A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank.

Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we performed direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing causal associations with 73 traits. We replicated 23 of 31 (74%) of these causal associations in the All of Us cohort. While this set included several known repeat expansion disorders, novel associations we found were attributable to common polymorphic variation in TR length rather than rare expansions and include e.g. a coding polyhistidine motif in HRCT1 influencing risk of hypertension and a poly(CGC) in the 5'UTR of GNB2 influencing heart rate. Causal TRs were strongly enriched for associations with local gene expression and DNA methylation. Our study highlights the contribution of multi-allelic TRs to the "missing heritability" of the human genome.

Neuroestimulación del nervio vago, hipocampal y de núcleos anteriores y centromedianos del tálamo en epilepsia temporal: revisión de la literatura / Neurostimulation of the vagus nerve, hippocampal and anterior and centromedian nuclei of the thalamus in temporal epilepsy: literature review

Introducción: En pacientes con epilepsia del lóbulo temporal refractarios que no son candidatos a cirugía, se debe considerar la estimulación eléctrica cerebral como una opción. Contenido: La estimulación eléctrica cerebral es la administración directa de pulsos eléctricos al tejido nervioso que permite modular un sustrato patológico, interrumpir la manifestación clínica de las crisis y reducir la gravedad de estas. Así, dada la importancia de estos tratamientos para los pacientes con epilepsia del lóbulo temporal refractaria, se hace una revisión de cuatro tipos de estimulación eléctrica. La primera, la del nervio vago, es una buena opción en crisis focales y crisis generalizadas o multifocales. La segunda, la del hipocampo, es más útil en pacientes no candidatos a lobectomía por riesgo de pérdida de memoria, con resonancia magnética normal o sin esclerosis mesial temporal. La tercera, la del núcleo anterior, es pertinente principalmente en pacientes con crisis focales, pero debe realizarse con precaución en pacientes con alto riesgo de cambios cognitivos, como los ancianos, o en los que presentan alteración del estado de ánimo basal, y, por último, la del núcleo centromediano se recomienda para el tratamiento crisis focales en el síndrome de Rasmussen y crisis tónico-clónicas en el síndrome de Lennox-Gastaut. Conclusiones: El interés por la estimulación eléctrica cerebral ha venido aumentando, al igual que las estructuras diana en las cuales se puede aplicar, debido a que es un tratamiento seguro y eficaz en pacientes con epilepsia del lóbulo temporal para controlar las crisis, pues disminuye la morbimortalidad y aumenta la calidad de vida.

Introduction: In patients with refractory temporal lobe epilepsy who are not candidates for surgery, electrical brain stimulation should be considered as another option. Contents: Electrical brain stimulation is the direct administration of electrical pulses to nerve tissue that modulates a pathological substrate, interrupts the clinical manifestation of seizures, and reduces their severity. Thus, given the importance of these treatments for patients with refractory temporal lobe epilepsy, four types of electrical stimulation are reviewed. The first, vagus nerve stimulation, is a good option in focal seizures and generalized or multifocal seizures. The second, hippocampal stimulation, is more useful in patients who are not candidates for lobectomy due to the risk of memory loss, with normal MRI or without mesial temporal sclerosis. The third, the anterior nucleus, is mainly in patients with focal seizures, but with caution in patients at high risk of cognitive changes such as the elderly, or in those with baseline mood disturbance and, finally, the centromedian nucleus is recommended for the treatment of focal seizures in Rasmussen's syndrome and tonic-clonic seizures in Lennox-Gastaut syndrome. Conclusions: the interest in brain electrical stimulation has been increasing as well as the target structures in which it can be applied because it is a safe and effective treatment in patients with temporal lobe epilepsy to control seizures, decreasing morbidity and mortality and increasing quality of life

POPULATION FREQUENCY OF REPEAT EXPANSIONS INDICATES INCREASED DISEASE PREVALENCE ESTIMATES ACROSS DIFFERENT POPULATIONS.

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions, and technological limitations leading to under-ascertainment. Here, leveraging whole genome sequencing data from 82,176 individuals from different populations we found an overall carrier frequency of REDs of 1 in 340 individuals. Modelling disease prevalence using genetic data, age at onset and survival, we show that REDs are up to 3-fold more prevalent than currently reported figures. While some REDs are population-specific, e.g. Huntington's disease type 2, most REDs are represented in all broad genetic ancestries, including Africans and Asians, challenging the notion that some REDs are found only in European populations. These results have worldwide implications for local and global health communities in the diagnosis and management of REDs both at local and global levels.

A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 as a significant cause of intellectual disability.

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites and underlie several congenital and late-onset disorders. Through a combination of DNA methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using PheWAS in 168,641 individuals from the UK Biobank, identifying 156 significant TRE:trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was linked with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared to controls. With a population prevalence that is at least 5-fold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a significant cause of neurodevelopmental delay.

Science for Others or the Self? Presumed Motives for Science Shape Public Trust in Science.

Science can improve life around the world, but public trust in science is at risk. Understanding the presumed motives of scientists and science can inform the social psychological underpinnings of public trust in science. Across five independent datasets, perceiving the motives of science and scientists as prosocial promoted public trust in science. In Studies 1 and 2, perceptions that science was more prosocially oriented were associated with greater trust in science. Studies 3 and 4a & 4b employed experimental methods to establish that perceiving other-oriented motives, versus self-oriented motives, enhanced public trust in science. Respondents recommend greater funding allocations for science subdomains described as prosocially oriented versus power-oriented. Emphasizing the prosocial aspects of science can build stronger foundations of public trust in science.

Genome-wide evaluation of the effect of short tandem repeat variation on local DNA methylation.

Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. Although the effect of STR variation on gene expression has been extensively assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local DNA methylation in the human genome and modify risk of common human traits. To address these questions, we first analyzed two independent data sets comprising PCR-free whole-genome sequencing (WGS) and genome-wide DNA methylation levels derived from whole-blood samples in 245 (discovery cohort) and 484 individuals (replication cohort). Using genotypes for 131,635 polymorphic STRs derived from WGS using HipSTR, we identified 11,870 STRs that associated with DNA methylation levels (mSTRs) of 11,774 CpGs (Bonferroni P < 0.001) in our discovery cohort, with 90% successfully replicating in our second cohort. Subsequently, through fine-mapping using CAVIAR we defined 585 of these mSTRs as the likely causal variants underlying the observed associations (fm-mSTRs) and linked a fraction of these to previously reported genome-wide association study signals, providing insights into the mechanisms underlying complex human traits. Furthermore, by integrating gene expression data, we observed that 12.5% of the tested fm-mSTRs also modulate expression levels of nearby genes, reinforcing their regulatory potential. Overall, our findings expand the catalog of functional sequence variants that affect genome regulation, highlighting the importance of incorporating STRs in future genetic association analysis and epigenetics data for the interpretation of trait-associated variants.

La ecografía de glándulas salivales en el diagnóstico del síndrome de Sjögren / Ultrasound of the salivary glands in the diagnosis of Sjögren´s syndrome

Objetivo: describir los hallazgos ecográficos en las glándulas salivares para el diagnóstico del síndrome de Sjögren primario. Metodología: se realizó una revisión narrativa de la literatura, con búsqueda en bases de datos seleccionando los principales artículos de revisión e investigaciones originales en español e inglés publicados en los últimos 20 años. Resultados: los hallazgos confirman el valor diagnóstico de la ecografía como estudio no invasivo de las glándulas salivares. Conclusión: la ecografía de glándulas salivares es un método útil y confiable para el diagnóstico del síndrome de Sjögren.

Objective: to describe salivary glands ultrasonography findings for the diagnosis of primary Sjögren ́s syndrome. Methodology: a narrative review of the literature by a database search selecting the main original review and research articles published in the last 20 years in Spanish and English. Results: findings confirm ultrasonography diagnostic value as a non-invasive method for salivary glands evaluation. Conclusion: sonographic evaluation of the salivary glands is a useful and reliable method for diagnosing Sjögren ́s syndrome.

Cerebral angiography as a tool for diagnosis and management of idiopathic intracranial hypertension syndrome.

