequencing techniques were developed. Subsequently the Sanger's dideoxy method of sequencing gained popularity over Maxam and Gilbert's chemical method of sequencing. However, in the last decade, we have observed revolutionary changes in DNA sequencing technologies leading to the emergence of next-generation sequencing (NGS) techniques. NGS technologies have enhanced the throughput and speed of sequencing combined with bringing down the overall cost of the process over a time. The major applications of NGS technologies being genome sequencing and resequencing, transcriptomics, metagenomics in relation to plant-microbe interactions, exon and genome capturing, development of molecular markers and evolutionary studies. In this review, we present a broader picture of evolution of NGS tools, its various applications in crop plants, and future prospects of the technology for crop improvement.


Assuntos
Produtos Agrícolas/genética , DNA de Plantas/genética , Genoma de Planta , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Raízes de Plantas/genética , Plantas/genética , Mapeamento Cromossômico , Cromossomos de Plantas/química , Produtos Agrícolas/microbiologia , DNA de Plantas/química , Marcadores Genéticos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/história , Sequenciamento de Nucleotídeos em Larga Escala/tendências , História do Século XX , História do Século XXI , Metagenômica/métodos , Raízes de Plantas/microbiologia , Plantas/microbiologia , Rizosfera , Simbiose , Transcriptoma
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