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1.
Bioorg Med Chem Lett ; 85: 129237, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36924945

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and a significant risk factor for ischemic stroke and heart failure. Marketed anti-arrhythmic drugs can restore sinus rhythm, but with limited efficacy and significant toxicities, including potential to induce ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potassium channel 1/4). Here we describe 14b, a potent GIRK1/4 inhibitor developed to cardiovert AF to sinus rhythm while minimizing central nervous system exposure - an issue with preceding GIRK1/4 clinical candidates.


Assuntos
Fibrilação Atrial , Humanos , Fibrilação Atrial/tratamento farmacológico , Cardioversão Elétrica , Átrios do Coração , Encéfalo
2.
Prostate ; 82(14): 1338-1345, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35789497

RESUMO

BACKGROUND: The objective of this study was to report acute changes in patient-reported quality of life (PRQOL) using the 26-item Expanded Prostate Index Composite (EPIC-26) questionnaire in a prospective study using hypofractionated intensity-modulated proton beam therapy (H-IMPT) targeting the prostate and the pelvic lymph nodes for high-risk or unfavorable intermediate-risk prostate cancer. METHODS: Fifty-five patients were enrolled. H-IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC-26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation. RESULTS: The mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (-13.5 and -2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (-13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful. CONCLUSIONS: UO, UI, and BF scores of PRQOL declined at the end of H-IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.


Assuntos
Neoplasias da Próstata , Terapia com Prótons , Incontinência Urinária , Humanos , Linfonodos/patologia , Masculino , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Próstata/patologia , Neoplasias da Próstata/patologia , Qualidade de Vida
3.
J Hum Nutr Diet ; 35(2): 363-375, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33908093

RESUMO

BACKGROUND: A 25-hydroxyvitamin D (25OHD) may exert immunomodulatory effects on respiratory health, which may translate to improvements in exercise physiology. Thus, we aimed to investigate whether plasma 25OHD is associated with lung function and aerobic fitness in people with cystic fibrosis (pwCF). METHODS: A multicentre retrospective review of pwCF (> 9 years old) attending the Royal Hospital for Sick Children (Edinburgh) or Wessex CF-Unit (Southampton) was performed between July 2017 and October 2019. Demographic and clinical data were collected. Plasma 25OHD measured closest in time to clinical cardiopulmonary exercise testing and/or spirometry [forced expiratory volume (FEV1 )% predicted] was recorded. Pancreatic insufficiency was diagnosed based on faecal elastase of < 100 µg g-1 . We performed multiple-regression analysis with aerobic fitness outcomes [peak oxygen uptake (VO2 peak )] and FEV1 % predicted as primary outcomes. RESULTS: Ninety pwCF [mean ± SD age: 19.1 ± 8.6 years, 54 (60%) children, 48 (53%) males and 88 (98%) Caucasian] were included. 25OHD deficiency and insufficiency was 15 (17%) and 44 (49%), respectively. 25OHD deficiency and insufficiency was significantly associated with pancreatic insufficiency (χ2  = 4.8, p = 0.02). Plasma 25OHD was not significantly associated with FEV1 % predicted (r2  = 0.06, p = 0.42, 95% CI = -0.09 to 0.19) or VO2 peak (r2  = 0.04, p = 0.07, 95% CI = -011 to 0.005) in all pwCF. However, 25OHD was significantly associated with both FEV1 % (r2  = 0.15, p = 0.02, 95% CI = 1.99-2.64) and VO2 peak (r2  = 0.13, p = 0.05, 95% CI = -0.26 to -0.005) in the paediatric cohort. CONCLUSIONS: We showed that 25OHD is associated with improved lung function and aerobic fitness in children and adolescents with CF. Mechanistic and high-quality prospective studies including both lung function and aerobic fitness as primary outcomes are now warranted.


