Epidemiological, clinical, biochemical and molecular characterization of Segawa disease

Introducción. En 2009, neuropediatras y neurólogos del Hospital Universitario Reina Sofia describieron un posible efecto fundador de la enfermedad de Segawa autosomica dominante en Córdoba (España) debido a la mutación c.265C> T (p. Q89*) en el gen GCH1. Se ha coordinado un estudio multicéntrico con el objetivo de mejorar el conocimiento de la situación de la enfermedad de Segawa en España y proporcionar una descripción fenotípica y genotípica detallada de los pacientes así como la respuesta al tratamiento y valorar posibles biomarcadores. Métodos. La información clínico-genética se obtuvo a partir de cuestionarios estandarizados que fueron completados por los neurólogos que atendieron a niños y/o adultos de 16 hospitales españoles. Se realizo el estudio in silico de las variantes genéticas noveles. El efecto fundador de la variante p.Q89* se analizó mediante el estudio de haplotipos satélites. Se analizaron prolactina sérica y pterinas en orina y en sangre seca como posibles biomarcadores para el diagnóstico y seguimiento de la enfermedad. Resultados. Ochenta sujetos pertenecientes a 24 familias mostraron mutaciones/deleciones en el gen GCH1 compatibles con la enfermedad de Segawa. Se describieron siete variantes genéticas exclusivas en la cohorte de pacientes, 5 de las cuales son mutaciones noveles. Se detectaron cinco familias con p.Q89*, no descritas previamente, en Andalucía debido a un posible efecto fundador. La mediana de latencia diagnostica fue de 5 anos (RIC 0- 16). Nueve de las 24 familias tenían miembros diagnosticados de la enfermedad de Parkinson en sus antecedentes familiares. Los signos y/o síntomas más frecuentes fueron distonía de miembros inferiores (38/56, 67,8%, p = 0,008) y fluctuaciones diurnas de la sintomatología motora (38/56, 67,8%, p = 0,008). Las fluctuaciones diurnas no estuvieron presentes en los fenotipos distintos de la distonía. Cincuenta y tres de 56 pacientes sintomáticos fueron tratados con un L-Dopa/inhibidor de decarboxilasa periférica durante (media +- DE) 12,4 +-} 8,12 años. En un 81% de casos se emplearon dosis inferiores a 350 mg/día (o ≤5 mg/kg/día en niños). Once de 53 (20%) pacientes presentaron síntomas que no respondían a L-Dopa/inhibidor de decarboxilasa periférica y que les afectaban en las actividades de la vida diaria. Las discinesias (en 4 sujetos) fueron los efectos adversos más destacados. No se observó deterioro de la respuesta al tratamiento con LDopa/ inhibidor de decarboxilasa periférica a largo plazo. Se analizo la prolactina sérica como posible biomarcador de seguimiento en 14 individuos, resultando normales en todos los casos. Se analizaron pterinas en orina y en sangre seca en 15 individuos afectos de la enfermedad y se comparó con un grupo control, observándose que presentaron valores significativamente más bajos tanto para la excreción de neopterina como de biopterina en orina (prueba t de Student; p T (p.Q89*) mutation in the GCH1 gene. A multicenter study has been coordinated to improve the knowledge of the situation of Segawa disease in Spain and to provide a detailed phenotypic and genotypic description of the patients as well as the response to treatment and to assess possible biomarkers. Methods. The clinical-genetic information was obtained from standardized questionnaires that were completed by neurologists who cared for children and/or adults from 16 Spanish hospitals. The in silico study of the novel genetic variants was carried out. The founder effect of p.Q89* was analyzed by studying satellite haplotypes. Serum prolactin and pterins in urine and dried blood were analyzed as possible biomarkers for the diagnosis and follow-up of the disease. Results. Eighty subjects belonging to 24 families showed mutations in GCH1 compatible with Segawa disease. Seven exclusive genetic variants have been described in the cohort of patients, 5 of which are novel mutations. Five previously undescribed families with p.Q89* were detected in Andalusia due to a possible founder effect. The median latency to diagnosis was 5 years (IQR 0-16). Nine of the 24 families had members diagnosed with Parkinson's disease in their family history. The most frequent signs and/or symptoms were lower limb dystonia (38/56, 67.8%, p = 0.008) and diurnal fluctuations in motor symptoms (38/56, 67.8%, p = 0.008). Diurnal fluctuations were not present in phenotypes other than dystonia. Fifty-three of 56 symptomatic patients were treated with an L Dopa/periferic decarboxylase inhibitor for (mean +-SD) 12.4 +-8.12 years. In 81% of cases, doses lower than 350 mg/day (or ≤5 mg / kg / day in children) were used. Eleven of 53 (20%) patients had non-responsive symptoms and that affected daily life activities. Dyskinesias (in 4 subjects) were the most prominent adverse effects. No deterioration in response to long-term L-Dopa/periferic decarboxylase inhibitor treatment was observed. Serum prolactin was analyzed as a possible follow-up biomarker in 14 individuals, all results were normal. Pterins were analyzed in urine and in dried blood in 15 individuals affected by the disease and compared with a control group, observing that they presented significantly lower values for both the excretion of neopterin and biopterin in urine (Student's t test; p < 0.0001). Conclusión. This study identified 5 novel disease-causing mutations in the GCH1 gene and 7 uniquely described in this cohort. Five new families carrying the p.Q89* mutation were detected, which supports the hypothesis of a founder effect of p.Q89* in Andalusia. New insights are provided about phenotypes and long-term response to treatment, which can improve early recognition and therapeutic management. It is noteworthy that the diurnal fluctuations of motor symptoms were found exclusively in early ages and phenotypes with dystonia. Despite being a disease with good response to treatment, 20% of patients described non-responsive symptoms to L-Dopa that affected their daily life. It was found a high prevalence of Parkinson's disease in families affected by Segawa disease. Serum prolactin does not seem to be useful in monitoring the disease, however, urine pterins could be of interest as a peripheral biomarker for biochemical diagnosis