PURPOSE: Idiopathic intracranial hypertension syndrome (IIH) is a pathology characterized by headache, visual disturbances, papilledema, increased cerebrospinal fluid pressure with normal cytochemistry that is not attributable to cerebral structural alterations. This study aimed to describe the usefulness of cerebral angiography in the diagnostic approach and management of patients with clinical suspicion of IIH at a fourth level hospital in Cali, Colombia. METHODS: This was a retrospective study. Patients diagnosed with IIH at the hospital [Blinded], Cali, Colombia, from October 2013 to May 2018 were included. Their medical records were reviewed, and clinical and diagnostic variables were collected along with outcomes and follow-up data. RESULTS: A series of 13 cases, 12 women and 1 man, between the second and fifth decade of life, with an average age of 29.4 years were included. All presented with headache; 12 had papilledema (92%), and diplopia and palsy of cranial nerve VI were observed in 3 cases (46%). All patients underwent simple CT scan of the brain and simple and gadolinium-enhanced MRI of the brain, none of which showed lesions that would explain the intracranial hypertension; however, upon resonance angiography followed by cerebral angiography, 8 cases (61%) of cerebral venous sinus involvement were found. CONCLUSION: Patients who present with a clinical picture compatible with IIH should undergo intra-arterial digital subtraction angiography (IADSA) to rule out cerebrovascular alterations.

A phenome-wide association study identifies effects of copy-number variation of VNTRs and multicopy genes on multiple human traits.

The human genome contains tens of thousands of large tandem repeats and hundreds of genes that show common and highly variable copy-number changes. Due to their large size and repetitive nature, these variable number tandem repeats (VNTRs) and multicopy genes are generally recalcitrant to standard genotyping approaches and, as a result, this class of variation is poorly characterized. However, several recent studies have demonstrated that copy-number variation of VNTRs can modify local gene expression, epigenetics, and human traits, indicating that many have a functional role. Here, using read depth from whole-genome sequencing to profile copy number, we report results of a phenome-wide association study (PheWAS) of VNTRs and multicopy genes in a discovery cohort of ∼35,000 samples, identifying 32 traits associated with copy number of 38 VNTRs and multicopy genes at 1% FDR. We replicated many of these signals in an independent cohort and observed that VNTRs showing trait associations were significantly enriched for expression QTLs with nearby genes, providing strong support for our results. Fine-mapping studies indicated that in the majority (∼90%) of cases, the VNTRs and multicopy genes we identified represent the causal variants underlying the observed associations. Furthermore, several lie in regions where prior SNV-based GWASs have failed to identify any significant associations with these traits. Our study indicates that copy number of VNTRs and multicopy genes contributes to diverse human traits and suggests that complex structural variants potentially explain some of the so-called "missing heritability" of SNV-based GWASs.

Pervasive cis effects of variation in copy number of large tandem repeats on local DNA methylation and gene expression.

Variable number tandem repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, because of their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole-genome sequencing to perform association analysis between copy number of ∼70,000 VNTRs (motif size ≥ 10 bp) with both gene expression (404 samples in 48 tissues) and DNA methylation (235 samples in peripheral blood), identifying thousands of VNTRs that are associated with local gene expression (eVNTRs) and DNA methylation levels (mVNTRs). Using an independent cohort, we validated 73%-80% of signals observed in the two discovery cohorts, while allelic analysis of VNTR length and CpG methylation in 30 Oxford Nanopore genomes gave additional support for mVNTR loci, thus providing robust evidence to support that these represent genuine associations. Further, conditional analysis indicated that many eVNTRs and mVNTRs act as QTLs independently of other local variation. We also observed strong enrichments of eVNTRs and mVNTRs for regulatory features such as enhancers and promoters. Using the Human Genome Diversity Panel, we define sets of VNTRs that show highly divergent copy numbers among human populations and show that these are enriched for regulatory effects and preferentially associate with genes that have been linked with human phenotypes through GWASs. Our study provides strong evidence supporting functional variation at thousands of VNTRs and defines candidate sets of VNTRs, copy number variation of which potentially plays a role in numerous human phenotypes.

Ecografía de la glándula salival mayor en pacientes con síndrome seco: descripción de una cohorte colombiana, reporte preliminar / Major salivary gland ultrasound in patients with dry syndrome: Description of a Colombian cohort, and a preliminary report

RESUMEN Introducción: El síndrome de Sjögren (SS) es una enfermedad autoinmune que afecta a las glándulas exocrinas condicionando síndrome seco. Los criterios diagnósticos se basan en pruebas serológicas, oftalmológicas, histopatológicas y flujo salival. Se ha propuesto el uso de la ecografía glandular salival como prueba diagnóstica. Escasos estudios se han realizado en Latinoamérica. Objetivo: Describir las alteraciones ecográficas en las glándulas salivales en una población colombiana que asiste al servicio de reumatología con síntomas secos. Materiales y métodos: Estudio de corte transversal; análisis preliminar de 50 pacientes que asisten por consulta externa (agosto de 2019 a enero de 2020). Evaluación sociodemográfica y clínica a través de cuestionario estructurado, pruebas paraclínicas y oftalmológicas, biopsia de glándula salival menor y valoración ecográfica de las glándulas salivales mayores (puntuación 0-6 basada en De Vita). Análisis univariado y bivariado (Chi-cuadrado y prueba de Fischer). Resultados: El 94% de la población eran mujeres y el 38% tenían SS. El promedio de edad fue de 55,9 ± 9,6 arios. La proporción de pacientes con ecografía positiva para el SS y diagnóstico por criterios del SS es mayor respecto a los pacientes con ecografía negativa (p< 0,0001). Los pacientes con ecografía positiva presentaron mayor proporción de anti-La (p = 0,002), ANA (p = 0,008), anti-Ro (p< 0,0001), linfopenia (p = 0,007), xerostomía objetiva (p = 0,019) y subjetiva (p = 0,041). Conclusiones: La ecografía podría considerarse una herramienta útil en el diagnóstico del SS, dado que los pacientes que presentan alteraciones ecográficas glandulares tienen una mayor proporción de perfil inmunológico positivo (anti-Ro, ANA, anti-La) y su positividad se encuentra asociada al SS por criterios. Se requieren nuevos estudios para evaluar las características operativas de la prueba.

ABSTRACT Introduction: Sjögren's syndrome (SS) is an autoimmune disease affecting the exocrine glands causing dry syndrome. The diagnostic criteria are based on serological, ophthalmological, histopathological, and salivary flow tests. The use of salivary gland ultrasound has been proposed as a diagnostic test. Few studies have been carried out in Latin America. Objective: To describe the ultrasound patterns in the salivary glands in the Colombian population seen in the Rheumatology Department due to dry symptoms. Materials and methods: Cross-sectional study; a preliminary analysis was performed on 50 patients attending the Outpatient Clinic (August-January 2020). A sociodemographic and clinical evaluation was made using a questionnaire. Paraclinical and ophthalmological tests, minor salivary gland biopsy, and ultrasound assessment of the major salivary glands (De Vita score 0-6) were the main items to evaluate. Univariate and bivariate analyses (Chi-squared, Fischer test) were performed. Results: Most (94%) of the population were women, and 38% had SS. The mean age was 55.9±9.6 years old. The proportion of patients with positive ultrasound for SS and a diagnosis using SS criteria was higher compared to patients with negative ultrasound (p<.0001). Patients with positive ultrasound had a higher proportion of anti-La (p=.002), ANAS (p=.008), anti-Ro (p<.0001), lymphopenia (p=.007), and objective and subjective xerostomia (p=.019 and p=.041, respectively). Conclusions: Ultrasound assessment could be considered a useful tool in the diagnosis of SS, since more patients presenting with glandular ultrasound abnormalities have a higher positive immunological profile (anti-Ro, ANAS, anti-La) and their positivity is associated with SS criteria. New studies are required to evaluate the operational characteristics of the test.

Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles.

Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.

A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions.

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ∼1 in 3,000 and ∼1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions.

Assessing Longitudinal Relationships among Thwarted Belongingness, Perceived Burdensomeness, and Eating Disorder Symptoms.

