Functional relevance of naturally occurring mutations in adhesion G protein-coupled receptor ADGRD1 (GPR133)

Background: A large number of human inherited and acquired diseases and phenotypes are caused by mutations in G protein-coupled receptors (GPCR). Genome-wide association studies (GWAS) have shown that variations in the ADGRD1 (GPR133) locus are linked with differences in metabolism, human height and heart frequency. ADGRD1 is a Gs protein-coupled receptor belonging to the class of adhesion GPCRs. Results: Analysis of more than 1000 sequenced human genomes revealed approximately 9000 single nucleotide polymorphisms (SNPs) in the human ADGRD1 as listed in public data bases. Approximately 2.4 % of these SNPs are located in exons resulting in 129 non-synonymous SNPs (nsSNPs) at 119 positions of ADGRD1. However, the functional relevance of those variants is unknown. In-depth characterization of these amino acid changes revealed several nsSNPs (A448D, Q600stop, C632fs [frame shift], A761E, N795K) causing full or partial loss of receptor function, while one nsSNP (F383S) significantly increased basal activity of ADGRD1. Conclusion: Our results show that a broad spectrum of functionally relevant ADGRD1 variants is present in the human population which may cause clinically relevant phenotypes, while being compatible with life when heterozygous

Fiberoptic bronchoscopy in the diagnosis and therapeutic decision for respiratory infections in hematological febrile neutropenic patients

Background: Febrile neutropenia is a common complication in patients undergoing chemotherapy or hematopoietic Stem Cell Transplantation (HSCT). Flexible fiberoptic bronchoscopy has been used to aid in the diagnosis of pulmonary diseases. However, there is no consensus regarding the benefit of the exam in establishing diagnosis and in changing the treatment of lung disease in this context. Previous retrospective studies, quite heterogeneous and with non-HIV immunocompromised patients, showed that the yield of fiberoptic bronchoscopy in establishing etiology ranges from 13% to 81%, and in changing therapy, from 5% to 51%.Aim: To evaluate the efficiency of Fiberoptic bronchoscopy and the procedure-related risk for neutropenic patients with hematologic malignancy.Methods: This retrospective cross-sectional study analyzed the medical records of patients with hematologic malignancy with febrile neutropenia who had undergone diagnostic fiberoptic bronchoscopy between January 2011 and December 2012 at the Hospital de Clínicas de Porto Alegre.Results: A total of 45 patients were included: 18 (36%) tested positive for bronchoalveolar lavage, with change in therapeutic management occurring for 95% of them. The procedure-related risk was 2.2%, with one patient showing desaturation immediately after the procedure.Conclusion:  Despite the limited number of patients, our findings indicate that fiberoptic bronchoscopy in neutropenic patients is safe, and the results are similar to those previously reported.

Fiberoptic bronchoscopy in the diagnosis and therapeutic decision for respiratory infections in hematological febrile neutropenic patients

INTRODUÇÃO: A neutropenia febril é uma complicação frequente dos pacientes submetidos ao tratamento quimioterápico ou Transplante de Célula Tronco Hematopioetica (TCTH). A fibrobroncoscopia(FBC) flexível tem sido utilizada para auxiliar no diagnóstico de doenças pulmonares. No entanto, não há consenso em relação ao benefício do exame para estabelecer diagnóstico e alterar o tratamento das doenças pulmonares nesse contexto. Estudos prévios, retrospectivos e bastante heterogêneos, com pacientes imunocomprometidos não-HIV mostraram que o rendimento da fibrobroncoscopia para estabelecer diagnóstico etiológico varia de 13 a 81% e gera alteração de terapêutica em 5 e 51%. O objetivo deste estudo foi avaliar o rendimento da Fibrobroncoscopia, o risco ao procedimento em pacientes hematológicos e neutropenicos. MÉTODOS: Estudo transversal retrospectivo que avaliou pacientes com neoplasia hematológica e neutropenia febril e que tenham sido submetidos à fibrobroncoscopia diagnóstica entre janeiro de 2011 e dezembro de 2012 internados no Hospital de Clínicas de Porto Alegre. RESULTADOS: Foram incluídos 45 pacientes: 18 (36%) tiveram resultado positivo no Lavado Broncoalveolar (LAB), sendo que houve mudança na conduta terapêutica em 95% dos pacientes que apresentaram positividade no LAB. Com relação ao risco do procedimento tivemos uma taxa de 2,2% de complicação, com um paciente que apresentou dessaturação imediatamente após o procedimento. CONCLUSÃO: Apesar do numero limitado de pacientes, nossos achados indicam que a realização da fibrobroncoscopia com LAB em pacientes neutropenicos é segura e com um rendimento semelhante aos descritos na literatura.INTRODUCTION: Febrile neutropenia is a common complication in patients undergoing chemotherapy or hematopoietic Stem Cell Transplantation (HSCT). Flexible fiberoptic bronchoscopy has been used to aid in the diagnosis of pulmonary diseases. However, there is no consensus regarding the benefit of the exam in establishing diagnosis and in changing the treatment of lung disease in this context. Previous retrospective studies, quite heterogeneous and with non-HIV immunocompromised patients, showed that the yield of fiberoptic bronchoscopy in establishing etiology ranges from 13% to 81%, and in changing therapy, from 5% to 51%. To evaluate the efficiency of Fiberoptic bronchoscopy and the procedurerelated risk for neutropenic patients with hematologic malignancy. METHODS: This retrospective cross-sectional study analyzed the medical records of patients with hematologic malignancy with febrile neutropenia who had undergone diagnostic fiberoptic bronchoscopy between January 2011 and December 2012 at the Hospital de Clínicas de Porto Alegre. RESULTS: A total of 45 patients were included: 18 (36%) tested positive for bronchoalveolar lavage, with change in therapeutic management occurring for 95% of them. The procedure-related risk was 2.2%, with one patient showing desaturation immediately after the procedure. CONCLUSION: Despite the limited number of patients, our findings indicate that fiberoptic bronchoscopy in neutropenic patients is safe, and the results are similar to those previously reported

