The importance of thyroid hormone signaling during early development: Lessons from the zebrafish model.

The zebrafish is an optimal experimental model to study thyroid hormone (TH) involvement in vertebrate development. The use of state-of-the-art zebrafish genetic tools available for the study of the effect of gene silencing, cell fate decisions and cell lineage differentiation have contributed to a more insightful comprehension of molecular, cellular, and tissue-specific TH actions. In contrast to intrauterine development, extrauterine embryogenesis observed in zebrafish has facilitated a more detailed study of the development of the hypothalamic-pituitary-thyroid axis. This model has also enabled a more insightful analysis of TH molecular actions upon the organization and function of the brain, the retina, the heart, and the immune system. Consequently, zebrafish has become a trendy model to address paradigms of TH-related functional and biomedical importance. We here compilate the available knowledge regarding zebrafish developmental events for which specific components of TH signaling are essential.

Diagnóstico clínico y genético de un caso de síndrome de Meretoja e intervención mediante lifting frontotemporal / Clinical and genetical diagnosis of a case of Meretoja syndrome and frontotemporal lifting procedure

Un varón de 56 años con antecedentes familiares de distrofia corneal consulta por mala visión subjetiva. La biomicroscopia revela una distrofia estromal reticular bilateral y la inspección facial muestra signos de disfunción muscular, como ptosis de cejas, debilidad y descolgamiento de la musculatura frontal, piel redundante en la frente e hiperelasticidad cutánea. El paciente es remitido a cirugía plástica para valoración de la afectación muscular frontal, siendo intervenido mediante lifting frontotemporal. Por otro lado, se realiza estudio genético que confirma la variante patogénica c.640G>A (p.Asp214Asn) en el gen GSN, que codifica la gelsolina, mutación asociada con la amiloidosis familiar tipo finlandés o síndrome de Meretoja (AU)

A 56-year-old male with family background of corneal dystrophy presents with poor subjective vision. Biomicroscopy reveals bilateral reticular stromal dystrophy and facial inspection shows signs of muscle dysfunction, such as eyebrow ptosis, weakness and sagging of the frontal muscles, redundant skin on the forehead and skin hyperelasticity. The patient is referred to plastic surgery for evaluation of the frontal muscle involvement, undergoing a frontotemporal lifting procedure. On the other hand, genetics confirms the pathogenic variant c.640G>A (p.Asp214Asn) in the GSN gene, encoding gelsolin, a mutation associated with Finnish-type familial amyloidosis or Meretoja syndrome (AU)

Clinical and genetical diagnosis of a case of Meretoja syndrome and frontotemporal lifting procedure.

A 56-year-old male with family background of corneal dystrophy presents with poor subjective vision. Biomicroscopy reveals bilateral reticular stromal dystrophy and facial inspection shows signs of muscle dysfunction, such as eyebrow ptosis, weakness and sagging of the frontal muscles, redundant skin on the forehead and skin hyperelasticity. The patient is referred to Plastic Surgery for evaluation of the frontal muscle involvement, undergoing a frontotemporal lifting procedure. On the other hand, genetics confirms the pathogenic variant c.640G>A (p.Asp214Asn) in the GSN gene, encoding gelsolin, a mutation associated with Finnish-type familial amyloidosis or Meretoja syndrome.

Revisión del diagnóstico de mano catastrófica a lo largo de 15 años en un hospital terciario: ¿hacemos un uso adecuado del término? / Review of catastrophic hand diagnosis over 15 years in a tertiary hospital: do we make proper use of the term?

