The Werner Syndrome Protein Suppresses Telomeric Instability Caused by Chromium (VI) Induced DNA Replication Stress

Telomeres protect the chromosome ends and consist of guanine-rich repeats coated by specialized proteins. Critically short telomeres are associated with disease, aging and cancer. Defects in telomere replication can lead to telomere loss, which can be prevented by telomerase-mediated telomere elongation or activities of the Werner syndrome helicase/exonuclease protein (WRN). Both telomerase and WRN attenuate cytotoxicity induced by the environmental carcinogen hexavalent chromium (Cr(VI)), which promotes replication stress and DNA polymerase arrest. However, it is not known whether Cr(VI)-induced replication stress impacts telomere integrity. Here we report that Cr(VI) exposure of human fibroblasts induced telomeric damage as indicated by phosphorylated H2AX (γH2AX) at telomeric foci. The induced γH2AX foci occurred in S-phase cells, which is indicative of replication fork stalling or collapse. Telomere fluorescence in situ hybridization (FISH) of metaphase chromosomes revealed that Cr(VI) exposure induced an increase in telomere loss and sister chromatid fusions that were rescued by telomerase activity. Human cells depleted for WRN protein exhibited a delayed reduction in telomeric and non-telomeric damage, indicated by γH2AX foci, during recovery from Cr(VI) exposure, consistent with WRN roles in repairing damaged replication forks. Telomere FISH of chromosome spreads revealed that WRN protects against Cr(VI)-induced telomere loss and downstream chromosome fusions, but does not prevent chromosome fusions that retain telomere sequence at the fusion point. Our studies indicate that environmentally induced replication stress leads to telomere loss and aberrations that are suppressed by telomerase-mediated telomere elongation or WRN functions in replication fork restoration

Phaeochromocytoma and functioning paraganglioma in childhood and adolescence: role of iodine 131 metaiodobenzylguanidine

Phaeochromocytomas and functioning paragangliomas are rare tumours in childhood and adolescence. We review our experience of 43 cases (24 men, 19 women) who were first diagnosed at the age of ⩽ 18 years. All patients were evaluated at some point in their illness with iodine 131 metaiodobenzylguanidine ( 131 I-mIBG) scintigraphy. Eight patients (19%) had bilateral adrenal tumours, 12 (28%) had solitary extra-adrenal tumours, and 8 (19%) had multiple tumours. In 10 patients (23%), the tumours were associated with a familial neurocristopathic syndrome. Thirteen of 24 (54%) unifocal tumours which were initially considered to be benign ultimately proved to be multi-focal and/or malignant. The final prevalence of malignancy was 60% − 26 patients, of whom only 15 (57%) had obviously malignant tumours at the time of diagnosis. Primary tumour size ⋝5 cm was more commonly associated with a malignant course in adrenal but not extra-adrenal tumours. No other clinical, biochemical or morphological characteristic was significantly associated with malignancy. Although the high prevalence of malignancy in this series at least partly reflects referral bias, the need for lifelong follow-up of these patients is underscored. 131 I-mIBG scintigraphy was positive in 36 patients (84%), with a somewhat lower false-negative rate (12%) than X-ray computed tomography (20%). Eight patients with malignant tumours received therapeutic doses of 131 I-mIBG, with partial tumour responses in 3. Thus, 131 I-mIBG is an efficacious, non-invasive, localising agent and may be considered as a palliative therapeutic agent when alternatives have failed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46831/1/259_2005_Article_BF02262730.pd

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Variações anatômicas e sinusopatias: estudo por tomografia computadorizada Anatomical variations and sinusitis: a computed tomographic study

