The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We ...aimed to assess the safety and immunogenicity of Butantan-DV.
We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422.
Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 845 of 19 participants in the Butantan-DV group and 13 76% of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4.
Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing.
Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Fundação Butantan.
To describe the phenotype and genotype of 10 Brazilian patients with variants in
, posterior microphthalmos and retinal findings.
Complete ophthalmological evaluation was done at 4 different ...Brazilian centers. Genetic analysis was performed using commercial next generation sequencing panels for inherited retinal disorders.
Ages of the patients ranged from 10 to 65 years and visual acuities from 0,05 to no perception of light. All were hyperopes (+4,25 to + 17,50) with a short axial length (14,4 mm to 18 mm). Common posterior segment features, though not present in all, were optic disc drusen (5/10), foveoschisis (5/10) and retinal pigmentary changes (8/10). Isolated patients presented with macular atrophy, serous retinal detachment, and chorioretinal folds. The most common variant in
found in our patients was a deletion in exon 5 (c.498delC; p.Asn267Thrfs *25), present in all except 2 patients. Other variants found were c.523C>T (p.Gln175*), c.298delG (p.Ala100Argfs *37), c.666del (p.Thr223Argfs *83) and the novel variant c.257C>A (p.Ala86Asp).
This is the first report of Brazilian patients with posterior microphthalmos and pathogenic variants in
and the first describe of the variant p.Ala86Asp in literature. Our cases confirm the previously reported phenotype of high hyperopia, optic disc drusen, alterations in foveal architecture, retinal pigmentary changes with loss of photoreceptor function and visual field constriction. Report of such a rare condition is important to increase awareness to the phenotype of posterior microphthalmia with associated retinal conditions.
Display omitted
•The olopatadine hydrochloride polymorphs were evaluated using the HS and QTAIM.•Physical chemistry properties were investigated using theoretical analysis.•The olopatadine polymorphs ...solubility was calculated with BSSE corrections.
Olopatadine hydrochloride is a selective H1 receptor antagonist used in ophthalmic solutions to treat the signs and symptoms of allergic conjunctivitis. This compound presents a phenomenon known as polymorphism, which can cause changes on physicochemical characteristics. Considering the worldwide regulatory requirements for drug registration and the complexity of the pharmacotechnical development of ophthalmic preparations, both supramolecular arrangements (carried out by the Hirshfeld surface) and theoretical calculations (through the quantum theory of atoms in molecules) led to understand the physicochemical properties of polymorphs I and II and possible differences in solubility. The supramolecular arrangement for both polymorphs consists of the chloride anion participating in strong NH ⋯ Cl and OH ⋯ Cl intermolecular interactions as well as two weak CH ⋯ Cl intermolecular interactions, which generate an ionic tetramer. The shape index HS shows the hydrophobic space, which is around the ionic tetramer formed by CH ⋯ π intermolecular interaction for form I as well as π ⋯ π stacking for form II. The supramolecular crystal arrangement provides an essential aspect of its solubility in drug polymorphs.
The structures of two methoxylated chalcones, namely (E)-1-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and (E)-3-(4-ethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one, reveal the effect ...of the inclusion of the methoxyl and ethoxyl substituents of the conformation on methoxy-chalcone. Structural comparative study between two chalcones was done in this work and some effects on geometric parameters, such as planarity and dihedral angles, were described. In addition, intermolecular interactions responsible for crystalline packaging were investigated by Hirshfeld surfaces and the values of those interactions were analysed by comparing experimental and theoretical models. The molecular stability was expressed in terms of softness and hardness, both obtained from frontier molecular orbitals. Finally, there is a good agreement between calculated and experimental infrared spectrum, which allowed the assignment of the normal vibrational modes.
To characterize scrotal involvement in children and adolescents with IgA vasculitis.
A cross-sectional retrospective study included 296 IgA vasculitis (EULAR/PRINTO/PRES criteria) patients, 150/296 ...(51%) were males and assessed by demographic/clinical/laboratory and treatments. Scrotal involvement was defined by the presence of scrotal edema and/or pain/tenderness in physical examination and/or testicular Doppler ultrasound abnormalities.
Scrotal involvement was observed in 28/150 (19%) IgA vasculitis patients. This complication was evidenced at IgA vasculitis diagnosis in 27/28 (96%). Acute recurrent scrotal involvement was observed in 2/150 (1%) and none had chronic subtype. Further analysis of patients with scrotal involvement at first episode (n = 27) compared to those without this complication (n = 122) revealed that the median age at diagnosis 4.0 (2.0-12) vs. 6 (1.3-13) years, p = 0.249 was similar in both groups. The frequency of elevated serum IgA was significantly lower in IgA vasculitis patients with scrotal involvement versus without this manifestation (18% vs. 57%, p = 0.017), whereas glucocorticoid (93% vs. 49%, p < 0.0001) and ranitidine use (63% vs. 30%, p = 0.003) were significantly higher in the former group.
