"Single nucleotide polymorphisms of the OPG/RANKL system genes in primary hyperparathyroidism and their relationship with bone mineral density"

<p>Abstract</p> <p>Background</p> <p>Primary hyperparathyroidism (PHPT) affects mainly cortical bone. It is thought that parathyroid hormone (PTH) indirectly regulates the activity of osteoclasts by means of the osteoprotegerin/ligand of the receptor activator of nuclear factor-κβ (OPG/RANKL) system. Several studies have confirmed that <it>OPG </it>(osteoprotegerin) and <it>RANKL </it>(ligand of the receptor activator of nuclear factor-κβ) loci are determinants of bone mineral density (BMD) in the general population. The aim of this study is to analyze the relationship between fractures and BMD and the rs3102735 (163 A/G), rs3134070 (245 T/G) and rs2073618 (1181 G/C) SNPs of the <it>OPG </it>and the rs2277438 SNP of the <it>RANKL</it>, in patients with sporadic PHPT.</p> <p>Methods</p> <p>We enrolled 298 Caucasian patients with PHPT and 328 healthy volunteers in a cross-sectional study. We analyzed anthropometric data, history of fractures or renal lithiasis, biochemical determinants including markers for bone remodelling, BMD measurements in the lumbar spine, total hip, femoral neck and distal radius, and genotyping for the SNPs to be studied.</p> <p>Results</p> <p>Regarding the age of diagnosis, BMI, menopause status, frequency of fractures or renal lithiasis, we found no differences between genotypes in any of the SNPs studied in the PHPT group. Significant lower BMD in the distal radius with similar PTH levels was found in the minor allele homozygotes (GG) compared to heterozygotes and major allele homozygotes in both <it>OPG </it>rs3102735 (163 A/G) and <it>OPG </it>rs3134070 (245 T/G) SNPs in those with PHPT compared to control subjects. We found no differences between genotypes of the <it>OPG </it>rs2073618 (1181 G/C) SNP with regard to BMD in the PHPT subjects. In the evaluation of rs2277438 SNP of the <it>RANKL </it>in PHPT patients, we found a non significant trend towards lower BMD in the 1/3 distal radius and at total hip in the minor allele homocygotes (GG) genotype group versus heterocygotes and major allele homocygotes (AA).</p> <p>Conclusions</p> <p>Our study provides the first evaluation of the relationship between SNPs of the <it>OPG/RANK </it>system and sporadic PHPT. Subjects with PHPT and minor homocygote genotype (GG) for the <it>OPG </it>rs3102735 (163 A/G) and <it>OPG </it>rs3134070 (245 T/G) SNPs have lower BMD in the distal radius, and this association does not appear to be mediated by differences in PTH serum levels.</p

Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations.

The B cell receptor immunoglobulin (BcR IG) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n=488) i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL) as well as provisional entities (n=76) according to the World Health Organization classification. The most striking IG gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different IG gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ IG sequence dataset with a large dataset of IG sequences (MZ-related or not; n=65,837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia but also rheumatoid factors and non-malignant spleen MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms, may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments.This work was supported in part by H2020 “AEGLE, An analytics framework for integrated and personalized healthcare services in Europe”, by the European Union (EU); H2020 No. 692298 project “MEDGENET, Medical Genomics and Epigenomics Network” by the EU; grant AZV 15-30015A from the Ministry of Health of the Czech Republic, and the project CEITEC2020 LQ1601 from the Ministry of Education, Youth, and Sports of the Czech Republic; Bloodwise Research Grant (15019); the Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Stockholm, the Lion’s Cancer Research Foundation, Uppsala, the Marcus Borgström Foundation and Selander’s Foundation, Uppsala

Estudio comparativo de biocompatibilidad entre la hemodiafiltración en línea y la hemodiafiltración con reinfusión endógena Biocompatibility comparative study between online hemodiafiltration and hemodiafiltration with endogenous reinfusion

