Anesthetic considerations in the perioperative management of the patient with Jarcho-Levin Syndrome.

Jarcho-Levin syndrome is an eponym used to describe a spectrum of small thoracic skeletal dysplasias with variable involvement of vertebrae and ribs. Initially considered lethal, it is currently compatible with life in its mildest forms. Bone alterations that lead to a restrictive respiratory pattern, recurrent respiratory infections and particular phenotype, can make perioperative anesthetic management difficult. The proper assessment of the airway is of special interest because it presents predictors of a difficult airway, as well as the prevention, early diagnosis and adequate treatment of respiratory failure. We present the case of a patient with Jarcho-Levin Syndrome who underwent vertebral distraction surgery, with its most notable implications in anesthetic management.

Quality of life and functional outcomes in tongue cancer patients: a long-term, prospective, comparative study.

BACKGROUND: The tongue has an indispensable role in communication, swallowing and breathing. Tongue cancer treatment involves direct resection of the tumor and surrounding tissue, which can limit many essential functions of the tongue. There are few patient-reported quality of life studies involving tongue cancer exclusively. There is also a lack of data on the outcomes of quality of life regarding different reconstructive methods, adjuvant non-surgical therapies and other predicting factors. Our objective is to assess the quality of life, functional status, and predicting factors in patients with tongue cancer up to one year after surgical resection. MATERIAL AND METHODS: Thirty-six patients with tongue cancer were prospectively identified between October of 2017 and January 2021. Patients were examined before and one, three, six and twelve months after surgical resection with the validated University of Washington Quality of Life questionnaire (UW-QOL). Data collection included patient age, sex, TNM staging, size of resection, neck dissection, tracheostomy, reconstructive method and adjuvant therapies. Outcome scores were compared using the Friedman test. Multiple linear regression analysis was used to identify the predictors of quality of life and functional status. RESULTS: The use of UWQOL scores as dependent variables revealed the following predicting factors: age, tobacco use, radiotherapy, chemotherapy, reconstruction method and neck dissection. CONCLUSIONS: The most relevant findings in our study are that flap reconstruction becomes increasingly necessary when a glossectomy resection is over 45 mm, in order to maintain tongue function. We established that the reconstructive flap type does not influence quality of life in the long term. Also, we have found that cervical sentinel node biopsy provides better quality of life over neck dissection in the first 3 months after surgery.

Lack of evidence for Mycoplasma spp. in bulk tank milk of herds located in mid-western Colombia / Falta de evidencia para Mycoplasma spp. en leche de tanques de enfriamiento de hatos del centro-occidente colombiano

ABSTRACT Mycoplasma spp. is reported as a highly contagious mastitis-causing bacteria in dairy cattle, without successful or low response to most common antibiotic treatments due to the lack of cell wall. In Colombia it has been reported in the Central Andean region during 2014. The aim was to estimate the prevalence of Mycoplasma spp. in bulk tank milk using microbiological and molecular diagnosis. A random longitudinal study enrolling 220 commercial dairy farms located in four provinces of the mid-western region of Colombia from four pasteurizer companies was performed. Bulk tank milk samples were collected once monthly for three months period for determining somatic cell count (SCC) and microbiological and molecular diagnosis of Mycoplasma spp. cultures were done without pre-enrichment procedures directly in mycoplasma agar with cefoperazone to inhibit growth of opportunistic microorganisms, plates were incubated under 37° C and atmosphere of 10% CO2 and inspected during a 10d period. Molecular analysis was done by a multiplex PCR using specific primers targeting the 16S-23S rARN gene of Mycoplasma spp. and from non-pathogenic bacteria occasionally found in milk. LnSCC average of included dairy farms was 6.19 x103 cells/mL, Mycoplasma spp. was not isolated during microbiological cultures, and no DNA belonging to the species was detected by PCR in the 220 bulk tanks milk, with an estimated prevalence lower than 2.3%. This finding shows that there is not microbiological or molecular evidence that demonstrates the presence of the pathogen in the milk from the mid-western region of Colombia at herd level.

