RESUMO
Previous studies on paternal epigenetic inheritance have shown that sperm RNAs play a role in this type of inheritance. The microinjection of sperm small noncoding RNAs into fertilised mouse oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. While sperm long noncoding RNAs (lncRNAs) have also been investigated in a previous study, their microinjection into fertilised oocytes did not yield conclusive results regarding their role in modulating brain development and adult behavioural phenotypes. Therefore, in the current study we sought to investigate this further. We used our previously established paternal corticosterone (stress hormone) model to assess sperm lncRNA expression using CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable element transcripts. Although they have limited functional annotation, bioinformatic approaches indicated the potential of these lncRNAs in regulating brain development and function. We then separated and isolated the sperm lncRNAs and performed microinjections into fertilised oocytes, to generate embryos with modulated lncRNA populations. We observed that the resulting adult offspring had lower body weight and altered anxiety and affective behavioural responses, demonstrating roles for lncRNAs in modulating development and brain function. This study provides novel insights into the roles of lncRNAs in epigenetic inheritance, including impacts on brain development and behaviours of relevance to affective disorders.
Assuntos
Corticosterona , Microinjeções , RNA Longo não Codificante , Espermatozoides , Animais , Masculino , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , Camundongos , Corticosterona/farmacologia , Espermatozoides/metabolismo , Microinjeções/métodos , Feminino , Epigênese Genética , Camundongos Endogâmicos C57BL , Ansiedade/metabolismo , Ansiedade/genética , Oócitos/metabolismo , Comportamento Animal/fisiologia , Estresse Psicológico/metabolismo , Encéfalo/metabolismoRESUMO
BACKGROUND: In peripheral lung tumours, stereotactic body radiotherapy (SBRT) is superior to conventional RT. SBRT has also shown high loco-regional control (LC) in centrally located tumours, but there is a high risk of severe toxicity. The STRICTSTARLung trial (NCT05354596) examines if risk-adapted SBRT for central tumours is feasible. In this study, we examined overall survival (OS), Disease-free survival (DSF), LC, and toxicity in patients with central tumours that could have been candidates for SBRT but received conventional RT. MATERIAL AND METHODS: Retrospectively, we evaluated 49 lung cancer patients that between 2008 and 2021 received RT (60-70Gy in 2 Gy fractions) for a solitary tumour or lymph node with a diameter <5cm located <2cm from the bronchial tree, oesophagus, aorta or heart. All tumours were pathologically verified; 30 were primary lung tumours (T1b-T4) and 19 were solitary lymph nodes (T0N1-N2). Chemotherapy was administered as concomitant (29) or sequential (4). OS and LC were analysed using Kaplan Meier. Cox proportional hazards model for OS and disease-free survival (DFS) was performed including tumour volume, histology, sex, T- vs N-site and chemotherapy. Toxicity was scored. RESULTS: In 42 patients, the tumour was located <1 cm to mediastinum. Median follow-up time was 44 months (range: 7-123). The median OS was 51 months. OS at 1-, 3- and 5-year was 88% (SE:5), 59% (SE:7) and 50% (SE:8). Loco-regional recurrences occurred in 16 patients resulting in 1-, and 3-year LC rates of 77% (SE:6) and 64% (SE:8). The majority occurred within 3 years after RT. Only stage showed significant impact on OS and DFS. No patients experienced grade 4-5 toxicity. Seven patients developed grade 3 toxicity (5 oesophageal stenosis, 2 pneumonitis). CONCLUSION: Conventional RT for patients with small central lung tumours or solitary lymph nodes is feasible. Median OS was 51 months, and toxicity was low with no grade 4-5 events.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Humanos , Estudos Retrospectivos , Neoplasias Pulmonares/patologia , Intervalo Livre de Doença , Radiocirurgia/métodos , Linfonodos/patologia , Resultado do TratamentoRESUMO
The glass transitions of amorphous ices as well as of aqueous phosphoric acid solutions were reported to display very large 1H/2H isotope effects. Using dielectric spectroscopy, in both types of glassformers for equimolar protonated/deuterated mixtures an almost ideal isotope-mixing behavior rather than a bimodal relaxation is found. For the amorphous ices this finding is interpreted in terms of a glass-to-liquid rather than an orientational glass transition scenario. Based on calorimetric results revealing that major 16O/18O isotope effects are missing, the latter scenario was previously favored for the amorphous ices. Considering the dielectric results on 18O substituted amorphous ices and by comparison with corresponding results for the aqueous phosphoric acid solutions, it is argued that the present findings are compatible with the glass-to-liquid scenario. To provide additional information regarding the deeply supercooled state of 1H/2H isotopically mixed and 18O substituted glassformers, the aqueous phosphoric acid solutions are studied using shear mechanical spectroscopy as well, a technique which so far could not successfully be applied to characterize the glass transitions of the amorphous ices.