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Consenso Delphi de las recomendaciones para el tratamiento de los pacientes con atrofia muscular espinal en España (consenso RET-AME)

Atrofia muscular espinal; Tratamiento; DelphiAtròfia muscular espinal; Tractament; DelphiSpinal muscular atrophy; Treatment; DelphiIntroduction Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. Methodology A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. Results Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. Conclusions The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA.Introducción La atrofia muscular espinal (AME) es una enfermedad neurodegenerativa, causada por una mutación bialélica del gen 5q SMN1, que afecta predominantemente a las neuronas motoras de la asta anterior medular causando una progresiva debilidad y atrofia muscular. La aparición de tratamientos modificadores del curso de la enfermedad está cambiando considerablemente la historia natural de la AME, pero existe todavía incertidumbre sobre qué pacientes se pueden beneficiar de estos tratamientos y cómo se debería medir ese beneficio. Metodología Un grupo de expertos especialistas en neurología, neuropediatría, rehabilitación y de la asociación de pacientes FundAME analizaron, siguiendo la metodología Delphi, 5 apartados relacionados con el uso de los nuevos tratamientos: aspectos generales; objetivos del tratamiento; herramientas de medición de resultados; requisitos de los centros tratantes; y regulación de su uso. Se definió como consenso cuando una respuesta recibió al menos el 80% de los votos. Resultados Los protocolos de tratamiento son útiles para regular el uso de medicamentos de alto impacto y deben constituir una guía para el tratamiento, pero se deben actualizar regularmente para recoger la evidencia más reciente disponible y su implementación se debe valorar de forma individualizada. La edad, la funcionalidad basal y, en el caso de los niños, el tipo de AME y el número de copias de SMN2 son características que se deben tener en cuenta a la hora de establecer los objetivos terapéuticos, las herramientas de medición y el uso de dichos tratamientos. El aspecto más determinante del coste-efectividad de estos tratamientos en la edad pediátrica es su inicio precoz, por lo que se recomienda la instauración de un cribado neonatal. Conclusiones Las recomendaciones del consenso RET-AME proporcionan un marco de referencia para el uso adecuado de tratamientos modificadores de la enfermedad en pacientes con AME

Copper-catalyzed Goldberg-type C–N coupling in deep eutectic solvents (DESs) and water under aerobic conditions

An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldbergtype C–N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium, though the employment of DESs expanded and improved the scope of the reaction to include also aliphatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for the synthesis of biologically active molecules

A(H3N2) antigenic variation of influenza is associated with low vaccine efficacy in the early 2018 influenza season in Mexico City

Objectives: We evaluated the VE and the mutations of the viruses present in the Mexican population at the beginning of 2018. Methods: We diagnosed influenza in outpatients with a high-performance Rapid Influenza Diagnostic Test (RIDT) qRT–PCR. Descriptive statistics were used to describe the study population, while the chi-square test was used to determine clinical variables. VE was analyzed through a negative test design. We sequenced the hemagglutinin (HA) gene, performed a phylogenetic analysis, and analyzed the nonsynonymous substitutions both in and outside antigenic sites. Results: Of the 240 patients analyzed, 42.5% received the trivalent vaccine, and 37.5% were positive for influenza. The VE for the general population for any influenza virus type or subtype was 37.0%, while the VE for the predominant influenza A(H3N2) subtype was the lowest (19.7%). The phylogenetic analysis of HA showed the co-circulation of clades and subclades 3C.2a1, 3C.2a1b, 3C.2a2, 3C.2a2re, 3C.2a3, and 3C.3a with identities approximately 97-98% similar to the vaccine composition. Conclusion: Low VE was related to the co-circulation of multiple clades and subclades of influenza A(H3N2), with sufficient genetic and phenotypic distance to allow for the infection of vaccinated individuals

Reseñas de Libros

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