OBJECTIVE: Past work has documented a cross-sectional relationship between eating disorders (ED) and suicidality, but few studies have examined the directionality of this relationship. Informed by the interpersonal-psychological theory of suicide (IPTS), this study examines the bidirectional, longitudinal relationship between ED symptoms and two determinants of suicide ideation-thwarted belongingness (TB) and perceived burdensomeness (PB). METHOD: Ninety-two treatment-seeking individuals with ED (94.5% White, 95.6% female) completed baseline (T1) measures of ED symptoms along with TB and PB. Of those, 75 (81.5%) completed a follow-up assessment eight weeks later (T2). RESULTS: Separate linear regression models revealed that T1 ED symptoms did not predict T2 TB (b = .03, p = .42) or T2 PB (b = -.01, p = .68). Similarly, T1 TB did not predict T2 ED symptoms (b = .25, p = .37). T1 PB did significantly predict T2 ED symptoms (b = 0.52, p = .04). Further, among participants with AN/sub-AN, T1 TB and PB predicted T2 ED symptoms (p's ≤ .03). CONCLUSION: Our results reveal the need for a nuanced understanding of the relationship between ED and suicidality. This study found that PB predicts greater ED symptoms and, among the AN/sub-AN sample, TB does as well.

Identification of rare de novo epigenetic variations in congenital disorders.

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.

Treatment of lumbar hernias by endoscopic nucleoplasty with radiofrequency / Tratamento de hérnias de disco lombar por nucleoplastia endoscópica com radiofrequência / Manejo de hernias de disco lumbar mediante nucleoplastía endoscópica con radiofrecuencia

ABSTRACT Objective: To evaluate the postoperative outcomes of minimally invasive technique for treating lumbar disc herniation in patients undergoing percutaneous endoscopic nucleoplasty with radiofrequency in the center of minimally invasive procedures Veracruz (CEMIVER) of the HRAEV.. Methods: A descriptive, comparative, ambispective and longitudinal study. The clinical records of patients who underwent herniated disc surgery were reviewed from March 2010 to March 2015. Inclusion criteria were individuals of both sexes, aged 18-65 years, with disc herniation diagnosis by MRI, evocative discography (pain) and clinical evaluation. The variables were analyzed by VAS, Oswestry disability index for functional assessment and Macnab criteria for modified retrospective cross clinical classification. Results: 161 patients were included, 81 female and 80 male, aged between 18 and 65 years with severe (83.8%) and moderate (16.2%) disability according to the Oswestry disability index; the total of excellent results was 83.8%, 9.5% were good, 4.8% were median and 1.9% were poor results, according to the Macnab criteria; the average time of surgery was 84 minutes per procedure, and the postoperative average bleeding was 65 ml. Of the total, 87.4% of the patients were on an outpatient basis and 7.6% had a short hospital stay.. Conclusion: It was found that percutaneous endoscopic nucleoplasty with radiofrequency technique is a procedure that offers great benefits for patients with lumbar disc herniation, including performing it under local anesthesia, with clear visualization of the surgical field, minimal pain, little bleeding, shorter operative time, does not cause instability of anatomical structures and has minimal rate of complications.

RESUMEN Objetivo: Evaluar resultados postquirúrgicos de técnica mínimamente invasiva para el tratamiento de hernias discales lumbares en pacientes sometidos a nucleoplastía endoscópica percutánea con radiofrecuencia en el centro de mínima invasión de Veracruz (CEMIVER) del HRAEV. Métodos: Estudio descriptivo, comparativo, ambispectivo y longitudinal. Se revisarán expedientes clínicos de pacientes después de cirugía de hernia discal en el periodo de marzo de 2010 a marzo de 2015. Los criterios de inclusión fueron sujetos de ambos sexos, con edades entre 18 y 65 años con diagnóstico de hernia de disco mediante resonancia magnética nuclear, discografía evocativa de dolor y evaluación clínica. Se dimensionaron las variables mediante escala EVA, Índice de discapacidad de Oswestry para valoración funcional y criterios de Macnab modificados para graduación clínica transversal retrospectiva. Resultados: Se incluyeron 161 pacientes, 81 mujeres y 80 hombres, con edades comprendidas entre 18 y 65 años, con discapacidad grave (83,8%) y moderada (16,2%) de acuerdo con el índice de discapacidad de Oswestry; se obtuvo un total de 83,8% resultados excelentes, 9,5% buenos, 4,8% medianos y 1,9% resultados pobres según los criterios de Macnab; el tiempo quirúrgico medio fue de 84 minutos por procedimiento, el sangrado postquirúrgico medio fue 65 ml, un total de 87,4% de los pacientes operados tuvieron estancia ambulatoria, 7,6% tuvieron estancia hospitalaria corta. Conclusión: Se comprueba que la técnica de nucleoplastía endoscópica percutánea con radiofrecuencia es un procedimiento que brinda grandes beneficios al paciente con hernias discales lumbares, incluyendo, realización bajo anestesia local, con clara visualización del campo quirúrgico, mínimo dolor, escaso sangrado, menor tiempo quirúrgico, no causa inestabilidad de estructuras anatómicas y tiene tasa mínima de complicaciones.