RESUMO
BACKGROUND: Lung cancer patients struggle with high toxicity rates. This study investigates if IMRT plans with individually set beam angles or uni-lateral VMAT plans results in dose reduction to OARs. We investigate if introduction of a RapidPlan model leads to reduced dose to OARs. Finally, the model is validated prospectively. MATERIAL AND METHODS: Seventy-four consecutive lung cancer patients treated with IMRT were included. For all patients, new IMRT plans were made by an experienced dose planner re-tuning beam angles aiming for minimized dose to the lungs and heart. Additionally, VMAT plans were made. The IMRT plans were selected as input for a RapidPlan model, which was used to generate 74 new IMRT plans. The new IMRT plans were used as input for a second RapidPlan model. This model was clinically implemented and used for generation of clinical treatment plans. Dosimetric parameters were compared using a Wilcoxon signed rank test or a 1-sided student's t-test. p < .05 was considered significant. RESULTS: IMRT plans significantly reduced mean doses to lungs (MLD) and heart (MHD) by 1.6 Gy and 1.7 Gy in mean compared to VMAT plans. MLD was significantly (p < .001) reduced from 10.8 Gy to 9.4 Gy by using the second RapidPlan model. MHD was significantly (p < .001) reduced from 4.9 Gy to 3.9 Gy. The model was validated in prospectively collected treatment plans showing significantly lower MLD after the implementation of the second RapidPlan model. CONCLUSION: Introduction of RapidPlan and beam angles selected based on the target and OARs position reduces dose to OARs.
Assuntos
Neoplasias Pulmonares , Radioterapia de Intensidade Modulada , Humanos , Neoplasias Pulmonares/radioterapia , Órgãos em Risco , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por ComputadorRESUMO
BACKGROUND: In radiotherapy (RT) of lung cancer, dose to functional lung (FL) volumes segmented with two different methods (perfusion SPECT (Q-SPECT) and 4D-CT (4D) ventilation (V)) have been shown to correlate with the incidence of radiation pneumonitis (RP). This study aims to compare the FL volumes identified by both methods. MATERIAL AND METHODS: Thirty lung cancer patients had a 4D and Q-SPECT prior to treatment. Seventeen of these patients also had a ventilation SPECT (V-SPECT). FL sub-volumes were segmented automatically, using cut-off values. The volumes were compared in terms of overlap fraction (OF) relative to the minimal volume, and intersection fraction (IF) of the FL volume relative to the total lung volume (VLung). RESULTS: Cut-off values suggested in literature for Q-SPECT and 4D-V resulted in volumes differing in size by a median 18% [6%;31%], and a median OF and IF of 0.48 [0.23;0.70] and 0.09 [0.02;0.25], respectively. Segmenting volumes of comparable size of about 1/3 of VLung (FL-m(1/3), m = method) resulted in a median OF and IF of 0.43 [0.23;0.58] and 0.12 [0.06;0.19], respectively. Twenty-five patients (83%) had a reasonable overlap between FL-Q(1/3) and FL-4D-V(1/3) volumes, with OF values above 0.33. IF increased significantly (p = .036) compared to using fixed cut-off values. Similarly, volumes of comparable size of about 1/3 VLung were produced for V-SPECT, and FL-Q(1/3), FL-V(1/3), and FL-4D-V(1/3) were compared. The overlaps and intersections of FL-V(1/3) with FL-Q(1/3) volumes were significantly (p<.001) larger than the corresponding overlaps and intersections of FL-Q(1/3) with FL-4D(1/3) and FL-V(1/3) with FL-4D(1/3). CONCLUSION: The Q-SPECT and 4D-V methods do not segment entirely the same FL volumes. A reasonable overlap of the volumes along with the findings of other studies that both correlate to RP incidence, suggests that a combination of both volumes, e.g. using the IF, may be useful in RT treatment planning.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonite por Radiação , Tomografia Computadorizada Quadridimensional , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Pneumonite por Radiação/etiologia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
