Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

[EN] Background Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. Methods We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. Results We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. Conclusion MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.The authors thank the patients and healthy relatives for having participated in this project. We are grateful to the Eurobiobank CIBERER and the Biobank La Fe for their participation in the collection and processing of patient samples. We also thank the technicians at the Department of Genomics and Translational Genetics (CIPF) who participated in the quality control and processing of DNA samples (Virginia Rejas and Laura Ramírez), and the Bachelor¿s thesis student Andrea Ballester who helped with some clinical data collection. This project was funded by the Instituto de Salud Carlos III (ISCIII), FEDER (Grants no. PI12/00946 and PI16/00403 to TS, PI15/00187 to CE). MF holds a grant funded by the IIS La Fe (Grant no. 2015/0085). AS-M holds a grant funded by the Fundació Per Amor a l'Art (FPAA). JFV-C holds a ' Rio Hortega' contract funded by the ISCIII.Lupo, V.; Frasquet, M.; Sánchez-Monteagudo, A.; Pelayo-Negro, A.; García-Sobrino, T.; Sedano, MJ.; Pardo, J.... (2018). Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. Journal of Medical Genetics. 55(12):814-823. https://doi.org/10.1136/jmedgenet-2018-105650814823551

Safety and effectiveness of CIMAvax-EGF administered in community polyclinics

In spite of the advances in immunotherapy and targeted therapies, lung cancer continues to be the leading cause of cancer-related death. The epidermal growth factor receptor is an established target for non-small cell lung cancer (NSCLC), and its overactivation by the ligands can induce accelerated proliferation, angiogenesis, and metastasis as well as proinflammatory or immunosuppressive signals. CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy that is approved for the treatment of NSCLC patients in Cuba. The study was designed as a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals. CIMAvax-EGF treatment consisted of four bi-weekly doses followed by monthly boosters. Overall, 741 NSCLC patients ineligible for further cancer-specific treatment were enrolled. CIMAvax-EGF was safe, and the most common adverse events consisted of mild-to-moderate injection site reactions, fever, chills, tremors, and headache. For patients completing the loading doses, the median survival was 9.9 months. For individuals achieving at least stable disease to the frontline and completing vaccination induction, the median survival was 12 months. Most of the functional activities and symptoms evaluated through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire improved over time. In conclusion, this real-world trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Remarkably, this community-based intervention was very important because it demonstrated the feasibility of treating advanced lung cancer patients with active immunotherapy in primary care institutions. In addition to CIMAvax-EGF, patients received supportive care at the community clinic. Vaccine administration by the family doctors at the polyclinics reduced the patients’ burden on the medical oncology services that continued providing chemotherapy and other complex therapies. We conclude that community polyclinics constitute the optimal scenario for administering those cancer vaccines that are safe and require prolonged maintenance in patients with advanced cancer, despite the continuous deterioration of their general condition.Clinical trial registrationhttps://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205

Prehipertensión arterial en la edad escolar, un reto para la Atención Primaria de Salud

Years ago it was considered that hypertension was manifested with low incidence in childhood; However, multiple studies in a variety of ethnic and racial groups have shown an increased prevalence in this age group. It was conducted a cross-sectional descriptive study at three medical offices of "Chiqui Gómez Lubián" Polyclinic in Santa Clara city, Villa Clara Province, during the period from January 2012 to May 2014 with the aim to identify how many children there are in this health area who have prehypertension as well as the risk factors that affect them. The study population was 104 schoolchildren and the sample was composed of 94 patients, it was  excluded  those patients who suffered from chronic noncommunicable diseases, except those who were   interesting to the investigation. Anthropometric study, measurement of blood pressure and a questionnaire developed for this purpose were used as techniques. The family medical history, inadequate eating habits and excess weight and improper physical exercise predominated in patients diagnosed with prehypertension or hypertension. Finally it was concluded that school-stricken modifiable risk factors are most affected by hypertensive disease, which shows that if the lifestyles of these patients were modified it would achieve delay their appearances, improve their outcomes and delay their complications.Años atrás se consideraba que la hipertensión arterial se manifestaba con baja incidencia en la edad infantil; sin embargo, múltiples investigaciones en una variedad de grupos étnicos y raciales han demostrado un aumento de su prevalencia en este grupo de edades. Se realizó un estudio descriptivo transversal en tres consultorios médicos del Policlínico “Chiqui Gómez Lubián” de la Ciudad de Santa Clara, Provincia de Villa Clara, durante el período de enero de 2012 a mayo de 2014 con el objetivo de identificar  cuántos niños existen en esta área de salud que padecen prehipertensión arterial, así como los factores de riesgos que los afectan. La población estudio fue de 104 escolares y la muestra quedó conformada por 94, se excluyeron aquellos pacientes que  padecían enfermedades crónicas no transmisibles, excepto las de interés para la investigación. Se utilizaron como técnicas el estudio antropométrico, la medición de la tensión arterial y la aplicación de un cuestionario elaborado al efecto. Predominaron los antecedentes patológicos familiares, los hábitos alimentarios inadecuados y el exceso de peso, así como una incorrecta práctica de ejercicios físicos en aquellos diagnosticados con prehipertensión o hipertensión arterial. Finalmente se concluyó que los escolares aquejados por factores de riesgo modificables son los más afectados por la enfermedad hipertensiva, lo que demuestra que si se modifican los estilos de vida de estos pacientes se lograría retrasar su aparición, mejorar su evolución y retrasar sus complicaciones

