To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1).
Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait ...instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1.
We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials.
There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment.
Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1.
This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.
Rickettsia bacteria are responsible for diseases in humans and animals around the world, however few details are available regarding its ecology and circulation among wild animals and human ...populations at high transmission risk in Brazil. The aim of this study was to investigate the occurrence of ticks and Rickettsia spp. in wild boars, corresponding hunting dogs and hunters.
Serum samples and ticks were collected from 80 free-range wild boars, 170 hunting dogs and 34 hunters from southern and central-western Brazil, from the Atlantic Forest and Cerrado biomes, respectively, between 2016 and 2018. Serum samples were tested by indirect immunofluorescent-antibody assay (IFA) to detect IgG antibodies against Rickettsia rickettsii, Rickettsia parkeri, Rickettsia bellii, Rickettsia rhipicephali and Rickettsia amblyommatis. Tick species were identified by morphological taxonomic keys, as previously described. A total of 164 ticks including A. sculptum, A. brasiliense and A. aureolatum were tested in PCR assays for Spotted Fever Group (SFG) Rickettsia spp.
A total of 58/80 (72.5%) wild boars, 24/170 (14.1%) hunting dogs and 5/34 (14.7%) hunters were positive (titers ≥ 64) to at least one Rickettsia species. A total of 669/1,584 (42.2%) ticks from wild boars were identified as Amblyomma sculptum, 910/1,584 (57.4%) as Amblyomma brasiliense, 4/1,584(0.24%) larvae of Amblyomma spp. and 1/1,584 (0.06%) nymph as Amblyolmma dubitatum. All 9 ticks found on hunting dogs were identified as Amblyomma aureolatum and all 22 ticks on hunters as A. sculptum. No tested tick was positive by standard PCR to SFG Rickettsia spp.
The present study was the concomitant report of wild boar, hunting dog and hunter exposure to SFG rickettsiae agents, performed in two different Brazilian biomes. Wild boar hunting may increase the risk of human exposure and consequently tick-borne disease Wild boars may be carrying and spreading capybara ticks from their original habitats to other ecosystems. Further studies can be required to explore the ability of wild boars to infecting ticks and be part of transmission cycle of Rickettsia spp.
BACKGROUND There is evidence that intrauterine growth restriction, resulting in newborn girls that are small for gestational age (SGA), may be related to the onset of polycystic ovary syndrome ...(PCOS). Thus, we studied whether women born SGA have a higher prevalence of PCOS than women born appropriate for gestational age (AGA). METHODS This was a prospective birth cohort study of 384 women born at term between June 1, 1978, and May 31, 1979, in Ribeirão Preto, Brazil. After exclusion, 165 women effectively participated in this study, of whom 43 were SGA and 122 were AGA. The prevalence of PCOS was analysed. At a mean age of 29 years, the women agreed to follow the study protocol, which included: anamnesis, physical examination, serum tests follicle stimulating hormone, luteinizing hormone, total and free testosterone, dehydroepiandrostenedione sulphate, 17-OH-progesterone, fasting insulin, sex steroid-binding globulin (SHBG) and fasting glucose and pelvic ultrasound. Data regarding gestational age, birthweight, age at menarche and maternal data were obtained from the files of the cohort. The adjusted relative risk (RR) values of the SGA, insulin resistance, body mass index, maternal smoking and parity variables were analysed using Poisson regression with robust adjustment of variance for the prediction of PCOS. RESULTS The prevalence of PCOS was higher in the SGA group than in the AGA group adjusted RR = 2.44, 95% CI (1.39–4.28). Hyperandrogenism was more prevalent in the SGA women than in the AGA women (P = 0.011). Circulating SHBG was lower in the SGA women than in the AGA women (P = 0.041), but fasting insulinemia was similar in both groups. CONCLUSIONS The prevalence of PCOS in SGA women was twice as high as in AGA women in our study population.