OBJECTIVES: Local recurrence (rec) in lung cancer is associated with poor survival. This study examined whether the pattern of failure is associated with the most PET avid volume in the planning-FDG-PET/CT scan (p-PET/CT). METHODS: 162 consecutive inoperable NSCLC patients (pts) receiving radiotherapy between January 2012 and April 2014 were reviewed. Radiotherapy was delivered in 2 Gy/fraction (5f/week) to a total dose of 60-66 Gy. Pts were followed with CT scans every third month. Patients with local rec as first event were analyzed. For the primary tumor (T) the overlap-fraction (OF) between 50% of SUVpeak on p-PET/CT and the volume of T-rec was calculated: OF = (SUVp50â©T-rec)/min(SUVp50, T-rec). Similarly for the GTV on the p-CT: OF = (GTVâ©T-rec)/min(GTV, T-rec). OF was based on a rigid registration between p-PET/CT and rec-CT with PET guided delineation of T- rec. For lymph nodes (LN), the correlation between the location of treated-LN and the location of recurrence-LN was evaluated. RESULTS: 67 patients developed local rec. 51 pts had rec in T-site, 45 pts in LN-site. Due to anatomical changes, reliable registration between p-CT and rec-CT was only obtained in 26 pts with T-rec. The median OFSUVp50 was 52, 8% [range 26; 100%] and the median OFGTV was 80.5% [19.7; 100%]. Eleven pts had higher OFSUVp50 than OFGTV. LN-rec predominantly occurred in the station 2R (32%), 4R (46%), 7 (46%) and right hilum (36%). Pts with malignant LNs in station 4R or 7 on p-CT had a high risk of rec in these stations; 4R (55%) and 7 (83%). CONCLUSIONS: This study indicates that the most PET active volume on p-PET-CT is a driver for rec at T-site. LN-recurrences predominantly appear in station 2R, 4R, 7 and right hilum. Additional confirmatory studies regarding lymph node mapping and selective lymph node irradiation is needed.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Fluordesoxiglucose F18 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Resultado do TratamentoRESUMO
Mocó cotton belong to the same species as the cultivated species, Gossypium hirsutum, and cultivated forms were mainly landraces but also developed as cultivars, bearing good fiber quality and drought tolerant when cropped as a perennial species. The northeast Brazil crop system based on this cotton type is finished, with a few small area planted in the three main States, where it was previously cultivated (Ceará, Paraíba, and Rio Grande do Norte), but in others, maintenance is accomplished by single dooryard plants. Plants were found in all visited Northeast Brazil municipalities, sometimes in the North of the country, and were collected for ex situ preservation and evaluation. Most of seeds had no fuzz (62.2%) and 94.6% of the genotypes presented spot in flowers. Seventy-one alleles were revealed in 12 loci. The genetic structure of the population evaluated by microsatellite markers shows two main groups, one comprising the Seridó region where landraces were originated and other comprising the state of Ceará, where a specific breeding program was developed. Genotypes collected in North Brazil States as well as those collected in Bahia, Alagoas, and Sergipe grouped with those collected in Ceará. The Mantel correlogram indicates a significant (P < 0.05) correlation between genetic and geographical distances up to 77 km. The ex situ maintenance and agronomical evaluation are the main concerns for mocó, as the use of the agricultural interesting traits, possibly introgressed to other genotypes, is predicted. The in situ preservation is still of interest since there is more diversity there than in the collected plants and some should be continued due to use as medicinal plant.
Assuntos
Pool Gênico , Gossypium/genética , Polimorfismo Genético , Brasil , Ecossistema , Evolução Molecular , Genótipo , Característica Quantitativa Herdável , Sementes/genética , Seleção ArtificialRESUMO
The objective of this study was to analyze the diversity and discrimination of high-performance Brazilian rice cultivars using microsatellite markers. Twenty-nine rice cultivars belonging to EMBRAPA Arroz e Feijão germplasm bank in Brazil were genotyped by 24 SSR markers to establish their structure and genetic discrimination. It was demonstrated that the analyzed germplasm of rice presents an expressive and significant genetic diversity with low heterogeneity among the cultivars. All 29 cultivars were differentiated genetically, and were organized into two groups related to their upland and irrigated cultivation systems. These groups showed a high genetic differentiation, with greater diversity within the group that includes the cultivars for irrigated system. The genotyping data of these cultivars, with the morphological e phenotypical data, are valuable information to be used by rice breeding programs to develop new improved cultivars.
Assuntos
Oryza/genética , Melhoramento Vegetal/métodos , Polimorfismo Genético , Brasil , Heterogeneidade Genética , Genótipo , Repetições de Microssatélites , Oryza/crescimento & desenvolvimento , Melhoramento Vegetal/normas , Sementes/genéticaRESUMO
One of the largest and longest Salmonella outbreaks in Germany within the last 10 years occurred in central Germany in 2013. To identify vehicles of infection, we analysed surveillance data, conducted a case-control study and food traceback. We identified 267 cases infected with Salmonella Infantis with symptom onset between 16 April and 26 October 2013 in four neighbouring federal states. Results of our study indicated that cases were more likely to have eaten raw minced pork from local butcher's shops [odds ratio (OR) 2·5, 95% confidence interval (CI) 1·1-5·8] and have taken gastric acid-reducing or -neutralizing medication (OR 3·8, 95% CI 1·3-13) than controls. The outbreak was traced back to contaminated raw pork products found in different butcher's shops supplied by one slaughterhouse, to pigs at one farm and to an animal feed producer. Characterization of isolates of human, food, animal, feed, and environmental origin by phage-typing and pulsed-field gel electrophoresis confirmed the chain of infection. Insufficient hygiene standards in the slaughterhouse were the most probable cause of the ongoing transmission. We recommend that persons taking gastric acid suppressants should refrain from consuming raw pork products. Improving and maintaining adequate hygiene standards and process controls during slaughter is important to prevent future outbreaks.
Assuntos
Surtos de Doenças , Microbiologia de Alimentos , Carne Vermelha/microbiologia , Intoxicação Alimentar por Salmonella/epidemiologia , Salmonella enterica/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Tipagem de Bacteriófagos , Criança , Pré-Escolar , Eletroforese em Gel de Campo Pulsado , Feminino , Alemanha/epidemiologia , Humanos , Higiene , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Intoxicação Alimentar por Salmonella/microbiologia , Sus scrofa , Adulto JovemRESUMO
The thermodynamic redox properties of ceria and ceria zirconia solid solutions are analysed with a new methodology for modelling such systems based on the statistical mechanics of lattice configurations. Experimental thermogravimetric equilibrium data obtained for small non-stoichiometry measurements are combined with literature data to cover a large range of non-stoichiometry (CeO2-δ, δ = 0.001-0.32), temperature (1073-1773 K) and oxygen partial pressure (1-10(-13) bar). A dilute species model of defect clusters , obeying the law of mass action, was sufficient to describe the system over the whole range of conditions, leading to a simple analytical equation of state for the system. This offers new physical insight into the redox properties of ceria based materials, and the theoretical methods developed should also be of great interest for other materials which exhibit continuous oxygen non-stoichiometry similar to ceria, such as perovskite oxides.