<i>C</i>*-Algebra Valued Modular <i>G</i>-Metric Spaces with Applications in Fixed Point Theory

This article introduces a new type of C*-algebra valued modular G-metric spaces that is more general than both C*-algebra valued modular metric spaces and modular G-metric spaces. Some properties are also discussed with examples. A few common fixed point results in C*-algebra valued modular G-metric spaces are discussed using the “C*-class function”, along with some suitable examples to validate the results. Ulam–Hyers stability is used to check the stability of some fixed point results. As applications, the existence and uniqueness of solutions for a particular problem in dynamical programming and a system of nonlinear integral equations are provided

Ausencia de asociación HLA-A*68-enfermedad renal crónica, en pacientes del occidente y centro de Cuba

La enfermedad renal crónica es un problema de salud a nivel mundial que frecuentemente evoluciona a la insuficiencia renal crónica terminal (IRC), que requiere el tratamiento de remplazo por métodos dialíticos o de trasplante renal. En un estudio reciente se evidenció la elevada frecuencia del gen HLA-A*68 en pacientes con IRC, lo que contrasta con los resultados de caracterizaciones HLA en la población Cubana reportados con anterioridad. Se realizó un estudio retrospectivo para determinar la posible asociación del gen HLA-A*68 con la IRC. Se analizaron las tipificaciones previas de 410 pacientes en diálisis, del occidente y centro de Cuba, y de 322 controles que incluían donantes de células progenitoras hematopoyéticas y donantes cadáveres de órganos sólidos, de las mismas regiones. La tipificación HLA se realizó con el estuche de baja resolución Olerup SSP® HLA-A-B-DR-DQ SSP (Olerup, Alemania). Las frecuencias alélicas se estimaron por algoritmo EM mediante el programa Arlequín 3.5, y para la comparación de la frecuencia de genes entre grupos se utilizó la prueba de Χ² con corrección de Yates, calculado en el programa Statistical 8.0. La frecuencia de expresión del gen HLA-A*68 fue de 0,060 en los pacientes con IRC y de 0,051 en los controles, sin diferencias estadísticamente significativas entre grupos (p = 0,590). Los presentes resultados no permiten establecer asociación entre el HLA-A*68 y la propensión a padecer IRC en los pacientes del occidente y centro de Cuba

The potential of surveillance data for dengue risk mapping : an evaluation of different approaches in Cuba

To better guide dengue prevention and control efforts, the use of routinely collected data to develop risk maps is proposed. For this purpose, dengue experts identified indicators representative of entomological, epidemiological and demographic risks, hereafter called components, by using surveillance data aggregated at the level of Consejos Populares (CPs) in two municipalities of Cuba (Santiago de Cuba and Cienfuegos) in the period of 2010–2015. Two vulnerability models (one with equally weighted components and one with data-derived weights using Principal Component Analysis), and three incidence-based risk models were built to construct risk maps. The correlation between the two vulnerability models was high (tau &gt; 0.89). The single-component and multicomponent incidence-based models were also highly correlated (tau ≥ 0.9). However, the agreement between the vulnerability- and the incidence-based risk maps was below 0.6 in the setting with a prolonged history of dengue transmission. This may suggest that an incidence-based approach does not fully reflect the complexity of vulnerability for future transmission. The small difference between single- and multicomponent incidence maps indicates that in a setting with a narrow availability of data, simpler models can be used. Nevertheless, the generalized linear mixed multicomponent model provides information of covariate-adjusted and spatially smoothed relative risks of disease transmission, which can be important for the prospective evaluation of an intervention strategy. In conclusion, caution is needed when interpreting risk maps, as the results vary depending on the importance given to the components involved in disease transmission. The multicomponent vulnerability mapping needs to be prospectively validated based on an intervention trial targeting high-risk areas