Assuntos
Fibrose Cística , Insuficiência Pancreática Exócrina , Adolescente , Adulto , Criança , Fibrose Cística/complicações , Feminino , Humanos , Pulmão , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Vitamina D/análogos & derivados , Adulto Jovem
4.
Clin Infect Dis ; 67(4): 614-616, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29579163

RESUMO

Doxycycline is recommended for persons with Ixodes scapularis tick bites in certain geographic areas, if the tick had fed for at least 36 hours. Based on the scutal index, over 40% of I. scapularis tick bites from patients seen at the Lyme Disease Diagnostic Center did not warrant antibiotic prophylaxis.


Assuntos
Antibioticoprofilaxia , Comportamento Alimentar , Ixodes/fisiologia , Doença de Lyme/tratamento farmacológico , Picadas de Carrapatos , Fatores de Tempo , Animais , Doxiciclina/uso terapêutico , Feminino , Humanos , Doença de Lyme/diagnóstico , New York
5.
Mol Ther ; 25(9): 2104-2116, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28750737

RESUMO

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.


Assuntos
Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Fibrose Cística/complicações , Óxido Nítrico/administração & dosagem , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Adolescente , Adulto , Carga Bacteriana , Relação Dose-Resposta a Droga , Humanos , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Infecções por Pseudomonas/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Escarro/microbiologia , Fatores de Tempo , Adulto Jovem
6.
J Appl Clin Med Phys ; 19(6): 140-148, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30328674

RESUMO

PURPOSE: To compare dosimetric performance of volumetric-modulated arc therapy (VMAT) and small-spot intensity-modulated proton therapy for stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: A total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity-modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D-CTs. The dose-volume-histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test. RESULTS: Compared with VMAT, IMPT delivered significantly lower cord Dmax , heart Dmean , and lung V5 Gy[ RBE ] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean , but were statistically worse in CTV dose coverage, cord Dmax , lung Dmean , and V5 Gy[ RBE ] . Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered. CONCLUSIONS: Small-spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Terapia com Prótons/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Radiometria/métodos , Dosagem Radioterapêutica , Estudos Retrospectivos
7.
Mol Ecol ; 25(19): 4963-77, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27588381

RESUMO

Blacklegged ticks (Ixodes scapularis) are one of the most important pathogen vectors in the United States, responsible for transmitting Lyme disease and other tick-borne diseases. The structure of a host's microbial community has the potential to affect the ecology and evolution of the host. We employed high-throughput sequencing of the 16S rRNA gene V3-V4 hypervariable regions in the first study to investigate the tick microbiome across all developmental stages (larvae, nymphs, adults). In addition to field-collected life stages, newly hatched laboratory-reared larvae were studied to determine the baseline microbial community structure and to assess transovarial transmission. We also targeted midguts and salivary glands due to their importance in pathogen maintenance and transmission. Over 100 000 sequences were produced per life stage replicate. Rickettsia was the most abundant bacterial genus across all sample types matching mostly the Ixodes rickettsial endosymbionts, and its proportion decreased as developmental stage progressed, with the exception of adult females that harboured a mean relative abundance of 97.9%. Laboratory-reared larvae displayed the lowest bacterial diversity, containing almost exclusively Rickettsia. Many of the remaining bacteria included genera associated with soil, water and plants, suggesting environmental acquisition while off-host. Female organs exhibited significantly different ß-diversity than the whole tick from which they were derived. Our results demonstrate clear differences in both α- and ß-diversity among tick developmental stages and between tick organs and the tick as a whole. Furthermore, field-acquired bacteria appear to be very important to the overall internal bacterial community of this tick species, with influence from the host bloodmeal appearing limited.


Assuntos
Bactérias/classificação , Ixodes/microbiologia , Microbiota , Animais , Feminino , Larva/microbiologia , New York , Ninfa/microbiologia , RNA Ribossômico 16S/genética , Rickettsia/classificação , Rickettsia/isolamento & purificação
8.
Bioorg Med Chem Lett ; 26(4): 1245-8, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26804232

RESUMO

Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diamida/química , Inibidores Enzimáticos/química , Animais , Linhagem Celular Tumoral , Diacilglicerol O-Aciltransferase/metabolismo , Diamida/síntese química , Diamida/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
J Med Entomol ; 52(5): 1103-10, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26336232

RESUMO

Ticks and whole blood were collected from American black bears (Ursus americanus Pallas) between October 2011 and October 2012 across four counties in northwestern New Jersey, an area where blacklegged ticks (Ixodes scapularis Say) and their associated tick-borne pathogens are prevalent. Adult American dog ticks (Dermacentor variabilis Say) were the most frequently collected tick species in late spring, whereas adult and nymphal blacklegged ticks were found in both the late spring and fall months. Additionally, for blacklegged ticks, we determined the quality of bloodmeals that females acquired from black bears compared with bloodmeals from white-tailed deer (Odocoileus virginianus Zimmerman), the most important host for the adult stage of this tick species. Measures of fecundity after feeding on each host species were not significantly different, suggesting that the bloodmeal a female blacklegged tick acquires from a black bear is of similar quality to that obtained from a white-tailed deer. These results establish the American black bear as both a host and quality bloodmeal source to I. scapularis. Thus, black bears may help support blacklegged tick populations in areas where they are both present. In addition, samples of black bear blood were tested for DNA presence of three tick-borne pathogens. Anaplasma phagocytophilum Foggie and Babesia microti Franca were found in 9.2 and 32.3% of blood samples, respectively. All blood samples were quantitative polymerase chain reaction-negative for Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt, & Brenner. Although circulating pathogens were found in blood, the status of black bears as reservoirs for these pathogens remains unknown.


Assuntos
Babesiose/epidemiologia , Ehrlichiose/epidemiologia , Ixodes/fisiologia , Doença de Lyme/epidemiologia , Infestações por Carrapato/veterinária , Ursidae/parasitologia , Anaplasma phagocytophilum/fisiologia , Animais , Babesia microti/fisiologia , Babesiose/microbiologia , Babesiose/transmissão , Borrelia burgdorferi/fisiologia , Ehrlichiose/microbiologia , Ehrlichiose/transmissão , Feminino , Doença de Lyme/microbiologia , Doença de Lyme/transmissão , Masculino , New Jersey/epidemiologia , Prevalência , Infestações por Carrapato/epidemiologia , Infestações por Carrapato/parasitologia
10.
Environ Microbiol ; 16(4): 1069-80, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24148079

RESUMO

Borrelia burgdorferi sensu lato (s.l.), transmitted by Ixodes spp. ticks, is the causative agent of Lyme disease. Although Ixodes spp. ticks are distributed in both Northern and Southern Hemispheres, evidence for the presence of B. burgdorferi s.l. in South America apart from Uruguay is lacking. We now report the presence of culturable spirochetes with flat-wave morphology and borrelial DNA in endemic Ixodes stilesi ticks collected in Chile from environmental vegetation and long-tailed rice rats (Oligoryzomys longicaudatus). Cultured spirochetes and borrelial DNA in ticks were characterized by multilocus sequence typing and by sequencing five other loci (16S and 23S ribosomal genes, 5S-23S intergenic spacer, flaB, ospC). Phylogenetic analysis placed this spirochete as a new genospecies within the Lyme borreliosis group. Its plasmid profile determined by polymerase chain reaction and pulsed-field gel electrophoresis differed from that of B. burgdorferi B31A3. We propose naming this new South American member of the Lyme borreliosis group B. chilensis VA1 in honor of its country of origin.


