Genetics applied to clinical practice in neurodevelopmental disorders

Las evidencias genéticas de los trastornos del neurodesarrollo están ampliamente sustentadas en la literatura médica. Los avances en la genética y la tecnología han incrementado la rentabilidad diagnóstica de los estudios actuales de un 3-5% a un 30-40% en los pacientes con discapacidad intelectual o trastornos del espectro autista. En este sentido, los estudios por microarrays cromosómicos muestran un mayor poder diagnóstico que las técnicas convencionales (cariotipo, análisis de subtelómeros…). Los protocolos más recientes en el apartado biomédico del estudio genético de estos trastornos sitúan los microarrays cromosómicos como análisis de primera línea, recomendando otros estudios específicos según las características clínicas del paciente (síndrome X frágil, mutación en PTEN...). En la evaluación de otros trastornos del neurodesarrollo (trastorno por déficit de atención/hiperactividad, trastornos del aprendizaje...), la realización de pruebas genéticas está limitada y condicionada a las características clínicas o antecedentes familiares o personales del paciente; incluso en estas situaciones, no existen protocolos de evaluación o derivación genéticaThe medical literature contains a wide body of evidence supporting genetic involvement in neurodevelopmental disorders. Advances made in genetics and technology have increased the diagnostic cost-effectiveness of current studies from 3-5% to 30-40% in patients with intellectual disability or autism spectrum disorders. In this regard, chromosomal microarray studies display greater diagnostic power than conventional techniques (karyotype, subtelomeric analyses, etc.). The latest protocols in the biomedical field of the genetic study of these disorders cite chromosomal microarrays as the first-line analysis, while also recommending other specific studies depending on the patient’s clinical features (fragile X syndrome, PTEN mutation, etc.). In the evaluation of other neurodevelopmental disorders (attention deficit hyperactivity disorder, learning disorders, etc.), the number of genetic tests carried out is limited and conditioned by the clinical characteristics or the patient’s familial or personal history. Even in these situations, there are no genetic referral or evaluation protocol

Should inflammatory bowel disease clinicians provide their patients with e-Health resources?: patients' and professionals' perspectives

[Abstract] Introduction: The internet is emerging as a source of information for patients with inflammatory bowel disease (IBD). However, it is not always reliable and may cause anxiety. We aim to assess patients' information habits and patients' and professionals' perceptions of a national website integrated as an educational resource for the IBD unit. Methods: Patients aged 18-65 years, comfortable with the internet, and attending follow-ups at participating IBD units (March-June 2019) and their professionals were invited to evaluate a recommended website through an online survey. Results: Three hundred eighty-nine patients and 95 professionals completed the survey. The internet (n = 109; 27.4%) was the second preferred source of information after the health care team (n = 229; 57.5%). Eighty percent of patients searched the internet for information on their disease and 28.6% did so at least once a week (n = 114), especially newly diagnosed ones (<2 years). Patients valued a website recommended by their professional (n = 379; 95.2%) and endorsed by the National Working Group (n = 377; 94.7%). They would attend online educational initiatives on the website (n = 279; 70.1%) and complete periodical surveys to improve its usefulness (n = 338; 84.9%). According to IBD professionals, this type of website is the best patient source of supplementary information (n = 76; 80%) and they "prescribe" it to most patients (67.0 ± 25.2%), especially the newly diagnosed patients (52.7 ± 26.5%). It effectively integrates routine face-to-face education (n = 95; 100%). Conclusions: Patients of IBD units, especially newly diagnosed ones, appreciate a trusted e-Health resource to back up professional information. The favorable opinion of patients and professionals will allow its use in training interventions

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

BACKGROUND: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. METHODS: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. RESULTS: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. CONCLUSION: Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent.This work was partially supported by grant IPT-2012-0198-090000 (“MARINMAB” project) from Ministerio de Economía y Competitividad (MINECO) and European Regional Development’s funds (ERDF) and by CSIC grant 2019AEP146.S

Intracranial atherosclerotic plaque enhancement and long-term risk of future strokes: A prospective, longitudinal study