RESUMO
Although the genus Tursiops has a worldwide distribution and is globally well-studied, some dolphin populations continue to face high risks of decline. Hence, it is necessary to assess the genetic diversity and structure of this genus to properly assess its conservation status and to implement appropriate management actions. In Brazil, genetic studies on this group remain rare, particularly for populations inhabiting offshore waters. Saint Peter and Saint Paul Archipelago (SPSPA) is a small group of islands located in the Mid- Atlantic Ridge, where recent studies of the Tursiops truncatus group indicate that individuals are resident throughout the year around the archipelago, exhibiting considerable site fidelity. A previous study with this group indicated that the individuals form an isolated population. To test this hypothesis, and describe the genetic diversity of SPSPA individuals, we assessed 12 microsatellite loci and a portion of the mitochondrial control region. Bayesian analysis revealed that SPSPA bottlenose dolphins form a unique population. In a phylogeographic perspective, we found that individuals from SPSPA shared mtDNA haplotypes with inshore and offshore individuals from North Atlantic, suggesting that they are not currently isolated from their conspecifics. Mirroring mtDNA findings, microsatellite analysis revealed that most of the pairs of individuals sampled seem to be unrelated (83.8%) and no indication of inbreeding, what would be expected if a small population such as SPSPA was reproductively isolated.
Assuntos
Golfinho Nariz-de-Garrafa/genética , Animais , Oceano Atlântico , Teorema de Bayes , Brasil , DNA Mitocondrial/genética , Feminino , Variação Genética , Genética Populacional , Haplótipos , Ilhas , Região de Controle de Locus Gênico , Masculino , Repetições de Microssatélites , Linhagem , Filogenia , Filogeografia , Análise de Sequência de DNA , Razão de MasculinidadeRESUMO
Depressive disorders have shown an increasing prevalence over the past decades. Growing evidence suggests that pregnancy and childbirth trigger depressive symptoms not only in women but likewise in men. This study estimates the prevalence of paternal perinatal depressiveness in a German community sample and explores its link to partnership satisfaction as well as birth-related concerns and concerns about the future. Data was gathered in a longitudinal study over the second and third trimester of their partner's pregnancy up to 6 weeks postpartum. In a two-stage screening procedure, 102 expectant fathers were assessed for symptoms of depression, anxiety, and partnership satisfaction using the Edinburgh Postnatal depression Scale (EPDS), the State/Trait Anxiety Inventory, a self-constructed questionnaire for birth concerns and the Questionnaire of Partnership. The prevalence of elevated depressive symptoms among expectant fathers was 9.8 % prenatally and 7.8 % postnatally. Prenatal relationship quality, prenatal EPDS scores, and birth concerns were significantly associated with and explained 47 % of the variance in paternal postnatal depressive symptoms. The prevalence of paternal depressive symptoms is a significant concern. Our findings point out the need for implementing awareness and screening for depressiveness in fathers in clinical routine in Germany as well as the necessity of developing a screening instrument for paternal birth-related anxiety.
Assuntos
Depressão/epidemiologia , Pai/psicologia , Comportamento Paterno/psicologia , Satisfação Pessoal , Adulto , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Depressão/diagnóstico , Depressão/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Feminino , Alemanha/epidemiologia , Humanos , Relações Interpessoais , Estudos Longitudinais , Masculino , Inventário de Personalidade , Período Pós-Parto , Gravidez , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
AIMS/HYPOTHESIS: Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease (PAD). However, the relationship between bilirubin and lower-limb amputation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb amputation. METHODS: The relationship between baseline plasma total bilirubin levels and amputation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint. RESULTS: Bilirubin concentrations were significantly inversely associated with lower-limb amputation, with a greater than threefold risk gradient across levels. Individuals with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 µmol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79, p = 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, γ-glutamyltransferase level, HbA1c, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, amputation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 µmol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81, p = 0.019). CONCLUSIONS/INTERPRETATION: Our results identify a significant inverse relationship between bilirubin levels and total lower-limb amputation, driven by major amputation. Our data raise the hypothesis that bilirubin may protect against amputation in type 2 diabetes.