Synthetic silver nanoparticles (AgNPs) are being extensively used in our daily lives; however, they may also pose a risk to public health and environment. Nowadays, biological AgNPs are considered an ...excellent alternative, since their synthesis occurs by a green technology of low cost and easy scaling. However, studies with these biological nanomaterials (NM) are still limited. Thus, a more careful assessment of their industrial application, economic feasibility and ecotoxicological impacts is crucial. The aim of this study was to investigate the effects of different concentrations of mangrove fungus Aspergillus tubingensis AgNPs on the aerobic heterotrophs soil microorganisms, rice seeds (Oryza sativa) and zebrafish (Danio rerio). Biogenic AgNPs were less harmful for soil microbiota compared to AgNO3. On rice seeds, the AgNPs displayed a dose-dependent inhibitory effect on germination and their subsequent growth and development. The percentage of inhibition of rice seed germination was 30, 69 and 80% for 0.01, 0.1 and 0.5 mM AgNPs, respectively. After 24 h of AgNPs exposition at a limit concentration of 0.2 mM, it did not induce mortality of the zebrafish D. rerio. Overall, A. tubingensis AgNPs can be considered as a suitable alternative to synthetic nanoparticles.
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•Susceptibility of soil microbiota to biogenic AgNPs.•Possible impacts from biogenic silver nanoparticles exposition on heterotrophic aerobic soil microorganisms.•AgNPs impact on germination, growth and development on rice seedlings.•AgNPs disrupts root and shoot biomass partition in rice seedlings.•Effect of biogenic AgNPs in the vertebrate model organism Danio rerio.
Gestational hypertension and pre-eclampsia are important causes of perinatal morbidity. The objective of the present study was to determine the increase in relative risk for developing hypertensive ...disorders of pregnancy based on the evaluation of pregnant women between 20 and 25 weeks of gestation, and to correlate the findings at this period with the outcome of pregnancy. We conducted a prospective cohort study, with a convenience sample of 1417 patients evaluated at this gestational age, of which 1306 were contacted at childbirth. We detected an increased relative risk of 2.69 (95%CI: 1.86 to 3.89) associated with pulsatility index of the uterine arteries, a 2.8 increase (95%CI: 1.58 to 5.03) in relative risk attributed to maternal age above 35 years, a 1.68 increase (95%CI: 1.17 to 2.40) attributed to parity greater than or equal to 3, and a 5.35 increase (95%CI: 4.18 to 6.85) attributed to chronic hypertension and obesity, with a progressive increase in relative risk according to the degree of overweight, i.e., grades 1, 2, 3, and morbid obesity (2.58, 3.06, 5.84, and 7.28, respectively).
Aims
Fungal diseases are among the main factors limiting high yields of soybean crop. Colletotrichum isolates from soybean plants with anthracnose symptoms were studied from different regions and ...time periods in Brazil using molecular, morphological and pathogenic analyses.
Methods and Results
Bayesian phylogenetic inference of GAPDH, HIS3 and ITS‐5.8S rDNA sequences, the morphologies of colony and conidia, and inoculation tests on seeds and seedlings were performed. All isolates clustered only with Colletotrichum truncatum species in three well‐separated clusters. Intraspecific genetic diversity revealed 27 distinct haplotypes in 51 fungal isolates; some of which were identical to C. truncatum sequences from other regions around the world, while others were related to alternative hosts. Conidia were falcate, hyaline, unicellular and aseptate, formed in acervuli, with variable dimensions. Despite being pathogenic to seedlings by both inoculation methods, variation was observed in the aggressiveness of the tested isolates, which was not correlated with genetic variation.
Conclusion
The identification of C. truncatum in the sampled isolates was evidenced as being the only causal agent of soybean anthracnose in Brazil until 2007, with relevant genetic, morphological and pathogenic variability as well as a broad geographical origin. The wide distribution of the predominant C. truncatum haplotype indicated the existence of a highly efficient mechanism of pathogen dispersal over long distances, reinforcing the role of seeds as the primary source of disease inoculum.
Significance and Impact of the Study
The characterization and distribution of Colletotrichum species in soybean‐producing regions in Brazil is fundamental for understanding the disease epidemiology and for ensuring effective control strategies against anthracnose.
