Expanding the Genetic Spectrum of ANOS1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism

STUDY QUESTION: What is the prevalence and functional consequence of ANOS1 (KAL1) mutations in a group of men with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Three of forty-two (7.1%) patients presented ANOS1 mutations, including a novel splice site mutation leading to exon skipping and a novel contiguous gene deletion associated with ichthyosis. WHAT IS KNOWN ALREADY: CHH is characterized by lack of pubertal development and infertility, due to deficient production, secretion or action of GnRH, and can be associated with anosmia/hyposmia (Kallmann syndrome, KS) or with a normal sense of smell (normosmic CHH). Mutations in the anosmin-1 (ANOS1) gene are responsible for the X-linked recessive form of KS. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 42 unrelated men with CHH (20 with KS and 22 with normosmic CHH). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were screened for mutations in the ANOS1 gene by DNA sequencing. Identified mutations were further investigated by RT-PCR analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Hemizygous mutations were identified in three (7.1%) KS cases: a novel splice acceptor site mutation (c.542-1G>C), leading to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing); a recurrent nonsense mutation (c.571C>T, p.Arg191*); and a novel 4.8 Mb deletion involving ANOS1 and eight other genes (VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X) in KS associated with ichthyosis. LIMITATIONS, REASONS FOR CAUTION: Objective olfactory testing was not performed in all cases of self-reported normosmia and this may have underestimated the olfactory deficits. WIDER IMPLICATIONS OF THE FINDINGS: This study further expands the spectrum of known genetic defects associated with CHH and suggests that patients with self-reported normal olfactory function should not be excluded from ANOS1 genetic testing. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Portuguese Foundation for Science and Technology. The authors have no conflicts of interest.info:eu-repo/semantics/publishedVersio

Expanding the Genetic Spectrum of ANOS1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism

STUDY QUESTION: What is the prevalence and functional consequence of ANOS1 (KAL1) mutations in a group of men with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Three of forty-two (7.1%) patients presented ANOS1 mutations, including a novel splice site mutation leading to exon skipping and a novel contiguous gene deletion associated with ichthyosis. WHAT IS KNOWN ALREADY: CHH is characterized by lack of pubertal development and infertility, due to deficient production, secretion or action of GnRH, and can be associated with anosmia/hyposmia (Kallmann syndrome, KS) or with a normal sense of smell (normosmic CHH). Mutations in the anosmin-1 (ANOS1) gene are responsible for the X-linked recessive form of KS. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 42 unrelated men with CHH (20 with KS and 22 with normosmic CHH). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were screened for mutations in the ANOS1 gene by DNA sequencing. Identified mutations were further investigated by RT-PCR analysis and multiplex ligation-dependent probe amplification (MLPA) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Hemizygous mutations were identified in three (7.1%) KS cases: a novel splice acceptor site mutation (c.542-1G>C), leading to skipping of exon 5 in the ANOS1 transcript in a patient with self-reported normosmia (but hyposmic upon testing); a recurrent nonsense mutation (c.571C>T, p.Arg191*); and a novel 4.8 Mb deletion involving ANOS1 and eight other genes (VCX3B, VCX2, PNPLA4, VCX, STS, HDHD1, VCX3A and NLGN4X) in KS associated with ichthyosis. LIMITATIONS, REASONS FOR CAUTION: Objective olfactory testing was not performed in all cases of self-reported normosmia and this may have underestimated the olfactory deficits. WIDER IMPLICATIONS OF THE FINDINGS: This study further expands the spectrum of known genetic defects associated with CHH and suggests that patients with self-reported normal olfactory function should not be excluded from ANOS1 genetic testing. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Portuguese Foundation for Science and Technology. The authors have no conflicts of interest.info:eu-repo/semantics/publishedVersio

Psychometric Properties of the Portuguese Version of the Iceland-Family Perceived Support Questionnaire in Parents of Children and Adolescents with Chronic Condition

Abstract: The support from nurses perceived by family members of children with chronic conditions has been shown to be a protective factor at different levels in a family’s health. As such, nurses need to have instruments that assess this perception to increase the quality of the care provided to those families. This methodological study aimed to analyze the psychometric properties of the Portuguese translation of the Iceland-Family Perceived Support Questionnaire (ICE-FPSQ) in parents of children/adolescents with chronic conditions. The ICE-FPSQ was administered to 237 parents recruited from the day hospital and outpatient services of four hospitals in Northern Portugal. Cronbach’s alpha reliability coefficients for the Total Scale, Cognitive Support, and Emotional Support subscales were excellent (α = 0.96, α = 0.93, α = 0.96, respectively). Reasonable fit indexes were found by confirmatory factor analysis (χ 2/df = 2.799; CFI = 0.960; PCFI = 0.791, and RMSEA = 0.087), indicating a good model fit to the original structure. The ICE-FPSQ is a valid and reliable instrument to measure perceived support.info:eu-repo/semantics/publishedVersio

CYP2D6 genetic polymorphisms are associated with susceptibility to pituitary tumors