Assuntos
Grupo Borrelia Burgdorferi/genética , Grupo Borrelia Burgdorferi/isolamento & purificação , Animais , Sequência de Bases , Grupo Borrelia Burgdorferi/classificação , Chile , DNA Bacteriano/genética , Cervos/parasitologia , Feminino , Ixodes/microbiologia , Ixodes/fisiologia , Masculino , Dados de Sequência Molecular , Filogenia , Roedores/parasitologia
11.
Urol Pract ; 11(1): 146-152, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37917577

RESUMO

INTRODUCTION: As overall survival in prostate cancer increases due to advances in early detection and management, there is a growing need to understand the long-term morbidity associated with treatment, including secondary tumors. The significance of developing radiation-associated secondary cancers in an elderly population remains unknown. METHODS: Patients diagnosed with prostate cancer between 1975 and 2016 in one of 9 Surveillance, Epidemiology, and End Results registries were included in this study. Risk of second primary pelvic malignancies (SPPMs) were assessed with death as a competing risk using the Fine-Gray model. Time-varying Cox proportional hazard models were employed to analyze risk to overall mortality based on secondary tumor status. RESULTS: A total of 569,167 primary prostate cancers were included in analysis with an average follow-up of 89 months. Among all prostate cancer patients, 4956 SPPMs were identified. After controlling for differences in age, year of diagnosis, and surgery at time of prostate cancer treatment, radiation receipt was associated with a significantly higher incidence of SPPMs (1.1% vs 1.8% at 25 years). Among those who received radiation during initial prostate cancer treatment (n = 195,415), developing an SPPM is significantly associated with worse survival (adjusted hazard ratio = 1.76), especially among younger patients (under age 63, adjusted hazard ratio = 2.36). CONCLUSIONS: While developing a secondary malignancy carries a detrimental effect on overall survival, the absolute risk of developing such tumors is exceedingly low regardless of radiation treatment.


Assuntos
Neoplasias Induzidas por Radiação , Segunda Neoplasia Primária , Neoplasias da Próstata , Masculino , Humanos , Idoso , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Prognóstico , Neoplasias Induzidas por Radiação/diagnóstico , Próstata , Neoplasias da Próstata/epidemiologia
12.
J Cyst Fibros ; 23(3): 375-387, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38789317

RESUMO

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.


Assuntos
Fibrose Cística , Fibrose Cística/terapia , Humanos , Padrão de Cuidado , Qualidade de Vida
13.
J Clin Microbiol ; 51(12): 4029-35, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24068019

RESUMO

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary function, leading to compromised airway clearance and chronic bacterial infection of the upper and lower airways. The compositions of these infections and the relationships between their characteristics and disease presentation are poorly defined. We describe here the first systematic culture-independent evaluation of lower airway bacteriology in PCD. Thirty-three airway samples (26 from sputum, 7 from bronchoalveolar lavage [BAL] fluid) were collected from 24 PCD patients aged 4 to 73 years. 16S rRNA quantitative PCR and pyrosequencing were used to determine the bacterial loads and community compositions of the samples. Bacterial loads, which ranged from 1.3 × 10(4) to 5.2 × 10(9) CFU/ml, were positively correlated with age (P = 0.002) but not lung function. An analysis of ∼7,000 16S rRNA sequences per sample identified bacterial species belonging to 128 genera. The concurrently collected paired samples showed high bacterial community similarity. The mean relative abundance of the dominant genera was 64.5% (standard deviation [SD], 24.5), including taxa reported through standard diagnostic microbiology (members of the genera Pseudomonas, Haemophilus, and Streptococcus) and those requiring specific ex vivo growth conditions (members of the genera Prevotella and Porphyromonas). The significant correlations observed included a positive relationship between Pseudomonas aeruginosa relative abundance and age and a negative relationship between P. aeruginosa relative abundance and lung function. Members of the genus Ralstonia were also found to contribute substantially to the bacterial communities in a number of patients. Follow-up samples from a subset of patients revealed high levels of bacterial community temporal stability. The detailed microbiological characterization presented here provides a basis for the reassessment of the clinical management of PCD airway infections.