Assuntos
Amputação Cirúrgica , Bilirrubina/sangue , Complicações do Diabetes/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Fenofibrato/uso terapêutico , Extremidade Inferior/patologia , Idoso , Antioxidantes/farmacologia , Bilirrubina/metabolismo , Biomarcadores/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores Sexuais , Resultado do TratamentoRESUMO
Gossypium mustelinum is the only cotton species native to Brazil; it is endemic to the semi-arid region of the northeast. The populations are found near perennial and semi-perennial sources of water, such as ponds or pools in intermittent streams. Problems with in situ conservation derive from human interference in its habitat, mainly because of excessive cattle grazing and deforestation. Establishing efficient strategies for in situ conservation requires knowledge of the genetic structure of the populations. We evaluated the structure and genetic variability of populations of G. mustelinum in the Tocó and Capivara Rivers (State of Bahia). Two hundred and eighteen mature G. mustelinum plants were genotyped with SSR markers. The molecular data were used to estimate the allelic frequencies, the heterozygosity, the F statistics, and the genetic distance among the populations and among individuals. We found high genetic diversity among the populations. The FST indexes for each population were also high and strongly correlated with physical distance. The high estimated level of endogamy and the low observed heterozygosity are indicative that the populations reproduce mainly by self-fertilization and crosses between related individuals. Consequently, strategies for in situ preservation should include at least three occurrence sites of G. mustelinum from each population. For ex situ conservation, the collections should include as many sites as possible.
Assuntos
Ecossistema , Variação Genética , Gossypium/genética , Repetições de Microssatélites/genética , Alelos , Animais , Brasil , Bovinos , DNA de Plantas/química , DNA de Plantas/genética , Frequência do Gene , Estruturas Genéticas , Genética Populacional , Genótipo , Geografia , Gossypium/classificação , Gossypium/crescimento & desenvolvimento , Humanos , Filogenia , Rios , Análise de Sequência de DNARESUMO
BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).
Assuntos
Oxazolidinonas , Tuberculose Pulmonar , Adulto , Humanos , Moxifloxacina/efeitos adversos , Linezolida , Quimioterapia Combinada , Antituberculosos , Oxazolidinonas/efeitos adversos , Tuberculose Pulmonar/diagnóstico , Resultado do TratamentoRESUMO
Potato can suffer from several abiotic stresses such as cold temperature, high soil salinity, lack of water or heavy metal exposure, to name a few. They are known to affect plant growth as well as productivity, with differential regulations at several levels. Potato response to cold and salt exposure was investigated at both transcriptomic and proteomic levels in a growth chamber experiment. Cold exposure in potato resulted in a higher number of significantly differentially regulated genes compared to salt exposure, whereas there were nearly three times more differentially regulated proteins after salt exposure when compared to cold exposure. The allocation of up and down-regulated genes at the functional category level also differed between salt and cold exposure although common trends, previously described in various abiotic stresses, were observed. In both stresses, the majority of photosynthesis-related genes were down-regulated whereas cell rescue and transcription factor-related genes were mostly up-regulated. In the other functional categories no common trend was observed; salt exposure results displayed a strong down-regulation of genes implicated in primary metabolism, detoxication apparatus and signal transduction, whereas upon cold exposure, up and down-regulated genes were similar in number. At the proteomic level, the abundance of the majority of identified proteins was increased except for the photosynthesis-related proteins, which were mostly less abundant after both salt and cold exposure. Common responses between salt and cold stress and specific responses inherent to these abiotic stresses are described.