Several polymorphisms of drug-metabolizing enzymes have been implicated in the susceptibility to tumor development. The role of the CYP2D6, GSTM1 and GSTT1 genes has been extensively studied, with alleles conferring different metabolic efficiencies and tumor risk. We studied the relationship between the main polymorphisms of these genes and the susceptibility to develop pituitary tumors, by performing a case-control study comprising 235 patients and 256 controls which were genotyped by means of PCR-RFLP based assays. Frequencies of the CYP2D6*1 and of the poor metabolizer allele CYP2D6*4, were determined along with the frequencies of the GSTM1 and GSTT1 null genotypes. CYP2D6 genotype frequencies were similar in patients and controls (p=0.087). CYP2D6*1 and CYP2D6*4 allele frequencies were 83.8%, 16.2% in cases and 78.3%, 21.7% in controls, showing a significant difference between the two groups (p=0.012). There were no significant differences between the frequencies of the GSTM1 and GSTT1 null genotypes in both groups. No association was found between histological type and any of the studied polymorphisms. Our data suggest an association of the CYP2D6*1 allele and the susceptibility to pituitary adenomas, which could be due to an increased metabolism of unidentified procarcinogens or to linkage disequilibrium with another gene involved in pituitary tumorigenesis

Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancer

OBJECTIVE: Xenobiotic-metabolizing enzymes are widely polymorphic and confer interindividual variation in the ability to detoxify carcinogens or to activate pro-carcinogens. A common polymorphism of cytochrome P450 2D6 (CYP2D6) results in lack of enzyme activity and has been associated with an altered susceptibility to several cancers. The aim of this study was to investigate the association between the CYP2D6 poor metaboliser genotype and the risk of papillary thyroid cancer (PTC). DESIGN: Retrospective case-control study. PATIENTS: One hundred and eighty-seven patients with PTC and 256 controls. MEASUREMENTS: Genotyping was performed by PCR and restriction enzyme analysis to detect the presence of the common CYP2D6*4 poor metaboliser allele. RESULTS: The frequency of individuals with the homozygous poor metaboliser genotype was lower in the patient group [1.6 vs. 5.5%, P = 0.037, OR = 0.28 (95% CI 0.09-0.93)]. The CYP2D6*4 allele frequency was also lower in the patient group [13.4 vs. 21.7%, P = 0.002, OR = 0.56 (95% CI 0.39-0.80)]. CONCLUSIONS: The results suggest that the poor metaboliser genotype is associated with a protective effect against PTC. This could be explained by a possible role of CYP2D6 on the metabolic activation of putative environmental chemical thyroid carcinogens or by linkage to another cancer-causing gene. Further research may allow the identification of metabolic risk factors and contribute towards understanding the molecular mechanisms involved in thyroid carcinogenesis

Actionable knowledge for environmental decision making: Broadening the usability of climate science

Despite the rapid evolution and growing complexity in models of science-society interaction, the rate and breadth of use of scientific knowledge in environmental decision making, especially related to climate variability and change, remain below expectations. This suggests a persistent gap between production and use that, to date, efforts to rethink and restructure science production have not been able to surmount. We review different models of science-policy interfaces to understand how they have luenced the organization of knowledge production and application. We then explore how new approaches to the creation of knowledge have emerged, involving both growing integration across disciplines and greater interaction with users. Finally, we review climate information use in the United States and United Kingdom to explore how the structure of knowledge production and the characteristics of users and their decision environments expose the challenges of broadening usable climate science

Anaplastic thyroid tumor: retrospective analysis of 12 cases

Anaplastic thyroid tumor is a rare tumor and constitutes 5 to 10% of thyroid carcinomas. Is one of the most aggressive solid tumors and the prognosis is always fatal with a mean survival of 3 to 7 months. The current therapeutics are scarce and inefficacious. A retrospective analysis was performed in 12 clinical cases of anaplastic thyroid tumor observed at the Department of Endocrinology, Diabetes and Metabolism of the University Hospital of Coimbra. We analysed data relative to sex, previous thyroid pathology, clinical signs and symptoms, date of diagnosis, treatment and outcome. In this series, the anaplastic thyroid carcinoma showed to be a highly malignant tumor with a mortality rate of 100% with a survival after the diagnosis between 15 days and 9 months

Referenciação pediátrica: que realidade?

Mesmo após a reestruturação de acesso à Urgência Pediátrica que teve inicio em Março de 2000, a afluência directa à Urgência Pediátrica no Hospital Fernando Fonseca sem referenciação médica é uma realidade diária. O presente estudo pretendeu determinar os motivos que levam as crianças à urgência daqueÌe hospital. Foi um estudo observacional descritivo, cuja recolha de dados ocorreu entre os dias 8 e 16 de Outubro de 2001 (apenas dias úteis) na Urgência Pediátrica (end-point 100 crianças). A maioria das crianças analisadas pertence aos Centros de Saúde do Cacém, Queluz e Mem Martins. O principal motivo da ida directa é a vontade dos acompanhantes, sendo a febre o principal motivo clínico da vinda das crianças. Não foi possível estabelecer qualquer relação entre o motivo para a vinda directa e a raça, escolaridade e o facto de ser primeiro filho. A maior parte das crianças teve alta para o domicílio (82%), sem necessitar de cuidados no hospital que não pudessem ter sido obtidos no Centro de Saúde da área. Apenas 18% necessitaram de tratamento hospitalar e destes seis porcento ficaram internados. Assim, para a maioria dos doentes (82%) é correcto ir ao Centro de Saúde e ser observado apenas pelo médico de Cuidados Primários. Tal representaria melhor utilização dos recursos médicos disponíveis com diminuição de custos para Sistema Nacional de Saúd

Thermodynamics of Two Dimensional Black Holes

Thermodynamic relations for a class of 2D black holes are obtained corresponding to observations made from finite spatial distances. We also study the thermodynamics of the charged version of the Jackiw-Teitelboim black holes found recently by Lowe and Strominger. Our results corroborate, in appropriate limits, to those obtained previously by other methods. We also analyze the stability of these black holes thermodynamically.Comment: 18 pages (One uncoded postscript file for figure appended), IP/BBSR/94-5