Assuntos
Bactérias/classificação , Bactérias/genética , Biota , Síndrome de Kartagener , Sistema Respiratório/microbiologia , Adolescente , Adulto , Idoso , Carga Bacteriana , Criança , Pré-Escolar , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Feminino , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Adulto Jovem
15.
J Infect Dis ; 205(6): 991-4, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21930606

RESUMO

A prior study in mice has shown that the timely application of topical antibiotics to the skin at the tick bite site could eradicate Borrelia burgdorferi infection. That study, however, did not evaluate antibiotic preparations that are considered suitable for use in humans. In this murine study, topical application of 2% erythromycin and 3% tetracycline preparations that are acceptable for use in humans was found to be ineffective in eliminating B. burgdorferi from the tick bite site or in preventing dissemination to other tissues. Reasons for the discrepant findings are discussed.


Assuntos
Antibacterianos/uso terapêutico , Borrelia burgdorferi/efeitos dos fármacos , Borrelia burgdorferi/patogenicidade , Eritromicina/uso terapêutico , Doença de Lyme/prevenção & controle , Tetraciclina/uso terapêutico , Administração Cutânea , Animais , Mordeduras e Picadas de Insetos/microbiologia , Doença de Lyme/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C3H
16.
Biomed Pharmacother ; 157: 114013, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36403566

RESUMO

BACKGROUND: Lyme disease is a serious infectious disease having a restricted worldwide distribution for which there is no vaccine available for human use. OBJECTIVE: This study was designed to determine common reactive antigens involved in Borrelia burgdorferi (Bb) infection that are recognized in mammalian sera that may be useful for vaccine development. METHODS: Blood samples were collected from patients with documented Lyme disease, and from rabbits and mice experimentally infected with either tick-transmitted or culture-grown Borrelia burgdorferi. All samples were then processed for sera. For performing the Western blots, sonicated Bb organisms (whole cell lysates) and protein ladders were separated by protein gel electrophoresis. Immune reactivities of the electrophoresed proteins with the serum samples were then probed with anti-HRP IgG reagent. RESULTS: Rabbit, mouse and human sera consistently reacted with the 41 kDa band of Bb which corresponded to the flagellin protein - the major protein component of this organism's periplasmic flagella, also known as axial filaments or fibrils. Various other Bb antigens of wide molecular weight ranges were also recognized by rabbit and human sera, and less frequently with mouse sera. CONCLUSION: The strong immune response to the 41 kDa flagellin protein by the different mammalian species suggests the utility of a possible vaccine targeting this protein, although other proteins may also be appropriate, for preventing Lyme disease following a bite from an infected tick.


Assuntos
Grupo Borrelia Burgdorferi , Borrelia burgdorferi , Doença de Lyme , Humanos , Camundongos , Coelhos , Animais , Vacinas contra Doença de Lyme , Doença de Lyme/prevenção & controle , Western Blotting , Flagelina , Mamíferos
17.
Int J Radiat Oncol Biol Phys ; 115(5): 1085-1094, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36427645

RESUMO

PURPOSE: To evaluate late gastrointestinal (GI) and genitourinary (GU) toxicity of moderately hypofractionated intensity modulated proton therapy (IMPT) targeting the prostate and pelvic lymph nodes. METHODS AND MATERIALS: A target accrual of 56 patients with high-risk or unfavorable intermediate risk prostate cancer were enrolled into a prospective study (ClinicalTrials.gov: NCT02874014) of moderately hypofractionated IMPT. IMPT with pencil beam scanning was used to deliver 6750 and 4500 cGy relative biological effectiveness in 25 daily fractions simultaneously to the prostate and pelvic lymph nodes, respectively. All received androgen deprivation therapy. Late GI and GU toxicity was prospectively assessed using Common Terminology Criteria for Adverse Events version 4.0, at baseline, weekly during radiation therapy, 3-month postradiation therapy, and then every 6 months. Actuarial rates of late GI and GU toxicity were estimated using Kaplan-Meier method. RESULTS: Median age was 75.5 years. Fifty-four patients were available for late toxicity evaluation. Median follow-up was 43.9 months (range, 16-66). The actuarial rate of late grade ≥2 GI toxicity at both 2 and 3 years was 7.4% (95% confidence interval [CI], 0.2%-14.2%). The actuarial rate of late grade 3 GI toxicity at both 2 and 3 years was 1.9% (95% CI, 0%-5.4%). One patient experienced grade 3 GI toxicity with proctitis. The actuarial rate of late grade ≥2 GU toxicity was 20.5% (95% CI, 8.9%-30.6%) at 2 years, and 29.2 % (95% CI, 15.5%-40.7%) at 3 years. None had grade 3 GU toxicity. The presence of baseline GU symptoms was associated with a higher likelihood of experiencing late grade 2 GU toxicity. CONCLUSIONS: A moderately hypofractionated IMPT targeting the prostate and regional pelvic lymph nodes was generally well tolerated. Patients with pre-existing GU symptoms had a higher rate of late grade 2 GU toxicity. A phase 3 study is needed to assess any therapeutic gain of IMPT, in comparison with photon-based radiation therapy.