The scrotal involvement occurred in almost one fifth of IgA vasculitis patients and was commonly evidenced as acute subtype at diagnosis. Scrotal signs/symptoms improved after a prompt use of glucocorticoid and was associated with low frequency of elevated IgA serum levels.
Objectives
Anti-ribosomal P protein (anti-P) autoantibodies are highly specific for systemic lupus erythematosus (SLE). However, the evaluation of this autoantibody in childhood-onset SLE (cSLE) ...populations has been limited to a few small series, hampering the interpretation of the clinical and laboratorial associations. Therefore, the objective of this multicenter cohort study was to evaluate demographic, clinical/laboratorial features, and disease damage score in cSLE patients with and without the presence of anti-P antibody.
Methods
This was a retrospective multicenter study performed in 10 pediatric rheumatology services of São Paulo state, Brazil. Anti-P antibodies were measured by ELISA in 228 cSLE patients.
Results
Anti-P antibodies were observed in 61/228 (27%) cSLE patients. Frequencies of cumulative lymphadenopathy (29% vs. 15%, p = 0.014), acute confusional state (13% vs. 5%, p = 0.041), mood disorder (18% vs. 8%, p = 0.041), autoimmune hemolytic anemia (34% vs. 15%, p = 0.001), as well as presence of anti-Sm (67% vs. 40%, p = 0.001), anti-RNP (39% vs. 21%, p = 0.012) and anti-Ro/SSA antibodies (43% vs. 25%, p = 0.016) were significantly higher in cSLE patients with anti-P antibodies compared to those without these autoantibodies. A multiple regression model revealed that anti-P antibodies were associated with autoimmune hemolytic anemia (odds ratio (OR) = 2.758, 95% confidence interval (CI): 1.304–5.833, p = 0.008) and anti-Sm antibody (OR = 2.719, 95% CI: 1.365–5.418, p = 0.004). The SLICC/ACR damage index was comparable in patients with and without anti-P antibodies (p = 0.780).
Conclusions
The novel association of anti-P antibodies and autoimmune hemolytic anemia was evidenced in cSLE patients and further studies are necessary to determine if anti-P titers may vary with this hematological manifestation.
Chalcones have gained attention due to their wide range of biological activities, including
anticancer
,
antimalarial
,
antimicrobial
,
antitubercular
,
antimutagenic
,
anti-inflammatory
, and
...anti-diabetic
effects, as well as their physical properties on nonlinear optical materials. This work describes the synthesis and extensive characterization of a new chalcone (2
E
)-3-(4-hydroxyphenyl)-1-(4-methylphenyl)prop-2-en-1-one. Single crystal X-ray diffraction and Hirshfeld surfaces were employed to analyze the molecular structure and supramolecular arrangement (stabilized primarily by O
2
–H
2
⋯O
1
and C
15
–H
15
⋯O
1
hydrogen bonds). The frontier molecular orbitals and molecular electrostatic potential maps were obtained to predict the chemical reactivity properties. The
structured media
supermolecule approach reaffirms its accuracy in gauging the dipole moment of crystals during their electric polarization processes. The significant shifts observed in molecular optical behaviors when placed within crystalline environments reinforce the impactful role of surroundings on both electrical and optical properties. This paper not only sheds light on the unique properties of the title compound but also underscores the potential applications of chalcones in both biological and material sciences.
Graphical abstract
A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the ...conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.
A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the ...conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two
missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these
variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic
variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.
Amide proton NMR signals from the N‐terminal domain of monomeric α‐synuclein (αS) are lost when the sample temperature is raised from 10°C to 35°C at pH 7.4. Although the temperature‐induced effects ...have been attributed to conformational exchange caused by an increase in α‐helix structure, we show that the loss of signals is due to fast amide proton exchange. At low ionic strength, hydrogen exchange rates are faster for the N‐terminal segment of αS than for the acidic C‐terminal domain. When the salt concentration is raised to 300 mM, exchange rates increase throughout the protein and become similar for the N‐ and C‐terminal domains. This indicates that the enhanced protection of amide protons from the C‐terminal domain at low salt is electrostatic in nature. Cα chemical shift data point to <10% residual α‐helix structure at 10°C and 35°C. Conformational exchange contributions to R2 are negligible at both temperatures. In contrast to the situation in vitro, the majority of amide protons are observed at 37°C in 1H‐15N HSQC spectra of αS encapsulated within living Escherichia coli cells. Our finding that temperature effects on αS NMR spectra can be explained by hydrogen exchange obviates the need to invoke special cellular factors. The retention of signals is likely due to slowed hydrogen exchange caused by the lowered intracellular pH of high‐density E. coli cultures. Taken together, our results emphasize that αS remains predominantly unfolded at physiological temperature and pH—an important conclusion for mechanistic models of the association of αS with membranes and fibrils.
PDF