Introdução: A tomografia computadorizada tem sido cada vez mais utilizada para a identificação e avaliação das variações anatômicas das cavidades nasais que podem levar às sinusites. Objetivo: Avaliar, por meio da tomografia computadorizada, a incidência de espessamento mucoso nos seios paranasais de pacientes com sintomas de sinusite e a correlação entre sinusopatias e presença de célula de Haller, concha média bolhosa e desvio de septo nasal localizado no meato médio. Forma de Estudo: Clínico retrospectivo. Material e Método: Foram avaliadas retrospectivamente 150 tomografias computadorizadas de seios paranasais de pacientes com idade igual ou superior a 13 anos, realizadas no Departamento de Diagnóstico por Imagem da Universidade Federal de São Paulo - Escola Paulista de Medicina, no período de julho de 1999 a outubro de 2001. Foram excluídos os exames de pacientes com pós-operatório de cirurgias de seios paranasais e de base de crânio, além dos portadores de lesões tumorais envolvendo estas regiões. Resultados: 70% dos pacientes apresentavam espessamento mucoso em pelo menos um dos seios paranasais. Observou-se a freqüência de 52,7% de sinusopatia maxilar, 28,0% de etmoidal, 13,0% de esfenoidal e 8,3% de frontal. Concha média bolhosa foi encontrada em 33,3% das cavidades nasais, desvio de septo nasal localizado no meato médio em 23,3% e célula de Haller em 9,3%. Conclusões: Os seios paranasais mais freqüentemente acometidos foram, em ordem decrescente: maxilar, etmoidal, esfenoidal e frontal. Não foi observado correlação entre sinusopatias e presença de célula de Haller, concha média bolhosa e desvio de septo nasal localizado no meato médio.<br>Introduction: Computed tomography has been increasingly used both to identify and to evaluate anatomy variations of nasal cavities that can lead to the development of sinusitis. Purpose: The purpose of the present study is to determine the incidence of mucosal abnormalities in paranasal sinuses found in CT scans of patients with symptons of sinusitis and analyze the correlation between sinusitis and presence of Haller's cell, concha bullosa and nasal septal deviation located in middle meatus. Study Design: Clinical retrospective. Material and Method: Paranasal sinus CT scans were obtained in 150 patients aged 13 years or more, from July 1999 to October 2001. The CT scans were performed in the Department of Radiology of Universidade Federal de São Paulo - Escola Paulista de Medicina. Patients with history of skull base or sinus surgery and tumor in these regions were excluded. Results: 70% of patients present mucosal abnormalities at least in one paranasal sinus. Maxillary sinusitis were observed in 52,7% of sinus, ethmoidal sinusitis in 28,0%, sphenoidal sinusitis in 13,0% and frontal sinusitis in 8,3%. Concha bullosa was observed in 33,3% of nasal cavities, nasal septal deviation (located in middle meatus) in 23,3% and Haller's cell in 9,3%. Conclusions: The most affected paranasal sinuses were: maxillary, ethmoid, sphenoid and frontal. Correlation between sinusitis and presence of Haller's cell, concha bullosa and nasal septal deviation (located in middle meatus) was not observed

SSRs, SNPs and DArTs comparison on estimation of relatedness and genetic parameters’ precision from a small half-sib sample population of Eucalyptus grandis

Simple sequence repeats (SSR) are the most widely used molecular markers for relatedness inference due to their multi-allelic nature and high informativeness. However, there is a growing trend toward using high-throughput and inter-specific transferable single-nucleotide polymorphisms (SNP) and Diversity Arrays Technology (DArT) in forest genetics owing to their wide genome coverage. We compared the efficiency of 15 SSRs, 181 SNPs and 2816 DArTs to estimate the relatedness coefficients, and their effects on genetic parameters’ precision, in a relatively small data set of an open-pollinated progeny trial of Eucalyptus grandis (Hill ex Maiden) with limited relationship from the pedigree. Both simulations and real data of Eucalyptus grandis were used to study the statistical performance of three relatedness estimators based on co-dominant markers. Relatedness estimates in pairs of individuals belonging to the same family (related) were higher for DArTs than for SNPs and SSRs. DArTs performed better compared to SSRs and SNPs in estimated relatedness coefficients in pairs of individuals belonging to different families (unrelated) and showed higher ability to discriminate unrelated from related individuals. The likelihood-based estimator exhibited the lowest root mean squared error (RMSE); however, the differences in RMSE among the three estimators studied were small. For the growth traits, heritability estimates based on SNPs yielded, on average, smaller standard errors compared to those based on SSRs and DArTs. Estimated relatedness in the realized relationship matrix and heritabilities can be accurately inferred from co-dominant or sufficiently dense dominant markers in a relatively small E. grandis data set with shallow pedigree.Fil: Cappa, Eduardo Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires; ArgentinaFil: Klápště, Jaroslav. Czech University Of Life Sciences Prague; República Checa. University of British Columbia; Canadá. New Zealand Forest Research Institute Ltd.; Nueva ZelandaFil: Garcia, Martín Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Investigación En Ciencias Veterinarias y Agronómicas; ArgentinaFil: Villalba, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Investigación En Ciencias Veterinarias y Agronómicas; ArgentinaFil: Marcucci Poltri, Susana Noemí. Investigación En Ciencias Veterinarias y Agronómicas; Argentin