Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence.

Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation. Here we show that epigenetic regulator and central transcriptional instructor in adult stem cells, Bmi1, protects against DCM by repressing cardiac senescence. Cardiac-specific Bmi1 deletion induces the development of DCM, which progresses to lung congestion and heart failure. In contrast, Bmi1 overexpression in the heart protects from hypertrophic stimuli. Transcriptome analysis of mouse and human DCM samples indicates that p16(INK4a) derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16(INK4a) levels reverses the pathology of Bmi1-deficient hearts. In parabiosis assays, the paracrine senescence response underlying the DCM phenotype does not transmit to healthy mice. As senescence is implicated in tissue repair and the loss of regenerative potential in aging tissues, these findings suggest a source for cardiac rejuvenation.

Light chain amyloidosis: Experience in a tertiary hospital: 2005-2013. / Amiloidosis de cadenas ligeras: experiencia en un hospital terciario 2005-2013.

BACKGROUND AND OBJECTIVES: AL amyloidosis is a rare condition whose management is undergoing changes due to recent advances in diagnosis and treatment. We describe a contemporary series of patients with AL amyloidosis to analyze the features that enable early diagnosis and optimal management. PATIENTS AND METHODS: We recruited for analysis 32 patients (19 women; mean age, 63 years) treated consecutively at our center. RESULTS: Eighty-four percent of the patients presented with asthenia, dyspnea or edema, with a previous duration of symptoms of 8 months (median). Cardiac (21/32) and renal impairment were the most common type (11/32). All of the patients, except one, had a monoclonal component in serum/urine or abnormal values for free light chains (78%, λ). The bone marrow (BM) showed clonal plasmacytosis in 29 cases. All of the cardiac biopsies and 50% of the BM biopsies showed amyloid deposits. The results of the echocardiogram and/or cardiac resonance were abnormal in 27/30 cases. The median NT-proBNP value at diagnosis was 5200 ng/ml. Thirteen patients died due to heart failure, 2 due to rejection after heart transplantation, 2 due to pneumonia and 1 after a stroke. Ten patients did not undergo treatment, 12 were treated with bortezomib and 5 were treated with alkylating agents. Five patients underwent heart transplantation and 4 underwent autologous bone marrow transplantation. Fourteen patients achieved a complete hematologic response and 10 achieved organ response. The median survival was 17 months. CONCLUSIONS: Cardiac involvement is the major determinant of prognosis. Yield of involved organ biopsy is high (100% heart biopsies). Antineoplastic treatment with bortezomib and/or autologous bone marrow transplantation achieves hematological responses with improvements in organ impairment.

Genetic testing of candidate genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a rare cardiac genetic disease characterized by the presence of structural alterations in the right ventricle which may cause ventricular arrhythmias and may induce sudden cardiac death. ARVC/D has been associated with mutations in genes encoding myocyte adhesion proteins. However, only 30%-50% of patients have mutations in these genes. Genetic testing is useful in obtaining a diagnosis, particularly in individuals who do not completely fulfill clinical criteria, thereby also enabling the undertaking of preventive strategies in family members. The main goal of this study was to identify mutations in candidate genes associated with intercalate disks that could be potentially involved in ARVC/D pathogenesis. We analyze a cohort of 14 Spanish unrelated patients clinically diagnosed with ARVC/D without any genetic alteration in all previously known responsible genes. Thus, a genetic screening has been performed in 7 additional potential candidate genes (ACTC1 -actin alpha cardiac muscle 1-, CDHN -cadherin 2 type 1 or N-cadherin-, CTNNA1 -catenin alpha 1-, Cx43 or GJA1 -gap junction protein alpha 1-, MVCL -Metavinculin-, MYL2 -myosin light chain 2- and MYL3 -myosin light chain 3-) by direct sequencing analysis. Our genetic analysis did not identify any disease-causing mutation. Thirty single nucleotides polymorphisms were found, six of them novel. In conclusion, our ARVC/D Spanish cohort has not shown any mutations in the analyzed candidate genes despite their involvement in formation and maintenance of the intercalated disk.