Assuntos
Neoplasias da Próstata , Terapia com Prótons , Radioterapia de Intensidade Modulada , Masculino , Humanos , Idoso , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Terapia com Prótons/efeitos adversos , Estudos Prospectivos , Antagonistas de Androgênios/uso terapêutico , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos
18.
J Cyst Fibros ; 22(3): 374-380, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36882349

RESUMO

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication.


Assuntos
Fibrose Cística , Transplante de Pulmão , Humanos , Fibrose Cística/cirurgia , Fibrose Cística/complicações , Transplante de Pulmão/efeitos adversos , Transplantados , Inquéritos e Questionários , Consenso
19.
Adv Radiat Oncol ; 8(2): 101143, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36845611

RESUMO

Purpose: There are limited data regarding using stereotactic body radiation therapy (SBRT) in the postprostatectomy setting. Here, we present a preliminary analysis of a prospective phase II trial that aimed to evaluate the safety and efficacy of postprostatectomy SBRT for adjuvant or early salvage therapy. Materials and Methods: Between May 2018 and May 2020, 41 patients fulfilled inclusion criteria and were stratified into 3 groups: group I (adjuvant), prostate-specific antigen (PSA) < 0.2 ng/mL with high-risk features including positive surgical margins, seminal vesicle invasion, or extracapsular extension; group II (salvage), with PSA ≥ 0.2 ng/mL but < 2 ng/mL; or group III (oligometastatic), with PSA ≥ 0.2 ng/mL but < 2 ng/mL and up to 3 sites of nodal or bone metastases. Androgen deprivation therapy was not offered to group I. Androgen deprivation therapy was offered for 6 months for group II and 18 months for group III patients. SBRT dose to the prostate bed was 30 to 32 Gy in 5 fractions. Baseline-adjusted physician reported toxicities (Common Terminology Criteria for Adverse Events), patient reported quality-of-life (Expanded Prostate Index Composite, Patient-Reported Outcome Measurement Information System), and American Urologic Association scores were evaluated for all patients. Results: The median follow-up was 23 months (range, 10-37). SBRT was adjuvant in 8 (20%) patients, salvage in 28 (68%), and salvage with the presence of oligometastases in 5 (12%) patients. Urinary, bowel, and sexual quality of life domains remained high after SBRT. Patients tolerated SBRT with no grade 3 or higher (3+) gastrointestinal or genitourinary toxicities. The baseline adjusted acute and late toxicity grade 2 genitourinary (urinary incontinence) rate was 2.4% (1/41) and 12.2% (5/41). At 2 years, clinical disease control was 95%, and biochemical control was 73%. Among the 2 clinical failures, 1 was a regional node and the other a bone metastasis. Oligometastatic sites were salvaged successfully with SBRT. There were no in-target failures. Conclusions: Postprostatectomy SBRT was very well tolerated in this prospective cohort, with no significant effect on quality of life metrics postirradiation, while providing excellent clinical disease control.

20.
J Cyst Fibros ; 22(1): 17-30, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36916675

RESUMO

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.


Assuntos
Fibrose Cística , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Padrão de Cuidado , Transporte de Íons , Transdução de Sinais , Mutação
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