RESUMO Objetivo: Avaliar os resultados pós-operatórios de técnica minimamente invasiva no tratamento de hérnia de disco lombar em pacientes submetidos à nucleoplastia endoscópica percutânea com radiofrequência no centro de procedimentos minimamente invasivos Veracruz (CEMIVER) do HRAEV. Métodos: Estudo descritivo, comparativo, ambispectivo e longitudinal. Foram revisados os prontuários clínicos de pacientes submetidos à cirurgia de hérnia de disco no período de março de 2010 a março de 2015. Os critérios de inclusão foram indivíduos de ambos os sexos, na faixa etária de 18 a 65 anos com diagnóstico de hérnia de disco por ressonância magnética nuclear, discografia evocativa da dor e avaliação clínica. As variáveis foram analisadas por EVA, Índice de incapacidade de Oswestry para avaliação funcional e critérios de Macnab modificados para classificação clínica transversal retrospectiva. Resultados: Foram incluídos 161 pacientes, sendo 81 do sexo feminino e 80 do sexo masculino, com faixa etária entre 18 e 65 anos, com incapacidade grave (83,8%) e moderada (16,2%) de acordo com o Índice de incapacidade de Oswestry; o total de resultados excelentes foi 83,8%, 9,5% foram bons, 4,8% foram medianos e 1,9% foram resultados ruins, segundo os critérios de Macnab; o tempo médio de cirurgia foi 84 minutos por procedimento, a hemorragia pós-cirúrgica média foi 65 ml. Do total, 87,4% dos pacientes operados ficaram em ambulatório e 7,6% tiveram internação hospitalar curta. Conclusão: Constatou-se que a técnica de nucleoplastia endoscópica percutânea com radiofrequência é um procedimento que oferece grandes benefícios para os pacientes com hérnia de disco lombar, entre os quais, realização sob anestesia local, com clara visualização do campo cirúrgico, dor mínima, pouco sangramento, menor tempo cirúrgico, não causa instabilidade de estruturas anatômicas e tem taxa mínima de complicações.

Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects.

BACKGROUND: Pseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis. METHODS: The HumanMethylation 450K BeadChip was used to analyze genome-wide methylation in 24 PHP patients with parathyroid hormone resistance and 20 age- and gender-matched controls. Patients were previously diagnosed with GNAS-specific differentially methylated regions (DMRs) and include 6 patients with known STX16 deletion (PHP(Δstx16)) and 18 without deletion (PHP(neg)). RESULTS: The array demonstrated that PHP patients do not show DNA methylation differences at the whole-genome level. Unsupervised clustering of GNAS-specific DMRs divides PHP(Δstx16) versus PHP(neg) patients. Interestingly, in contrast to the notion that all PHP patients share methylation defects in the A/B DMR while only PHP(Δstx16) patients have normal NESP, GNAS-AS1 and XL methylation, we found a novel DMR (named GNAS-AS2) in the GNAS-AS1 region that is significantly different in both PHP(Δstx16) and PHP(neg), as validated by Sequenom EpiTYPER in a larger PHP cohort. The analysis of 58 DMRs revealed that 8/18 PHP(neg) and 1/6 PHP(Δstx16) patients have multi-locus methylation defects. Validation was performed for FANCC and SVOPL DMRs. CONCLUSIONS: This is the first genome-wide methylation study for PHP patients that confirmed that GNAS is the most significant DMR, and the presence of STX16 deletion divides PHP patients in two groups. Moreover, a novel GNAS-AS2 DMR affects all PHP patients, and PHP patients seem sensitive to multi-locus methylation defects.

[Treatment of thoracic disc herniation. Case report]. / Tratamiento de hernia discal torácica. Reporte de 2 casos.