The diagnosis of paucibacillary (PB) leprosy cases remains a challenge because of the absence of a confirmatory laboratory method. While quantitative polymerase chain reaction (qPCR) has been shown ...to provide reliable sensitivity and specificity in PB diagnoses, a thorough investigation of its efficacy in clinical practice has not yet been published. The present study evaluated patients with suspected leprosy skin lesions by using qPCR to identify PB individuals in the Leprosy Outpatient clinic at the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil.
One hundred seventy-two suspected PB cases were included in the study. The patients were evaluated by a dermatologist at three different times. The clinical dermato-neurological examination and collected samples were performed on the first visit. On the second visit, the results of the histopathological analysis and PCR assay (DNA-based Mycobacterium leprae qPCR-targeting 16S gene) results were analyzed, and a decision regarding multi-drug therapy was made. A year later, the patients were re-examined, and the consensus diagnosis was established.
In 58% (100/172) of cases, a conclusive diagnosis via histopathological analysis was not possible; however, 30% (30/100) of these cases had a positive PCR. One hundred ten patients (110/172) attended the third visit. The analysis showed that while the sensitivity of the histopathological test was very low (35%), a qPCR alone was more effective for identifying leprosy, with 57% sensitivity.
The use of qPCR in suspected PB cases with an inconclusive histology improved the sensitivity of leprosy diagnoses.
Mammalian chromosomes fold into arrays of megabase‐sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal ...substructures that are often cell type specific, but their higher‐order organization remains elusive. Here, we investigate TAD higher‐order interactions with Hi‐C through neuronal differentiation and show that they form a hierarchy of domains‐within‐domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree‐like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.
Synopsis
Genome‐wide mapping of chromatin architecture reveals a hierarchical folding of chromatin that involves higher‐order domains interactions across the whole chromosomes, reflects epigenomic features and reorganizes upon differentiation‐induced gene expression changes.
Chromatin architecture is mapped genome‐wide using Hi‐C and a neuronal differentiation model from mESC to post‐mitotic neurons.
Mammalian chromosomes fold hierarchically in a manner that reflects epigenomic features and involves higher‐order domains (metaTADs) up to the chromosome scale.
metaTAD topologies are relatively conserved through differentiation, and their reorganization is related to gene expression changes.
Polymer modelling shows that hierarchical chromatin folding promotes efficient packaging without the loss of contact specificity.
Genome‐wide mapping of chromatin architecture reveals a hierarchical folding of chromatin that involves higher‐order domains interactions across the whole chromosomes, reflects epigenomic features and reorganizes upon differentiation‐induced gene expression changes.
A prospective cohort study was conducted on a convenience sample of 1370 pregnant women with a gestational age of 20 to 25 weeks in the city of Ribeirão Preto. Data on obstetrical history, maternal ...age, parity, smoking habit, and a history of preterm delivery was collected with the application of a sociodemographic questionnaire. Cervical length was determined by endovaginal ultrasound, and urine and vaginal content samples were obtained to determine urinary tract infection (UTI) and bacterial vaginosis (BV), respectively. The aim of this study was to verify the association of cervical length and genitourinary infections with preterm birth (PTB). Ultrasound showed no association of UTI or BV with short cervical length. PTB rate was 9.63%. Among the women with PTB, 15 showed UTI (RR: 1.55, 95%CI: 0.93-2.58), 19 had BV (RR: 1.22, 95%CI: 0.77-1.94), and one had both UTI and BV (RR: 0.85, 95%CI: 0.13-5.62). Nineteen (14.4%) PTB occurred in women with a cervical length ≤2.5 cm (RR: 2.89, 95%CI: 1.89-4.43). Among the 75 patients with PTB stratified as spontaneous, 10 showed UTI (RR: 2.02, 95%CI: 1.05-3.86) and 14 had a diagnosis of BV (RR: 1.72, 95%CI: 0.97-3.04). A short cervical length between 20 and 25 weeks of pregnancy was associated with PTB, whereas UTI and BV determined at this age were not associated with short cervical length or with PTB, although UTI, even if asymptomatic, was related to spontaneous PTB.
The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we ...report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.
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