Assuntos
Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Solanum tuberosum/fisiologia , Estresse Fisiológico , Temperatura Baixa , Perfilação da Expressão Gênica , Genes de Plantas , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Plantas/genética , Proteômica , Tolerância ao Sal , Solanum tuberosum/genéticaRESUMO
Between 1985 and 2008, a total of 102,387 wild boar sera originating from Eastern Germany covering an area of 108 589 km2 were tested for the presence of Aujeszky's disease virus (ADV)-specific antibodies. From 1985 until 1991 and from 1992 until 2008, wild boar sera were exclusively investigated using either conventional seroneutralization assays (n=39 621) or commercial gB and full antigen ELISAs (n=62,766), respectively. Spatial-temporal analysis revealed an increasing ADV seroprevalence from 0·4% to 15·9%, on average, during the 24-year observation period that went along with a continuous spread of the infection in a western direction. During 2006 and 2008, 18% of the 66 affected districts had ADV seroprevalences >30%. There was a significant correlation between ADV seroprevalence and the hunting index of population density (HIPD) of wild boar in the entire study area, although this did not hold true for some regions. Seroprevalences did not differ between sexes but were age-dependent. East Germany has been officially free of Aujeszky's disease (pseudorabies) in domestic pigs since 1985. Although a risk for domestic pigs cannot be completely ruled out, experience has shown that ADV in domestic pigs could be eliminated although the virus was present in the wild boar population. Despite increasing ADV seroprevalence in the East German wild boar population no spillover infections from wild boar to domestic pigs have been reported. To further trace ADV infections in the wild boar population in Germany, a nationwide serological monitoring programme should be implemented.
Assuntos
Pseudorraiva/epidemiologia , Sus scrofa , Doenças dos Suínos/epidemiologia , Animais , Animais Selvagens , Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Alemanha/epidemiologia , Herpesvirus Suídeo 1/imunologia , Masculino , Testes de Neutralização/veterinária , Vigilância da População , Pseudorraiva/imunologia , Estudos Soroepidemiológicos , Sorotipagem/veterinária , Suínos , Doenças dos Suínos/imunologiaRESUMO
Lobomycosis, a disease caused by the uncultivable dimorphic onygenale fungi Lacazia loboi, remains to date as an enigmatic illness, both due to the impossibility of its aetiological agent to be cultured and grown in vitro, as well as because of its unresponsiveness to specific antifungal treatments. It was first described in the 1930s by Brazilian dermatologist Jorge Lobo and is known to cause cutaneous and subcutaneous localised and widespread infections in humans and dolphins. Soil and vegetation are believed to be the chief habitat of the fungus, however, increasing reports in marine mammals has shifted the attention to the aquatic environment. Infection in humans has also been associated with proximity to water, raising the hypothesis that L. loboi may be a hydrophilic microorganism that penetrates the skin by trauma. Although its occurrence was once thought to be restricted to New World tropical countries, its recent description in African patients has wrecked this belief. Antifungals noted to be effective in the empirical management of other cutaneous/subcutaneous mycoses have proven unsuccessful and unfortunately, no satisfactory therapeutic approach for this cutaneous infection currently exists.
Assuntos
Doenças Transmissíveis Emergentes/diagnóstico , Doenças Transmissíveis Emergentes/epidemiologia , Golfinhos/microbiologia , Lobomicose/diagnóstico , Lobomicose/epidemiologia , Animais , Doenças Transmissíveis Emergentes/microbiologia , Doenças Transmissíveis Emergentes/veterinária , Modelos Animais de Doenças , Humanos , Lobomicose/microbiologia , Lobomicose/veterináriaRESUMO
OBJECTIVE: To evaluate temporomandibular disorder (TMD) treatment with a prefabricated, hydrostatic oral splint (HOS) based on self-reported patient's symptoms using a standardized questionnaire. METHODS: Two hundred fifty-eight questionnaires from patients diagnosed with TMD and subsequently treated with HOS were collected from two independent private practices. Based on patient's comfort the questionnaire recorded TMD symptoms and symptom regression. Descriptive and comparative statistics was carried out using SPSS. RESULTS: A total of 221 questionnaires were analyzed. Patients reported TMD symptoms such as pain (93.2%), TMJ clicking (66.1%), headache (25.8%), cervical spine disorders (23.5%), restricted mouth opening (22.6%) and tinnitus (11.8%). For most symptoms, improvement was reported mostly after two weeks, except for tinnitus, where positive effects were usually reported after four weeks. CONCLUSION: HOS seem to be effective for immediate treatment of pain and other TMD symptoms. Based on the available data, a treatment period of four weeks can be recommended.