Biomarkers detected in cord blood predict vaccine responses in young infants

Introduction Factors influencing vaccine immune priming in the first year of life involve both innate and adaptive immunity but there are gaps in understanding how these factors sustain vaccine antibody levels in healthy infants. The hypothesis was that bioprofiles associated with B cell survival best predict sustained vaccine IgG levels at one year. Methods Longitudinal study of plasma bioprofiles in 82 term, healthy infants, who received standard recommended immunizations in the United States, with changes in 15 plasma biomarker concentrations and B cell subsets associated with germinal center development monitored at birth, soon after completion of the initial vaccine series at 6 months, and prior to the 12-month vaccinations. Post vaccination antibody IgG levels to Bordetella pertussis, tetanus toxoid, and conjugated Haemophilus influenzae type B (HiB) were outcome measures. Results Using a least absolute shrinkage and selection operator (lasso) regression model, cord blood (CB) plasma IL-2, IL-17A, IL-31, and soluble CD14 (sCD14) were positively associated with pertussis IgG levels at 12 months, while CB plasma concentrations of APRIL and IL-33 were negatively associated. In contrast, CB concentrations of sCD14 and APRIL were positively associated with sustained tetanus IgG levels. A separate cross-sectional analysis of 18 mother/newborn pairs indicated that CB biomarkers were not due to transplacental transfer, but rather due to immune activation at the fetal/maternal interface. Elevated percentages of cord blood switched memory B cells were positively associated with 12-month HiB IgG levels. BAFF concentrations at 6 and 12 months were positively associated with pertussis and HiB IgG levels respectively. Discussion Sustained B cell immunity is highly influenced by early life immune dynamics beginning prior to birth. The findings provide important insights into how germinal center development shapes vaccine responses in healthy infants and provide a foundation for studies of conditions that impair infant immune development

The effect of pH, grain size, and organic ligands on biotite weathering rates

Biotite dissolution rates were determined at 25 °C, at pH 2–6, and as a function of mineral composition, grain size, and aqueous organic ligand concentration. Rates were measured using both open- and closed-system reactors in fluids of constant ionic strength. Element release was non-stoichiometric and followed the general trend of Fe, Mg > Al > Si. Biotite surface area normalised dissolution rates (ri) in the acidic range, generated from Si release, are consistent with the empirical rate law: ri=kH,iaxiH+ where kH,i refers to an apparent rate constant, aH+ designates the activity of protons, and xi stands for a reaction order with respect to protons. Rate constants range from 2.15 × 10−10 to 30.6 × 10−10 (molesbiotite m−2 s−1) with reaction orders ranging from 0.31 to 0.58. At near-neutral pH in the closed-system experiments, the release of Al was stoichiometric compared to Si, but Fe was preferentially retained in the solid phase, possibly as a secondary phase. Biotite dissolution was highly spatially anisotropic with its edges being ∼120 times more reactive than its basal planes. Low organic ligand concentrations slightly enhanced biotite dissolution rates. These measured rates illuminate mineral–fluid–organism chemical interactions, which occur in the natural environment, and how organic exudates enhance nutrient mobilisation for microorganism acquisition