Background and Purpose The prognostic significance of postcontrast enhancement of intracranial atheromatous plaque is uncertain. Prospective, long-term follow-up studies in Caucasians, using a multicenter design, are lacking. We aimed to evaluate whether this radiological sign predicts long-term new stroke in symptomatic and asymptomatic intracranial atherosclerotic disease (ICAD) patients. Methods This was a prospective, observational, longitudinal, multicenter study. We included a symptomatic and an asymptomatic cohort of ICAD patients that underwent 3T MRI including high-resolution sequences focused on the atheromatous plaque. We evaluated grade of stenosis, plaque characteristics, and gadolinium enhancement ratio (postcontrast plaque signal/postcontrast corpus callosum signal). The occurrence of new events was evaluated at 3, 6, 9, and 12 months and annually thereafter. The association between plaque characteristics and new stroke was studied using Cox multiple regression survival analysis and Kaplan-Meier curves. Results Forty-eight symptomatic and 13 asymptomatic patients were included. During 56.3 ± 16.9 months, 11 patients (18%) suffered a new event (seven ischemic, two hemorrhagic, and two transient ischemic attacks). A receiver operating characteristic curve identified an enhancement ratio of >1.77 to predict a new event. In a multivariable Cox regression, postcontrast enhancement ratio >1.77 (hazard ratio [HR]= 3.632; 95% confidence interval [CI], 1.082-12.101) and cerebral microbleeds (HR = 5.244; 95% CI, 1.476-18.629) were independent predictors of future strokes. Patients with a plaque enhancement ratio >1.77 had a lower survival free of events (p < .05). Conclusions High intracranial postcontrast enhancement is a long-term predictor of new stroke in ICAD patients. Further studies are needed to elucidate whether postcontrast enhancement reflects inflammatory activity of intracranial atheromatous plaque.This study has been funded by the Spanish Ministry of Science, via FIS project PI13/02544, PI16/01396, and PI19/01398 and through the INVICTUS PLUS research network RD16/0019. Beatriz Gómez-Vicente received a research contract from the Junta de Castilla y León and European Social Fund, Spain. María Hernandez-Perez was funded by The Instituto de Salud Carlos III, Spain (JR17/00006)

Attention deficit/hyperactivity disorde: Study habits

El trastorno por déficit de atención/hiperactividad (TDAH) es uno de los trastornos más prevalentes en la población infanto-juvenil, con un impacto ya conocido sobre el aprendizaje y rendimiento escolar. La falta de atención, la disfunción ejecutiva asociada y los problemas comórbidos –particularmente los relacionados con el aprendizaje y la ansiedad–, condicionan marcadamente este dominio conceptual. Los jóvenes afectos, tienen más problemas para la toma de apuntes, finalización de trabajos, programación escolar y menor motivación al estudio. A pesar de una mayor dedicación al estudio y mayor uso de recursos de apoyo, el fracaso escolar y la no consecución de objetivos curriculares son más frecuentes en estos pacientes. El diagnóstico temprano del TDAH y sus comorbilidades, la intervención psicoeducativa y farmacológica adecuada e individualizada, han demostrado mejorar el pronóstico académico a corto y largo plazo. Para este propósito, es imprescindible la participación activa de profesionales de la salud y la educaciónAttention deficit / hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child-youth population, with a known impact on learning and school performance. Lack of attention, associated executive dysfunction and comorbid problems –particularly those related to learning and anxiety–, strongly determine this conceptual domain. Affected youths have more problems for taking notes, completion of homework, school programming and less motivation to study. Despite greater dedication to homework and greater use of support resources, school failure and nonachievement of curricular objectives are more frequent in these patients. The early diagnosis of ADHD and its comorbidities, the adequate and individualized psychoeducational and pharmacological intervention, have been shown to improve academic prognosis in the short and long term. For this purpose, the active participation of health and education professionals is essential.Este estudio fue financiado por el Ministerio de Economía, Industria y Competitividad (proyecto PSI2017-84922-R

Brain atrophy and the risk of futile endovascular reperfusion in acute ischemic stroke

[Background and Purpose]: We aimed to evaluate the impact of brain atrophy on long-term clinical outcome in patients with acute ischemic stroke treated with endovascular therapy, and more specifically, to test whether there are interactions between the degree of atrophy and infarct volume, and between atrophy and age, in determining the risk of futile reperfusion.[Methods]: We studied consecutive patients with acute ischemic stroke with proximal anterior circulation intracranial arterial occlusions treated with endovascular therapy achieving successful arterial recanalization. Brain atrophy was evaluated on baseline computed tomography with the global cortical atrophy scale, and Evans index was calculated to assess subcortical atrophy. Infarct volume was assessed on control computed tomography at 24 hours using the formula for irregular volumes (A×B×C/2). Main outcome variable was futile recanalization, defined by functional dependence (modified Rankin Scale score >2) at 3 months. The predefined interactions of atrophy with age and infarct volume were studied in regression models.[Results]: From 361 consecutive patients with anterior circulation acute ischemic stroke treated with endovascular therapy, 295 met all inclusion criteria. Futile reperfusion was observed in 144 out of 295 (48.8%) patients. Cortical atrophy affecting parieto-occipital and temporal regions was associated with futile recanalization. Total global cortical atrophy score and Evans index were independently associated with futile recanalization in an adjusted logistic regression. Multivariable adjusted regression models disclosed significant interactions between global cortical atrophy score and infarct volume (odds ratio, 1.003 [95%CI, 1.002–1.004], P<0.001) and between global cortical atrophy score and age (odds ratio, 1.001 [95% CI, 1.001–1.002], P<0.001) in determining the risk of futile reperfusion.[Conclusions]: A higher degree of cortical and subcortical brain atrophy is associated with futile endovascular reperfusion in anterior circulation acute ischemic stroke. The impact of brain atrophy on insufficient clinical recovery after endovascular reperfusion appears to be independently amplified by age and by infarct volume.This study has been partially funded by the Spanish Ministry of Science, via FIS projects PI13/02544 and PI16/01396, and through the INVICTUS PLUS research network RD16/0019.Peer reviewe

