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

Analysis of drugs returned by inpatient services after unit dose distribution in a portuguese public hospital

Unit-dose has been considered the most effective dispensing system in hospital pharmacy, however not all drugs are administered, are then returned to the pharmacy. The analysis of non-administered drugs might provide important data regarding pharmacotherapeutic follow-up, but also regarding pharmacy management decisions. The present study aims at depicting the drugs returned to the pharmacy following their previous unit-dose dispensing. Methods: During a period of 45 days, the unused returned drugs of five different inpatient clinical services were analyzed regarding the state of conservation, justification for return, inpatient clinical service provenance, and dosage regimen. Of a total of 65280 unit-dose dispensed drugs, 25.2% were returned (n=16431) and 74.9% of SOS (i.e. medications prescribed as needed) drugs (n=6583) were unused. Excluding SOS drugs, more than a half of the returned drugs (52.4%, n=4967), were probably returned due to unintended omission of administration, after excluding patients that were not physically on the unit and patients whose treatments were modified. The large majority of returned drugs (98.6%, n=16201) were suitable for reintroduction in the medication circuit. In order to accomplish the basic principles of unit-dose dispensing genesis, the returned drugs must be kept to a minimum. Therefore, the suspension of dispensing SOS drugs by unit-dose should be considered. Additionally, the careful analysis of returned drugs should be promoted, in order to avoid, as much as possible, the omission of administration.info:eu-repo/semantics/publishedVersio

Multiple gestation epidemiology--15 years survey

Between January of 1987 and December of 2001 were born 1243 twins related to 609 multiple pregnancies, in Maternidade Bissaya-Barreto. Data were grouped in periods of three years and several parameters were studied. The rate of multiple gestation has increased probably due to the contribution of the assisted conception techniques, and to the increase of the number of multiple fetal pregnancies (two or more) and to the increase of the mother age. These more frequent obstetric problems were preterm birth, gestational hypertension and abnormal sonographic data of fetal growth. The average age of delivery was 34 weeks and the birth weight has decreased. The most important factors for neonatal morbidity were hyaline membranous disease, intraventricular haemorrhage and the twin-twin transfusion syndrome. The neonatal mortality decreased in the last studied period

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform

OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoform

Stability of hybrid versus vaccine immunity against BA.5 infection over 8 months

© 2022 Elsevier Ltd. All rights reserved.The coverage of SARS-CoV-2 vaccination in large parts of the world, together with the high number of breakthrough infections, especially following the emergence of Omicron subvariants, makes hybrid immunity (resulting from vaccine and infection) common. Hybrid immunity, particularly after BA.1 or BA.2 infection, confers substantial protection against the BA.5 infection. However, although the waning of protection afforded by natural infection in non-vaccinated individuals or by vaccination has been well documented, the stability of hybrid immunity, specifically against the BA.5 subvariant, now dominant in many countries, has not been thoroughly addressed.info:eu-repo/semantics/publishedVersio

Role of the reversible electrochemical deprotonation of phosphate species in anaerobic biocorrosion of steels

Sulphate reducing bacteria are known to play a major role in anaerobic microbiological influenced corrosion of steels, but mechanisms behind their influence are still source of debates as certain phenomena remain unexplained. Some experiments have shown that hydrogen consumption by SRB or hydrogenase increased the corrosion rate of mild steel. This was observed only in the presence of phosphate species. Here the cathodic behaviour of phosphate species on steel was studied to elucidate the role of phosphate in anaerobic corrosion of steel. Results showed: a linear correlation between reduction waves in linear voltammetry and phosphate concentration at a constant pH value; that phosphate ions induced considerable anaerobic corrosion of mild steel, which was sensitive to hydrogen concentration in the solution; and that the corrosion potential of stainless steel in presence of phosphate was shifted to more negative values as molecular hydrogen was added to the atmosphere in the reaction vessel. Phosphate species, and possibly other weak acids present in biofilms, are suggested to play an important role in the anaerobic corrosion of steels via a reversible mechanism of electrochemical deprotonation that may be accelerated by hydrogen removal

PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency

OBJECTIVE: Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. DESIGN, PATIENTS AND MEASUREMENTS: A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. RESULTS: PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. CONCLUSIONS: This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic cause