Experiencia cubana con el uso terapéutico de células madre adultas Cuban experience with the therapeutic use of adult stem cells

Las investigaciones básicas y clínicas realizadas en los últimos años sobre las células madre y sus posibilidades terapéuticas, son en la actualidad uno de los temas más excitantes de la medicina contemporánea. Ya se han obtenido importantes avances en el estudio y aplicación de las células madre adultas que muestran notables ventajas sobre las embrionarias, pues su manipulación resulta más simple, económica y se pueden obtener del propio individuo que va a ser tratado. Para la introducción en Cuba de la terapia celular regenerativa, en el Instituto de Hematología e Inmunología se seleccionaron como fuentes celulares las células madre adultas derivadas de la médula ósea y las movilizadas a la sangre periférica. Para facilitar la extensión del tratamiento a otros centros hospitalarios, se estandarizó una técnica para la movilización de las células madre hematopoyéticas a la sangre periférica, mediante un factor estimulador de colonias de granulocitos (Filgrastim, de producción nacional) y se desarrolló un método simple, económico y también más tolerable para los enfermos. De esta forma, se ha extendido la terapia celular a 6 provincias cubanas y hasta abril del año 2009 se habían tratado 563 casos con trasplante de células madre adultas autólogas, de los cuales el 81,7 % corresponde a pacientes con enfermedades angiológicas, en los que se ha logrado disminuir significativamente la indicación de amputaciones mayores. También los resultados han sido muy prometedores en las lesiones óseas y procesos periodontales, entre otras enfermedades tratadas. Los resultados obtenidos hasta el momento se pueden considerar como un nuevo logro de la ciencia revolucionaria y de nuestros sistemas nacionales de salud y de ciencia y técnica. El método empleado es un proceder económico y factible para instituciones con recursos limitados

Cardiopulmonary resuscitation in adults over 80 : outcome and the perception of appropriateness by clinicians

OBJECTIVES: To determine the prevalence of clinician perception of inappropriate cardiopulmonary resuscitation (CPR) regarding the last out‐of‐hospital cardiac arrest (OHCA) encountered in an adult 80 years or older and its relationship to patient outcome. DESIGN: Subanalysis of an international multicenter cross‐sectional survey (REAPPROPRIATE). SETTING: Out‐of‐hospital CPR attempts registered in Europe, Israel, Japan, and the United States in adults 80 years or older. PARTICIPANTS: A total of 611 clinicians of whom 176 (28.8%) were doctors, 123 (20.1%) were nurses, and 312 (51.1%) were emergency medical technicians/paramedics. RESULTS AND MEASUREMENTS: The last CPR attempt among patients 80 years or older was perceived as appropriate by 320 (52.4%) of the clinicians; 178 (29.1%) were uncertain about the appropriateness, and 113 (18.5%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the “appropriate” subgroup was 8 of 265 (3.0%), 1 of 164 (.6%) in the “uncertain” subgroup, and 2 of 107 (1.9%) in the “inappropriate” subgroup (P = .23); 503 of 564 (89.2%) CPR attempts involved non‐shockable rhythms. CPR attempts in nursing homes accounted for 124 of 590 (21.0%) of the patients and were perceived as appropriate by 44 (35.5%) of the clinicians; 45 (36.3%) were uncertain about the appropriateness; and 35 (28.2%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the nursing home patients was 0 of 107 (0%); 104 of 111 (93.7%) CPR attempts involved non‐shockable rhythms. Overall, 36 of 543 (6.6%) CPR attempts were undertaken despite a known written do not attempt resuscitation decision; 14 of 36 (38.9%) clinicians considered this appropriate, 9 of 36 (25.0%) were uncertain about its appropriateness, and 13 of 36 (36.1%) considered this inappropriate. CONCLUSION: Our findings show that despite generally poor outcomes for older patients undergoing CPR, many emergency clinicians do not consider these attempts at resuscitation to be inappropriate. A professional and societal debate is urgently needed to ensure that first we do not harm older patients by futile CPR attempts. J Am Geriatr Soc 68:39–45, 201