Mutación de novo en KAT6B, síndrome Say-Barber-Biesecker-Young-Simpson y trastorno específico del lenguaje

Sin financiación3.109 JCR (2020) Q3, 115/208 Clinical Neurology0.595 SJR (2020) Q2, 1138/2446 Medicine (miscellaneous)No data IDR 2020UE

Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma

[Background]: The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model. [Methods]: NOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 × 200 μg) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively. [Results]: The anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated. [Conclusions]: The anti-CCR7 mAb exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies.BSC is supported by the Fundación Leucemia Linfoma and Fundación Vistare. Grants from the Fondo de Investigaciones Sanitarias to CMC (PI09/01336 and PI12/00494), JMZ (PI12/01135) and EFR (PI11/00128) and from IMMED to CMC supported this work.Peer Reviewe

Anemia drepanocítica:: actualización del protocolo de actuación en urgencias

In our hospital we work in a plan of improvement of paediatric emergencies, one of the objectives is the protocolization andpermanent evaluation of the most prevalent emergencies.PATIENTS AND METHODSThe registries of emergencies and clinical histories of children who suffered sickle cell disease that consult about acute symp-tons were reviewed from January 2005 to September 2007 establishing quality indicators to evaluate the future fulfillmentof the protocol.RESULTSA total of 83 sickle cell disease patients, with 0 to 15 years old, were considered.The main reason for consultation was forvaso-occlusive crises.The number of admission was 37.3%.DISCUSSIONIt has been tried to evaluatethe most important acute complications of sickle cell disease and the diagnostic and therapeu-tic manage being an important part the right hydration and analgesia.The protocolization is an important aspect and theevaluation introduce ourself in the procese of learning and improvement.En nuestro hospital se trabaja en un plan de mejora de urgencias pediátricas,uno de cuyos objetivos es la protocolizacióny evaluación permanente de las urgencias más prevalentes.MATERIAL Y MÉTODOSe revisaron los registros de urgencias e historias clínicas de los niños afectos de drepanocitosis que consultaronpor sintomatología aguda, de enero de 2005 a septiembre de 2007, estableciéndose los indicadores de calidad paraevaluar el futuro cumplimiento del protocolo.RESULTADOSSe recogieron un total de 83 consultas de pacientes afectos de anemia de células falciformes con edades compren-didas entre 0 y 15 años, siendo el motivo de consulta más frecuente el dolor vaso-oclusivo. El número de ingresosfue de un 37,3% de las consultas realizadas.COMENTARIOSSe han pretendido evaluar las principales complicaciones agudas de la anemia drepanocítica y su manejo diagnósti-co y terapéutico, siendo una parte importante del mismo la hidratación y analgesia adecuadas. La protocolización esun aspecto importante y la evaluación nos ha introducido en el ciclo de aprendizaje y mejor

Indole-3-carbinol synergizes with and restores fludarabine sensitivity in chronic lymphocytic leukemia cells irrespective of p53 activity and treatment resistances

[Purpose]: Chronic lymphocytic leukemia (CLL) still is lacking a cure. Relapse and development of refractoriness to current treatments are common. New therapies are needed to improve patient prognosis and survival. [Experimental design]: Indole-3-carbinol (I3C) is a natural product with antitumor properties already clinically tested. The effect of I3C, F-ara-A, and combinations of both drugs on CLL cells from patients representing different Rai stages, IGHV mutation status, cytogenetic alterations, p53 functionality, and treatment resistances was tested, as well as the toxicity of these treatments in mice. [Results]: I3C induces cytotoxicity in CLL cells but not in normal lymphocytes. I3C strongly synergized with F-ara-A in all CLL cells tested, including those with p53 deficiency and/or F-ara-A resistance. The mechanism of cell death involved p53-dependent and -independent apoptosis. The combination of I3C + F-ara-A was equally effective in CLL cells irrespective of IGHV mutation stage and patient refractoriness. Moreover, CLL survival and treatment resistance induced by co-culturing CLL cells on stroma cells were overcome by the combinatory I3C + F-ara-A treatment. No toxicity was associated with the combined I3C + fludarabine treatment in mice. [Conclusions]: I3C in combination with F-ara-A is highly cytotoxic in CLL cells from refractory patients and those with p53 deficiency. The striking dose reduction index for F-ara-A in combination with I3C would reduce fludarabine toxicity while having a similar or better anti-CLL effectiveness. Moreover, the low toxicity of I3C, already clinically tested, supports its use as adjuvant and combinatory therapy in CLL, particularly for patients with relapsed or refractory disease.This work was supported by grants from the Ministerio de Economia y Competitividad (PI12/01135 to J.M. Zapata, PI12/00494 to C. Muñoz-Calleja, and PI11/00708 to I. Buño) and from the Asociacion Española Contra el Cancer and Fundacion LAIR (to I. Buño). G. Perez-Chacon was the recipient of a JAE Doc contract from CSIC. The cost of this publication was paid in part by FEDER funds.Peer Reviewe