Objetivo: Comparar la biocompatibilidad entre la hemodiafiltración en línea (HDF) y la hemodiafiltración con reinfusión endógena (HFR). Material y método: Estudio comparativo observacional en una población de 15 pacientes en hemodiálisis crónica elegidos al azar entre los pacientes de nuestra unidad. Se compararon cambios en el perfil hematológico, nivel de PCR y constantes vitales, pre y post hemodiálisis, tras someterse a ambas técnicas de hemodiafiltración. Se comparó las diferencias entre los parámetros estudiados pre y post hemodiálisis en cada técnica. Resultados: Los niveles de plaquetas descendieron más en la HDF (HDF -1,33 vs HFR -19,73 x10³/mm³, p=0,005). El nivel de leucocitos disminuyó en la HDF y aumentó en la HFR (HDF -0,46 vs HFR +0,8 x10³/mm³; p=0,006). Respecto a la fórmula leucocitaria hubo resultados dispares: segmentados HDF -1,7 vs HFR +5,4%, pAim: To compare biocompatibility between online hemodiafiltration (HDF) and hemodiafiltration with endogenous reinfusion. Methods: Observational comparative study in a population of 15 chronic hemodialysis patients randomly selected among the patients in our unit. We compared changes in hematological profile, CRP level and vital signs, pre and post hemodialysis, after undergoing both hemodiafiltration techniques. Comparing the differences between the parameters studied before and after each hemodialysis technique. Results: Platelet levels decreased more in the HDF (HDF -1,33 vs HFR -19,73 x10³/mm³, p=0,005). Leukocyte levels decreased in the HDF and increased with HFR (HDF -0,46 vs HFR +0,8 x10³/mm³; p=0,006). Regarding the leukocyte formula had mixed results: segmented HDF -1,7 vs HFR +5,4%, p<0,001; lymphocytes HDF +1,96 vs HFR -3,62%, p<0,001. With the HFR decreased CRP levels less (HDF -0,05 vs HFR -0,001 mg/dl; p= NS). Regarding vital signs, systolic blood pressure decreased more in the HFR than HDF (HDF -9,93 vs HFR -10,33 mmHg; p<0,001), conversely that the diastolic blood pressure (HDF -5,2 vs HFR -3 mmHg; p=0,007), and heart rate (HDF -1,46 vs HFR +1,73 lpm; p=NS). Body temperature increased more with the HDF that the HFR (HDF +0,35 vs HFR +0,06 ºC; p=NS). Conclusions: According to our results the HFR seems more biocompatible than the HDF, probably derived by exogenous reinfusion of HDF

Estudio comparativo de biocompatibilidad entre la hemodiafiltración en línea y la hemodiafiltración con reinfusión endógena

Objetivo: Comparar la biocompatibilidad entre la hemodiafiltración en línea (HDF) y la hemodiafiltración con reinfusión endógena (HFR). Material y método: Estudio comparativo observacional en una población de 15 pacientes en hemodiálisis crónica elegidos al azar entre los pacientes de nuestra unidad. Se compararon cambios en el perfil hematológico, nivel de PCR y constantes vitales, pre y post hemodiálisis, tras someterse a ambas técnicas de hemodiafiltración. Se comparó las diferencias entre los parámetros estudiados pre y post hemodiálisis en cada técnica. Resultados: Los niveles de plaquetas descendieron más en la HDF (HDF -1,33 vs HFR -19,73 x103/mm3, p=0,005). El nivel de leucocitos disminuyó en la HDF y aumentó en la HFR (HDF -0,46 vs HFR +0,8 x103/mm3; p=0,006). Respecto a la fórmula leucocitaria hubo resultados dispares: segmentados HDF -1,7 vs HFR +5,4%,

Estudio comparativo de biocompatibilidad entre la hemodiafiltración en línea y la hemodiafiltración con reinfusión endógena

International audienc

Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B cell receptor immunoglobulins (BcR IG). Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR IG stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR IG stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. In order to address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29,856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed 'satellites', were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification