Seven-chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes.

BACKGROUND: In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. RESULTS: In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. CONCLUSIONS: Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Population-based Influenza and Respiratory Syncytial Virus Hospitalizations and In-hospital Mortality Rates Among Mexican Children Less Than Five Years of Age.

BACKGROUND: Population-based information regarding the impact of respiratory syncytial virus (RSV) and influenza on hospital admissions and mortality is scant for many countries. METHODS: Prospective testing of RSV and influenza virus was undertaken in patients <5 years old admitted to hospital with acute respiratory infection (ARI) between July, 2014 and June, 2015, and mortality rates for children living in 3 municipalities in the state of San Luis Potosí were calculated. RESULTS: During the 12-month study period, 790 children living in these municipalities were admitted with ARI. RSV was detected in 245 (31%) and influenza in 47 (5.9%). History of preterm birth was recorded for 112 children on admission. For children <5 years old, ARI-, RSV- and influenza-associated admission rates were 23.2, 7.2 and 1.4 (per 1000 population), respectively. The corresponding admission rates per 1000 infants <1 year old were 78, 25.2 and 4.4. Preterm infant admission rates were 2 times higher than those of term infants. Six children died; RSV was detected in 4 (66.6%) of the deceased, while no deaths were associated with influenza. ARI and RSV in-hospital mortality rates for children <5 years were 0.18 and 0.12 per 1000 population. ARI and RSV mortality rates in preterm infants were 7 and 14 times higher than in term infants, respectively. CONCLUSIONS: RSV was associated with both high admission and in-hospital mortality rates in children <5 years old. Specific interventions, such as active or passive immunization, to prevent RSV infections are required to reduce ARI-associated infant mortality.

Impact of the implementation of a telemedicine program on patients diagnosed with asthma.

BACKGROUND: Asthma is one of the most common respiratory ailments worldwide. Despite broad understanding of the illness and of the available therapeutic options for it, patients with serious asthma suffer poor monitoring of their illness in 50% of cases. AIM: To assess the impact of the implementation of a mobile application (ESTOI) to control asthma in patients diagnosed with the illness, their adherence to treatment, and their perceived quality of life. METHODOLOGY: Randomized clinical trial with 52 weeks' follow-up of patients with asthma seen in a specialized hospital for their treatment in Spain. Some 108 included patients will be divided into two groups. The intervention group will undergo more exhaustive follow-up than normal, including access to the ESTOI application, which will have various categories of attention: control of symptoms, health recommendations, current treatment and personalized action plan, PEF record, nutritional plan, and chat access with a medical team. The asthma control questionnaire ACT is the main assessment variable. Other variables to be studied include an adherence test for the use of inhalers (TAI), the number of exacerbations, maximum exhalation flow, exhaled nitric oxide test, hospital anxiety and depression scale, asthma quality-of-life questionnaire, forced spirometry parameters (FVC, FEV1, and PBD), and analytic parameters (eosinophilia and IGE). The data will be collected during outpatient visits. TRIAL REGISTRATION: This trial has registered at ClinicalTrials.gov (Identifier: NCT06116292).

Screening criteria for interstitial lung disease associated to rheumatoid arthritis: Expert proposal based on Delphi methodology.

OBJECTIVE: To develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients. METHODS: A systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the available evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies. RESULTS: Screening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated. CONCLUSION: A selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study.

Galectin-1: A Potential Biomarker Differentiating between Early Rheumatoid Arthritis and Spondyloarthritis.

Galectin-1 (Gal1) plays a regulatory role in the immune system. We have recently validated that Gal1 serum (sGal1) levels are increased in rheumatoid arthritis (RA) patients compared to healthy donors (HDs); however, there is no information on Gal1 in spondyloarthritis (SpA). Objective: To compare Gal1 levels in patients with SpA versus RA as a diagnostic biomarker. Methods: We studied sGal1 levels in HD (n = 52), SpA (n = 80) and RA patients (n = 64) who were randomly divided into discovery and validation sets. Synovial fluid (SF) from osteoarthritis (OA) (n = 28), peripheral SpA (n = 28) and RA (n = 28) were studied. In SpA patients, we analyzed the association between clinical parameters and sGal1 levels. Results: sGal1 levels were significantly lower in patients with SpA with respect to RA and similar to those of the HD. A cut-off of 20.50 ng/mL (sGal1) allowed one to differentiate RA patients from SpA and HD (Odd Ratio (OR) 8.23 and 12.64, respectively). Gal1 SF levels in SpA were slightly lower than OA patients and significantly lower than RA patients. No correlation was observed between sGal1 levels and clinical parameters in SpA patients. Conclusion: Gal1 could act as a diagnostic biomarker of RA and would allow one to distinguish SpA and RA patients.

Recomendaciones SER-SEPAR para el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide. Parte 2: tratamiento / SER-SEPAR recommendations for the the management of rheumatoid arthritis-related interstitial lung disease. Part 2: Treatment

Objetivo: Elaborar unas recomendaciones multidisciplinares para mejorar el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide (EPID-AR). Métodos: Un panel de reumatólogos y neumólogos expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Se realizaron revisiones sistemáticas de la evidencia, que se graduó de acuerdo con los criterios del SIGN. Tras ello, se formularon las recomendaciones. Resultados: Se seleccionaron seis preguntas PICO, tres de las cuales específicamente evaluaron la seguridad y la eficacia de los glucocorticoides, fármacos de acción lenta moduladores de la enfermedad (FAME) sintéticos clásicos e inmunosupresores, FAME biológicos, FAME sintéticos dirigidos y antifibróticos en el tratamiento de los pacientes con EPID-AR. Se formularon un total de 12 recomendaciones específicas sobre este tema con base en la evidencia encontrada y/o consenso de expertos. Conclusiones: Se presenta el primer documento oficial SER-SEPAR de recomendaciones específicas para el abordaje terapéutico de la EPID-AR con el fin de ayudar en la toma de decisiones a los clínicos directamente implicados en su manejo.(AU)

Objective: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD). Methods: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made. Results: Six PICO questions were selected, three of which analysed the safety and effectiveness of glucocorticoids, classical synthetic disease-modifying anti-rheumatic drugs (DMARDs) and other immunosuppressants, biological agents, targeted synthetic DMARDs, and antifibrotic therapies in the treatment of this complication. A total specific of 12 recommendations on this topic were formulated based on the evidence found and/or expert consensus. Conclusions: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions, reduce clinical healthcare variability, and facilitate decision-making for patients.(AU)

Recomendaciones SER-SEPAR para el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide. Parte 1: epidemiología, factores de riesgo y pronóstico / SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 1: Epidemiology, risk factors and prognosis

Objetivo: Elaborar unas recomendaciones multidisciplinares para mejorar el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide (EPID-AR). Métodos: Un panel de reumatólogos y neumólogos expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Se realizaron revisiones sistemáticas de la evidencia, que se graduó de acuerdo con los criterios del Scottish Intercollegiate Guidelines Network (SIGN). Tras ello, se formularon las recomendaciones. Resultados: Se seleccionaron seis preguntas PICO, tres de las cuales específicamente evaluaron la incidencia y la prevalencia de esta complicación, los factores de riesgo para su desarrollo, y los factores pronósticos de mortalidad y de progresión de la EPID-AR. Se formularon un total de 6 recomendaciones específicas sobre estos aspectos, estructuradas por pregunta, con base en la evidencia encontrada y/o consenso de expertos. Conclusiones: Se presenta el primer documento oficial SER-SEPAR de recomendaciones específicas para el abordaje la EPID-AR, con el fin de ayudar en la toma de decisiones a los clínicos directamente implicados en su manejo y aproximar la práctica asistencial a la mejor evidencia posible.(AU)

Objective: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD). Methods: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made. Results: Six PICO questions were selected, three of which analysed the incidence and prevalence of RA-ILD, associated risk factors, and predictors of progression and mortality. A total of 6 specific recommendations on these topics, structured by question, were formulated based on the evidence found and/or expert consensus. Conclusions: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions and facilitate decision-making for patients.(AU)

SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 2: Treatment.

OBJECTIVE: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD). METHODS: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made. RESULTS: Six PICO questions were selected, three of which analysed the safety and effectiveness of glucocorticoids, classical synthetic disease-modifying anti-rheumatic drugs (DMARDs) and other immunosuppressants, biological agents, targeted synthetic DMARDs, and antifibrotic therapies in the treatment of this complication. A total of 12 recommendations were formulated based on the evidence found and/or expert consensus. CONCLUSIONS: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions, reduce clinical healthcare variability, and facilitate decision-making for patients.

SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 1: Epidemiology, risk factors and prognosis.

OBJECTIVE: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD). METHODS: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made. RESULTS: Six PICO questions were selected, three of which analysed the incidence and prevalence of RA-ILD, associated risk factors, and predictors of progression and mortality. A total of 6 specific recommendations on these topics, structured by question, were formulated based on the evidence found and/or expert consensus. CONCLUSIONS: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions and facilitate decision-making for patients.

Genetic LGALS1 Variants Are Associated with Heterogeneity in Galectin-1 Serum Levels in Patients with Early Arthritis.

Galectin 1 (Gal1) exerts immunomodulatory effects leading to therapeutic effects in autoimmune animal models. Patients with rheumatoid arthritis have been reported to show higher Gal1 serum levels than the healthy population. Our study aimed to find genetic variants on the Gal1 gene (LGALS1) modulating its expression and/or clinical features in patients with early arthritis (EA). LGALS1 was sequenced in 53 EA patients to characterize all genetic variants. Then, we genotyped rs9622682, rs929039, and rs4820293, which covered the main genetic variation in LGALS1, in 532 EA patients. Gal1 and IL-6 serum levels were measured by ELISA and Gal1 also by western blot (WB) in lymphocytes from patients with specific genotypes. Once disease activity improved with treatment, patients with at least one copy of the minor allele in rs9622682 and rs929039 or those with GG genotype in rs4820293 showed significantly higher Gal1 serum levels (p < 0.05). These genotypic combinations were also associated with higher Gal1 expression in lymphocytes by WB and lower IL-6 serum levels in EA patients. In summary, our study suggests that genetic variants studied in LGALS1 can explain heterogeneity in Gal1 serum levels showing that patients with higher Gal1 levels have lower serum IL-6 levels.

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. METHODS: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. FINDINGS: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. INTERPRETATION: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems. FUNDING: The Instituto de Salud Carlos III.

Association between psychological factors and temporomandibular disorders in adolescents of rural and urban zones.

BACKGROUND: Temporomandibular disorders (TMD) are related to psychological factors. Adolescence is one of the stages in life with more psychosocial vulnerability, which is dissimilar in rural and urban zones. Thus, the aim of this investigation was to evaluate the association between psychological factors (symptoms of anxiety, depression and somatization) and TMD in adolescents between 12 and 15 years, belonging to urban and rural zones of Colombia. METHODS: 180 subjects aged 12-15 years (mean 13.8, SD 1.2), enrolled in public schools in the rural (n = 90) and urban (n = 90) zones were included. All subjects were evaluated using the DC/TMD instrument; the Axis I was applied for the clinical examination and the Axis II for the psychological evaluation. Data were analyzed by means of T-student, Mann-Whitney, Kruskall-Wallis tests, Pearson Chi square and multiple-variable analysis with logistic regression. RESULTS: Forty percent of the included subjects presented some type of TMD. TMD related to pain were the most common (25.5% of the studied adolescents), being myalgia the most common (20% of the adolescents in urban zone and 31.1% of the adolescents in the rural zone). There was no difference between the TMD present in males and females, but there were differences in the symptoms of Anxiety, and Somatization (p < 0.05). TMD and psychological factors were more prevalent in children with 13 years of age. A statistically significant association between TMD and symptoms of Anxiety (Pearson Chi squared 25.57, p = 0.04), depression (Pearson Chi squared 33.28, p = 0.03) and somatization (Pearson Chi squared 25.79, p = 0.04) was found in subjects from rural zones. No associations between psychological aspects and TMD were found in subjects from urban zones, but overall all psychological factors significantly influenced TMD. CONCLUSION: This study indicates Myalgia to be the most prevalent TMD in studied Colombian adolescents. Pain-related TMDs are associated with psychological factors in the adolescent population of rural Colombia. Symptoms of anxiety, depression and somatization were found to be associated to TMD, even when the frequency was not necessarily severe.

Gaps between research and recommendations in rheumatoid arthritis.

OBJECTIVES: To identify recommendations on the diagnosis and management of rheumatoid arthritis (RA) supported by low recommendation grades, to study the causes of this low grading, and to propose solutions. METHODS: A group of six rheumatologists, with extensive experience in the development of systematic reviews, reviewed national and international RA recommendations and practice guidelines. They identified all recommendations with a low level of evidence or recommendation grade (levels equivalent to 4, 5, or grades C or D of the Oxford Levels of Evidence), classified them by areas (diagnosis, follow-up, treatment, others), and analyzed plausible causes of low graduation. A Delphi was used to select 10 recommendations where it was most important to obtain quality evidence to support them. Subsequently, actions were proposed to improve evidence and recommendation grading. RESULTS: Fourteen documents were analyzed, in which 192 recommendations with low evidence/grade of recommendation were identified, most of which were on treatment. The two most frequent causes of this low level are the absence of studies and the discrepancy between the wording of the recommendation and the evidence used. Finally, the proposed solution to the critical recommendations is a list of unanswered research questions and possible designs to answer them. CONCLUSIONS: We propose to design and promote research that truly supports or rectifies clinical practice and, thus, bridges the gap between existing evidence and critical recommendations.

Validation of galectin-1 as potential diagnostic biomarker of early rheumatoid arthritis.

Galectin 1 (Gal1) is a lectin with a wide cellular expression that functions as a negative regulator of the immune system in several animal models of autoimmune diseases. Identification of patients with rheumatoid arthritis (RA) has improved during the last decade, although there is still a need for biomarkers allowing an early diagnosis. In this regard, it has been recently proposed that Gal1 serum levels are increased in patients with RA compared to the general population. However, this topic is controversial in the literature. In this work, we provide additional information about the potential usefulness of Gal1 serum levels as a biomarker for RA diagnosis. We studied Gal1 serum and synovial fluid levels and clinical parameters in samples from 62 patients with early arthritis belonging to the PEARL study. In addition, 24 healthy donors were studied. We found that both patients fulfilling RA criteria and patients with undifferentiated arthritis showed higher Gal1 levels than healthy donors. Similar findings were observed in synovial fluid, which showed even higher levels than serum. However, we did not find correlation between Gal1 levels and disease activity or disability. Therefore, our results suggest that Gal1 could be a diagnostic but not a severity biomarker.

Respiratory syncytial virus acute respiratory infection-associated hospitalizations in preterm Mexican infants: A cohort study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of severe acute respiratory infections (ARI) in preterm infants. The incidence of RSV-associated hospitalizations has not been defined in Mexico. OBJECTIVES: To determine the incidence of ARI- and RSV-associated hospitalizations in preterm infants during the first year of life. METHODS: Prospective cohort study of 294 preterm infants followed up through monthly telephone calls and routine outpatient visits. Hospitalized children were identified through daily visits to pediatric wards of participating hospitals and through telephone calls. Respiratory samples were tested for RSV by RT-PCR. RESULTS: Mean gestational age of participating infants was 33 weeks. Ninety-six infants were diagnosed with bronchopulmonary dysplasia (BPD) and 17 with congenital heart disease (CHD); 11 had both conditions. There were 71 hospitalization episodes in 53 infants. Respiratory samples for RSV detection were available in 44 hospitalization episodes, and the result was positive in 16 (36.3%). At least one hospitalization for ARI was recorded in 33 of 96 participants with BPD, in seven of 17 with CHD, and 18 of 192 infants without these diagnoses. Five (71.4%) of CHD infants who required admission also had BPD. RSV-confirmed hospitalization rates were 9.4%, 5.9%, and 2.6% for infants with BPD, CHD, and otherwise healthy preterm infants, respectively. Attributable RSV admission frequencies were estimated to be 13.6%, 16.5%, and 4.1%, respectively. CONCLUSIONS: Mexican preterm infants, particularly those with BPD, have high rates of ARI- and RSVassociated hospitalizations. Specific interventions to reduce the incidence of severe infections in this highrisk group are required.

Colgajo libre de piel para defecto de cubrimiento de piel peneana ­ reporte de caso / Skin Free Flap for Penile Skin Covering Defect ­ Case Report

Introducción Reportar el caso de un paciente con lipogranuloma esclerosante de pene llevado a corrección de curvatura peneana compleja, con injerto de espesor parcial y posterior retracción secundaria, que generó curvatura peneana impidiendo el coito y que al momento de corrección quirúrgica, se generó un defecto de cubrimiento dérmico que requirió el uso de colgajo con piel de la pared abdominal. Materiales y Métodos Hombre de 46 años con antecedente de resección de lipogranuloma esclerosante en cara dorsal del pene resecado en el año 2006 y disfunción eréctil en manejo con terapia intracavernosa con prostaglandina E2; con necesidad de injertos de piel de abdomen en 2 oportunidades para cubrimiento de defecto de piel, con posterior fibrosis y curvatura peneana dorsal de aproximadamente 60° asociado a dolor con la erección. Llevado a corrección de curvatura peneana compleja en Hospital Universitario Mayor- Méderi. Se realiza plicatura de la túnica albugínea con técnica de Yachia hasta la verificación de corrección de curvatura dorsal en un 90%. Se identifica área con defecto de cubrimiento, por lo cual se levanta colgajo en región hipogástrica abdominal y se realiza anclaje del colgajo en borde distal del defecto de cubrimiento. Seis semanas después, es llevado a segundo tiempo quirúrgico, con liberación y remodelación del colgajo y se realiza el anclaje del colgajo en el borde proximal del defecto. Tres meses después, se revalúa el paciente encontrándose cubrimiento completo del área cruenta en región dorsal del pene. Se induce erección con alprostadil intracavernoso evidenciándose curvatura peneana dorsal de menos de 5°. Discusión Los pacientes con lipogranuloma esclerosante del pene generan placas en túnicas peneanas que al momento de ser resecadas, pueden requerir el uso de segmentos de piel para cubrimiento con injertos o colgajos pediculados en un terreno con alta probabilidad de daño por isquemia de dichos tejidos. En los casos en los que ocurre contracción del injerto se generan curvaturas peneanas que en caso de que impidan el coito requieren corrección de la misma. El uso de injertos autólogos o aloinjertos ha presentado resultados satisfactorios, sin embargo, puede requerir dos tiempos quirúrgicos para la obtención de tejido. En pacientes en quienes la piel peneana no es suficiente para cubrir el defecto, la segunda opción es la piel escrotal, que conserva características similares, así como una excelente vascularización. Cuando no se cuenta con piel escrotal en buen estado, se usa un injerto de piel de espesor total como última opción con resultados satisfactorios. Conclusiones Actualmente, el uso de piel de abdomen en esos defectos de piel no tiene amplia acogida dada la presencia de anexos dérmicos que terminan generando un aspecto estético no óptimo, sin embargo, se evidencia en este caso, que es un tejido que se adapta fácilmente a su nueva ubicación y permite el fin último, que es lograr una adecuada función del órgano receptor.

Introduction Report the case of a patient with penile sclerosinglipogranuloma who was taken to corrrection of complex penile curvature with split-thickness graft with later secondary retraction that caused penile curvature preventing intercourse and during surgical mangement generated a skin coverge defect that required the use of free skin flap from the abdominal wall. Material and Methods 46 year old men with a history of surgical resection of sclerosinlipogranuloma in dorsal penile resected in 2006 and erectile dysfunction managed with intracavernous therapy with prostaglandin E2; that required abdominal skin grafts in 2 opportunities for skin defect coverage, with subsequent fibrosis and dorsal penile curvature of ∼60 degrees associated with pain during erection. Carried complex penile curvature correction in Hopsital Universitario Mayor ­ Méderi. Plication of the tunica albuginea with Yachia technique is performed until correction of dorsal curvature in 90%. Coverage defect area is identified, so that flap of hypogastric abdominal region is lifted and anchored in the distal edge of coverage defect. 6 weeks later is taken to second surgical procedure, with release and remodeling of the flap and anchorage of it in the proximal edge of the defect. 3 months after, the patient is reassessed finding complete coverage of the area on the dorsal surface of the penis. Erection is induced by intracavernousalprostadil showing dorsal penile curvature of less than 5 degrees. Discussion Patients with sclerosing penile lipogranuloma undergo plaques in penile layers that when resected may require the use of skin grafts or pedicle flaps for coverage in an area with high probability of ischemia in these tissues. In cases in which the graft contraction result in penile curvature, that in the event of preventing coitus require surgical correction thereof. The use of autologous grafts or allografts have shown satisfactory results, but may require two surgical procedures to obtain adecuate tissue. In patients in whom the penile skin is not enough to cover the defect, the second option is scrotal skin, which retains similar characteristics, as well as an excellent vascularization. When there is no adecuate scrotal skin, full thickness skin grafting as last option is used with satisfactory results. Conclusions Currently, the use of abdominal skin in these skin defects has no wide acceptance because of the presence of dermal annexes, ending in a suboptimal aesthetic appearance, however, it is evident in this case, is a tissue that is easily adapted to its new location and allows the latter, which is to achieve adequate organ receptor function.

Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients.

BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination.

Erroneous DNA repair by heterologous recombination (Ht-REC) is a potential threat to genome stability, but evidence supporting its prevalence is lacking. Here we demonstrate that recombination is possible between heterologous sequences and that it is a source of chromosomal alterations in mitotic and meiotic cells. Mechanistically, we find that the RTEL1 and HIM-6/BLM helicases and the BRCA1 homolog BRC-1 counteract Ht-REC in Caenorhabditis elegans, whereas mismatch repair does not. Instead, MSH-2/6 drives Ht-REC events in rtel-1 and brc-1 mutants and excessive crossovers in rtel-1 mutant meioses. Loss of vertebrate Rtel1 also causes a variety of unusually large and complex structural variations, including chromothripsis, breakage-fusion-bridge events, and tandem duplications with distant intra-chromosomal insertions, whose structure are consistent with a role for RTEL1 in preventing Ht-REC during break-induced replication. Our data establish Ht-REC as an unappreciated source of genome instability that underpins a novel class of complex genome rearrangements that likely arise during replication stress.

Description of a novel variant in the MAMLD1 gene in isolated hypospadias / Descripción de una nueva variante del gen MAMLD1 en hipospadias aislado

Introduction Hypospadias is a multifactorial malformation. Among previously described genes, the MAMLD1 has recently been identified in association with the development of hypospadias. So far, there are no studies in Latin America addressing this gene. The aim of this paper is to describe the presence of variants in exon 3 of the MAMLD1 in our population. Materials and Methods Using the Bio-Repository's database of the Human Genetics Institute, we identified 51 patients between 2008 and 2012 with varying degrees of isolated hypospadias. Exon 3 was sequenced looking for polymorphisms. These were assessed with in silico prediction algorithms to describe the effect of these changes on the function and structure of the protein. Results Four patients with 3 variants were identified. The p.S364P variant has not been previously described and has a deleterious effect. The other two, rs41313406 and rs61740566, have been previously described and are not considered variations with harmful effect on the protein function. The genotype-phenotype correlation varies in severity between the variables described. Conclusions For the first time a Latin American population is molecularly analyzed. The p.S364P variation has never been described before. Variations with different degrees of hypospadias are described.

Introducción El hipospadias es una malformación multifactorial. Dentro de los genes asociados descritos, el MAMLD1 se ha identificado recientemente como asociado al desarrollo de esta enfermedad. Hasta el momento no hay estudios en Latinoamérica sobre este gen. El objetivo del presente trabajo es describir la presencia de variantes en el exón 3 del MAMLD1 en nuestra población. Material and Métodos Basados en los registros del Biorrepositorio del Instituto de Genética Humana, se identificaron 51 pacientes entre el año 2008 y el 2012 con diferentes grados de hipospadias aislado. A estos se les realizó la secuenciación del exón 3. Los polimorfismos identificados fueron evaluados con algoritmos de predicción in silico para evaluar el efecto de estos cambios sobre la función y estructura de la proteína. Resultados Se encontraron 4 pacientes con 3 variantes. La variante p.S364P no ha sido descrita previamente y tiene un efecto deletéreo. Las otras 2, rs41313406 y rs61740566, han sido descritas previamente y no se consideran variaciones con potencial de efecto deletéreo sobre la función de la proteína. La correlación fenotipo-genotipo varía en severidad entre las variables descritas. Conclusiones Por primera vez se analiza molecularmente una población latinoamericana, encontrando la variante p.S364P no descrita previamente, y 2 variantes ya descritas previamente.

Impacto de variantes genéticas del transportador de membrana que une ATP B1, la aicar transformilasa/IMP ciclohidrolasa, la folilpoliglutamatosintetasa y la metilen-tetrahidrofolatorreductasa en la toxicidad de metotrexato / Impact of genetic variants of ATP binding cassette B1, AICAR transformylase/IMP cyclohydrolase, folyl-polyglutamatesynthetase, and methylenetetrahydrofolatereductase on methotrexate toxicity

Objetivo. Analizar el efecto de polimorfismos de nucleótido único (SNPs) de la metilen-tetrahidrofolatorreductasa (MTHFR; rs1801131 y rs1801133), el transportador de membrana que une ATP B1 (ABCB1; rs1045642), la aicartransformilasa/IMP ciclohidrolasa (ATIC; rs2372536) y la folilpoliglutamatosintetasa (FPGS; rs1544105) en la toxicidad hepática y medular de metotrexato (MTX). Pacientes y métodos. Se analizaron 1.415 visitas (732 con MTX, 683 sin MTX) de 350 pacientes del Princesa Early Arthritis Register Longytudinal study. El genotipo de los diferentes SNP se determinó mediante sondas TaqMan (Applied Biosystems). Se realizaron análisis multivariables mediante modelos lineales generalizados en los que las variables dependientes fueron los niveles séricos de transaminasa glutámico-pirúvica (toxicidad hepática), leucocitos, plaquetas o hemoglobina (toxicidad hematológica) y se ajustaron por variables clínicas (actividad de la enfermedad, etc.), analíticas (función renal, etc.), sociodemográficas (edad, sexo, etc.) y las variantes genéticas de MTHFR, ABCB1, ATIC y FPGS. También se analizaron las variables que influyeron en las dosis de MTX administradas a lo largo del seguimiento. Resultados. Cuando recibían MTX los portadores del genotipo CC del SNP rs1045642 de ABCB1 presentaron niveles significativamente mayores de GPT (7,1±2,0U/l; p<0,001). Los portadores de al menos un alelo G de rs1544105 en FPGS presentaron niveles significativamente menores de leucocitos (−0,67±0,32; 0,038), hemoglobina (−0,34±0,11g/dl; p=0,002) y de plaquetas (−11,8±4,7; p=0,012). La presencia del alelo G de rs1544105 (FPGS) y T de rs1801133 (MTHFR) se asoció, de forma aditiva y significativa, al uso de menores dosis de MTX. Discusión. Nuestros datos sugieren que variantes genéticas de las enzimas FGPS y MTHFR, y del transportador ABCB1, podrían ayudar a detectar pacientes con mayor riesgo de toxicidad por MTX (AU)

Objective. To analyze the effect of single nucleotide polymorphisms (SNPs) with well-known functional impact of methylenetetrahydrofolatereductase (MTHFR; rs1801131 and rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP cyclohydrolase (ATIC; rs2372536) and folyl-polyglutamatesynthetase (FPGS; rs1544105), on liver and bone marrow toxicity of methotrexate (MTX). Patients and methods. We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX). The different SNPs were genotyped using specific TaqMan probes (Applied Biosystems). Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase (liver toxicity), leukocytes, platelets or hemoglobin (hematologic toxicity) and adjusted for clinical variables (disease activity, etc.), analytical (renal function, etc.), sociodemographic (age, sex, etc.) and genetic variants of MTHFR, ABCB1, ATIC and FPGS. The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient. Results. When taking MTX, those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels (7.1±2.0 U/L; P<.001). Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte (−0.67±0.32; 0.038), hemoglobin (−0.34±0.11g/dL; P=.002), and platelet (−11.8±4.7; P=.012) levels. The presence of the G allele of rs1544105 in FPGS, and the T allele of rs1801133 in MTHFR, was significantly associated with the use of lower doses of MTX. Discussion. Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity (AU)