Objetivo: Describir las características de los pacientes diagnosticados de «mano catastrófica» por el Servicio de Cirugía Plástica en un hospital de tercer nivel en el periodo comprendido entre 2000 y 2015; analizar la evolución del uso del término «mano catastrófica», y realizar una revisión bibliográfica con el objetivo de proponer la definición más óptima de dicha expresión. Material y método: Realizamos un estudio descriptivo y retrospectivo de los pacientes diagnosticados de «mano catastrófica» que requirieron atención hospitalaria por el Servicio de Cirugía Plástica de un hospital terciario en el periodo comprendido entre 2000 y 2015. Efectuamos una revisión bibliográfica acerca del uso del término «mano catastrófica» y aplicamos a nuestros resultados las clasificaciones propuestas en las publicaciones consultadas. Resultados: El número de diagnósticos de «mano catastrófica» fue de 133. Objetivamos una tendencia descendente en el empleo del mencionado término con el transcurso de los años. Aplicando clasificaciones basadas en la imposibilidad de recuperación de una mano aceptable (presencia de 3 dedos largos y pulgar) mediante procedimientos reconstructivos, tan solo 9 de 133 pacientes podían ser considerados «manos catastróficas», constituyendo un 6,7% del total de casos. Discusión: El término «mano catastrófica» posee diferentes acepciones, generando ambigüedad. El uso de una clasificación basada en la posibilidad de obtener una mano aceptable disminuye su utilización y mejora el abordaje de dichas lesiones. Conclusión: Abogamos por limitar el uso de «mano catastrófica» a los casos que cumplan criterios de «mano mutilada» y «mano metacarpiana» para evitar su uso indiscriminado y optimizar su manejo terapéutico

Objective: To describe the characteristics of patients diagnosed with 'catastrophic hand' by the plastic surgery department in a tertiary hospital in the period between 2000-2015, analyse the evolution of the use of the term 'catastrophic hand' and conduct a review of the literature with a view to proposing the optimal definition for said expression. Material and method: We conducted a descriptive and retrospective study of patients diagnosed with 'catastrophic hand' who required hospital care by the plastic surgery department of a tertiary hospital in the period between 2000-2015. We conducted a literature review on the use of the term 'catastrophic hand' and we applied the classifications proposed in the publications consulted to our results. Results: The number of 'catastrophic hand' diagnoses was 133. We observed a downward trend in the use of the term over the years. Applying classifications based on the impossibility of recovery of an acceptable hand (presence of three long fingers and thumb) by reconstructive procedures, only 9 out of 133 patients could be considered to have 'catastrophic hands', constituting 6.7% of the total cases. Discussion: The term 'catastrophic hand' has different meanings, and this generates ambiguity. The use of a classification based on the possibility of obtaining an acceptable hand diminishes its use and improves the approach for such injuries. Conclusion: We advocate limiting the use of 'catastrophic hand' to cases that meet criteria of 'mutilated hand' and 'metacarpal hand' to avoid indiscriminate use of the term and optimise therapeutic management

Review of catastrophic hand diagnosis over 15 years in a tertiary hospital: do we make proper use of the term? / Revisión del diagnóstico de mano catastrófica a lo largo de 15 años en un hospital terciario: ¿hacemos un uso adecuado del término?

OBJECTIVE: To describe the characteristics of patients diagnosed with 'catastrophic hand' by the plastic surgery department in a tertiary hospital in the period between 2000-2015, analyse the evolution of the use of the term 'catastrophic hand' and conduct a review of the literature with a view to proposing the optimal definition for said expression. MATERIAL AND METHOD: We conducted a descriptive and retrospective study of patients diagnosed with 'catastrophic hand' who required hospital care by the plastic surgery department of a tertiary hospital in the period between 2000-2015. We conducted a literature review on the use of the term 'catastrophic hand' and we applied the classifications proposed in the publications consulted to our results. RESULTS: The number of 'catastrophic hand' diagnoses was 133. We observed a downward trend in the use of the term over the years. Applying classifications based on the impossibility of recovery of an acceptable hand (presence of three long fingers and thumb) by reconstructive procedures, only 9 out of 133 patients could be considered to have 'catastrophic hands', constituting 6.7% of the total cases. DISCUSSION: The term 'catastrophic hand' has different meanings, and this generates ambiguity. The use of a classification based on the possibility of obtaining an acceptable hand diminishes its use and improves the approach for such injuries. CONCLUSION: We advocate limiting the use of 'catastrophic hand' to cases that meet criteria of 'mutilated hand' and 'metacarpal hand' to avoid indiscriminate use of the term and optimise therapeutic management.

Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder. However, a considerable interindividual variability exists in clinical outcome, which may reflect underlying genetic influences. We analyzed 57 single-nucleotide polymorphisms in 9 dopamine-related candidate genes (TH, DBH, COMT, DAT1 and DRD1-5) as potential predictors of MPH efficacy and tolerability, and we considered prenatal and perinatal risk factors as environmental hazards that may influence treatment effects in a gene-by-environment analysis. Our results provide evidence for the contribution of DRD3 (P=0.041; odds ratio (OR)=4.00), DBH (P=0.032; OR=2.85), TH (P=5.5e-03; OR=4.34) and prenatal smoking (P=1.7e-03; OR=5.10) to the clinical efficacy of MPH, with a higher risk for treatment failure in genetically susceptible subjects whose mother smoked during pregnancy. Adverse events after MPH treatment were significantly associated with variation in DBH (P=6.4e-03; OR=0.28) and DRD2 (P=0.047; OR=3.76). This study suggests that the dopaminergic system together with prenatal smoking exposure may moderate MPH treatment effects.

Preliminary evidence for association of genetic variants in pri-miR-34b/c and abnormal miR-34c expression with attention deficit and hyperactivity disorder.

Attention deficit and hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by impairment to sustain attention and inability to control impulses and activity level. The etiology of ADHD is complex, with an estimated heritability of 70-80%. Under the hypothesis that alterations in the processing or target binding of microRNAs (miRNAs) may result in functional alterations predisposing to ADHD, we explored whether common polymorphisms potentially affecting miRNA-mediated regulation are involved in this psychiatric disorder. We performed a comprehensive association study focused on 134 miRNAs in 754 ADHD subjects and 766 controls and found association between the miR-34b/c locus and ADHD. Subsequently, we provided preliminary evidence for overexpression of the miR-34c-3p mature form in peripheral blood mononuclear cells of ADHD subjects. Next, we tested the effect on gene expression of single-nucleotide polymorphisms within the ADHD-associated region and found that rs4938923 in the promoter of the pri-miR-34b/c tags cis expression quantitative trait loci for both miR-34b and miR-34c and has an impact on the expression levels of 681 transcripts in trans, including genes previously associated with ADHD. This gene set was enriched for miR-34b/c binding sites, functional categories related to the central nervous system, such as axon guidance or neuron differentiation, and serotonin biosynthesis and signaling canonical pathways. Our results provide preliminary evidence for the contribution to ADHD of a functional variant in the pri-miR-34b/c promoter, possibly through dysregulation of the expression of mature forms of miR-34b and miR-34c and some target genes. These data highlight the importance of abnormal miRNA function as a potential epigenetic mechanism contributing to ADHD.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.

Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-γ production, as well as a marked decrease in survival, interleukin- 17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-)/Dusp6(-/-) double-knockout mice. Il10(-/-)/Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.

Hiperplasia nodular focal en mujer joven / Focal nodular hyperplasia in a young woman

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[Perianal ulcers of tubercular origin. A report of 3 new cases]. / Ulceras perianales de origen tuberculoso. Aportación de tres nuevos casos.

The rate of patients with extrapulmonary tuberculosis has increased in the last years (about 5% of all cases), and displaying a wide spectrum of clinical manifestations. Among them, the anal localization is a rare occurrence (0.7%) according to available published data. During the last two years, we have diagnosed and treated three patients with perianal tuberculous lesions manifested by ulcers. All three were males, associated with active pulmonary tuberculosis, and one with intestinal involvement which required surgical treatment. Based on this experience, we have reviewed the different etiopathogenic, clinical, diagnostic and therapeutic manifestations of this picture, emphasizing the importance of suspicion, and its diagnostic easiness if the different infectious and inflammatory diseases at this level are taken into account.