BACKGROUND: Herniated thoracic intervertebral disc is a rare cause of spinal cord compression. Its frequency varies from 0.15% to 1.7% of all disc herniations, and produces symptoms in 0.5% to 0.8%. CLINICAL CASES: Case 1. A 50-year-old woman, with pain and burning sensation in left hemithorax of four months of onset. It was treated as a herpetic syndrome, with no improvement. She was seen after thirteen days of exacerbation of clinical symptoms. The physical examination showed asymmetric paraparesis, lower left pelvic limb 1/5, and right pelvic limb 3/5¸ sensory level T8, with left Babinski positive. A thoracic disc herniation in space T8-T9 was diagnosed. CASE 2: A 55-year-old patient with a history of presenting pain in lumbar area of 5 years onset. She also had radicular pain that radiated to the right pelvic limb, with intensity 10/10 on a Visual Analogue Scale. Her physical examination showed muscle strength 5/5, with normal sensitivity in all dermatomes and tendon reflexes, and a positive right Babinski. Thoracic disc herniation T7-T8 level was diagnosed. DISCUSSION: Due to anatomical conditions that define this type of hernia, the extracavitary posterolateral approach should be the recommended surgical procedure when the simultaneously performed anterior decompression and fixation with posterior instrumentation are the treatments proposed. CONCLUSION: Despite the different anatomical structures of this special area, it was possible to obtain satisfactory results for both clinical cases.

Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting.

Familial recurrent hydatidiform mole (RHM) is a maternal-effect autosomal recessive disorder usually associated with mutations of the NLRP7 gene. It is characterized by HM with excessive trophoblastic proliferation, which mimics the appearance of androgenetic molar conceptuses despite their diploid biparental constitution. It has been proposed that the phenotypes of both types of mole are associated with aberrant genomic imprinting. However no systematic analyses for imprinting defects have been reported. Here, we present the genome-wide methylation profiles of both spontaneous androgenetic and biparental NLRP7 defective molar tissues. We observe total paternalization of all ubiquitous and placenta-specific differentially methylated regions (DMRs) in four androgenetic moles; namely gain of methylation at paternally methylated loci and absence of methylation at maternally methylated regions. The methylation defects observed in five RHM biopsies from NLRP7 defective patients are restricted to lack-of-methylation at maternal DMRs. Surprisingly RHMs from two sisters with the same missense mutations, as well as consecutive RHMs from one affected female show subtle allelic methylation differences, suggesting inter-RHM variation. These epigenotypes are consistent with NLRP7 being a maternal-effect gene and involved in imprint acquisition in the oocyte. In addition, bioinformatic screening of the resulting methylation datasets identified over sixty loci with methylation profiles consistent with imprinting in the placenta, of which we confirm 22 as novel maternally methylated loci. These observations strongly suggest that the molar phenotypes are due to defective placenta-specific imprinting and over-expression of paternally expressed transcripts, highlighting that maternal-effect mutations of NLRP7 are associated with the most severe form of multi-locus imprinting defects in humans.

Dermatomiositis hipomiopática y calcinosis universal: reporte de un caso / Hypomyopathic dermatomyositis and universal calcinosis: a case report

Presentamos el caso de una mujer de 32 años, con dos años de evolución de lesiones enpiel tipo placas, induradas, nodulares, dolorosas, inicialmente en miembros inferiores conposterior compromiso generalizado, con evidencia de lesiones cutáneas sugestivas dedermatomiositis y biopsia de piel que reporta calcinosis; inicialmente sin evidencia clínicani paraclínica que sugiriera compromiso muscular inflamatorio asociado. La resonanciamagnética nuclear de músculos y la biopsia muscular confirmaron la presencia de estecompromiso, definiendo los diagnósticos de dermatomiositis hipomiopática y calcinosisuniversal, dos espectros de una patología con baja frecuencia de presentación en lapoblación adulta.

The case is presented of a 32 year-old woman with indurated, raised and painful plaques in the skin of 2 years onset. It began in the legs, but later with a generalized extension to other regions, with evidence of cutaneous lesions very suggestive of dermatomyositis. The skin biopsy reported as calcinosis; initially without clinical evidence of inflammatory muscle compromise. A Nuclear Magnetic Resonance study and muscle biopsy showed this compromise, leading to the diagnosis of hypomyopathic dermatomyositis and universal calcinosis, two pathologies with rare presentation in an adult patient.