[Epidemiological analysis of the improving areas for blood pressure control at Primary Care practice]. / Análisis de las áreas de mejora del control de la hipertensión arterial en Atención Primaria.

BACKGROUND AND OBJECTIVES: Most hypertensive patients do not have their blood pressure (BP) under control. This study aims to evaluate Primary Care physicians' management of hypertension by analyzing the four main areas proposed by experts to improve BP control. MATERIAL AND METHODS: From February to May 2003 a questionnaire was completed by 195 Primary Care physicians from 33 Primary Care centers of Madrid, Spain. Four aspects of clinical practice were examined: a) knowledge of hypertension guidelines and objectives; b) diagnosis and follow-up of patients; c) hypertension treatment, and d) drug compliance. RESULTS: Guidelines were followed by 90.6% of the physicians. Twenty six percent of the physicians perceived that guideline objectives are too strict and only 32% identified systolic BP as the component that provides more risk. Only 14% used automatic devices to measure BP while 89% still use the mercury sphygmomanometer. Diuretics were included among the 3 most used antihypertensive drugs by 94% of the physicians, ACEI by 91%, beta blockers by 62% and combinations only by 24%. Eighty eight percent believed that more than 40% of their patients have their BP under control and 53% felt that less than 20% of their patients were non-compliant with antihypertensive treatment. CONCLUSIONS: Hypertension management among Primary Care physicians showed some deficiencies in the 4 analyzed areas. Thus, perception of excessively rigorous guideline objectives, underrating of systolic BP, underuse of automatic devices and drug associations, and the overestimation of BP control and therapeutic compliance are specific areas that should be modified to improve BP control.

[Cost savings derived from the participation in clinical trials]. / Ahorro derivado de la participación en ensayos clínicos.

BACKGROUND: Medical care of patients with essential hypertension implies considerable expenses for the National Health System (NHS). During the performance of clinical trials (CT), the promoter (usually the pharmaceutical industry) covers the expenses of patient care, which implies savings for the NHS. In this work, we quantitated cost savings derived from the participation of patients in clinical trials on essential hypertension in a tertiary care level Insalud hospital. PATIENTS AND METHODS: Savings were defined as the difference between the economical expenses of a patient before being enrolled in a clinical trial (CT) and that generated during his/her participation in the CT. Expenses of a given patient to the NHS were calculated from his/her clinical record during a time period equal to CT length in which the patient participated. Three financial allottments in four CT were analyzed (three with a 52-week duration and one of 14 weeks) that meant cost savings (total or partial): a) antihypertensive drugs; b) complementary tests, and c) medical visits. RESULTS: Seventy-three patients with essential hypertension were enrolled in the 4 CT; 59 (81%) patients were randomly assigned and 57 patients concluded the CT. The overall savings derived from the participation of the 57 patients was 2,950,423 pesetas. Most of these savings corresponded to drugs (70.7%). Savings derived from laboratory tests (14.1%) and medical visits (15.1%) were similar. The mean savings derived from the participation of one patient in a CT for 12 months was, at least, 70,564 pesetas (5,880 pesetas/patient/month). CONCLUSIONS: The participation of patients with essential AH implies considerable savings for the NHS.

Characterization of the MHC class I-related MR1 locus in nonhuman primates.

We characterized the MHC-related 1 ( MR1) locus in two nonhuman primates species, Pongo pygmaeus and Pan troglodytes. MR1 cDNA sequences encoding several isoforms generated through alternative splicing were observed in both species. Amino acid alignment between the five species in which MR1 has been characterized to date - human, chimpanzee, orangutan, mouse, and rat - reveals a very high degree of conservation specially in the alpha1 and alpha2 domains of the molecule. The main differences concentrate in the transmembrane and cytoplasmic domains. In the three primates species there is a lysine residue inside the putative transmembrane domain which is not present in rodents. Furthermore, the MR1 cytoplasmic region is longer in rodents, with a conserved serine-containing motif that could be involved in endocytosis; remarkably, this motif is absent in the three primate species. We also describe the presence in the chimpanzee of a sequence homologous to the MR1P1 pseudogene previously found in humans.