RESUMEN Mycoplasma spp. está descrito como una bacteria causante de mastitis altamente contagiosa en ganado lechero, sin o con baja respuesta a tratamientos antibióticos convencionales debido a que carece de pared celular. En Colombia ha sido reportado en la región Andina Central durante 2014. El objetivo fue estimar la prevalencia de Mycoplasma spp. en leche de tanques de enfriamiento empleando diagnósticos microbiológicos y moleculares. Se realizó un estudio aleatorio longitudinal que incluyó 220 lecherías comerciales en cuatro departamentos del centro-occidente colombiano acopiadas por cuatro compañías pasteurizadoras. Se recolectaron muestras de leche del tanque de enfriamiento mensualmente durante tres meses para determinar el recuento de células somáticas (SCC) y el diagnóstico microbiològico y molecular de Mycoplasma spp. Los cultivos se realizaron sin procedimientos de preenriquecimiento directamente en agar micoplasma con cefoperazona para inhibir crecimiento de microorganismos oportunistas, los agares se incubaron a 37° C con una atmosfera del 10% CO2 e inspeccionados durante 10d. Los análisis moleculares se realizaron por PCR multiplex usando cebadores específicos para los genes 16S-23S rRNA del Mycoplasma spp. y de algunas bacterias oportunistas ocasionales en la leche. El promedio del LnSCC fue de 6.19 x103 células/ mL, Mycoplasma spp. no fue aislado de los cultivos microbiológicos y no se encontró ADN de a esta especie mediante PCR en los 220 tanques de leche. Lo anterior indica una prevalencia estimada menor a 2,3%. Se concluye que no existe evidencia micro-biológica ni molecular para demostrar la presencia del patógeno en la leche de la región centro-occidente colombiana a nivel de hato.

PHARMACOLOGICAL AND MECHANISTIC STUDIES OF UREQUINONA, A MOLECULE FROM ROOTS OF PENTALINON ANDRIEUXII MUELL-ARG THAT HEALS MURINE LEISHMANIA MEXICANA INFECTION.

In this work we tested both the in vitro and in vivo anti-Leishmania mexicana activity of a molecule we originally identified in the root of Pentalinon andrieuxii Muell-Arg, a plant that is widely used in Mayan traditional medicine. The chemical name of this molecule is 24-methylcholesta-4-24(28)-dien-3-one, but for simplicity's sake, we assigned the short and trivial name of urequinona that will be used throughout this work. It induces necrosis and apoptosis of promastigotes cultured in vitro and extensive ultrastructural damage of amastigotes. It also induces production of Interleukin (IL)-2 and interferon (IFN)-γ by splenic cells from infected and urequinona treated mice stimulated in vitro with parasite antigen (Ag) but inhibits the production of IL-6 and IL-12p70 by bone-marrow-derived macrophages (BMM) infected in vitro and then treated with urequinona. It also induces activation of transcription factors such as NFkB and AP-1 (NFkB/AP-1) in RAW reporter cells. We also developed a novel pharmaceutical preparation of urequinona encapsulated in hydroxyethyl cellulose for dermal application that significantly reduced (P < 0.05) experimentally induced ear lesions of C57BL/6 mice. We conclude the preparation containing this molecule is a good candidate for a novel anti-leishmanial drug's preparation.

Dosimetry with gafchromic films based on a new micro-opto-electro-mechanical system.

This work presents the first tests performed with radiochromic films and a new Micro‒Opto‒Electro-Mechanical system (MOEMS) for in situ dosimetry evaluation in radiotherapy in real time. We present a new device and methodology that overcomes the traditional limitation of time-delay in radiochromic film analysis by turning a passive detector into an active sensor. The proposed system consists mainly of an optical sensor based on light emitting diodes and photodetectors controlled by both customized electronic circuit and graphical user interface, which enables optical measurements directly. We show the first trials performed in a low‒energy proton cyclotron with this MOEMS by using gafchromic EBT3 films. Results show the feasibility of using this system for in situ dose evaluations. Further adaptation is ongoing to develop a full real‒time active detector by integrating MOEM multi‒arrays and films in flexible printed circuits. Hence, we point to improve the clinical application of radiochromic films with the aim to optimize radiotherapy treatment verifications.

LGI1-antibody associated epilepsy successfully treated in the outpatient setting.

We report six patients with anti-LGI1 associated epilepsy. Two patients presented with new-onset generalized tonic-clonic seizures, four developed faciobrachial dystonic seizures and two piloerection. All patients had significant cognitive complaints at the time of diagnosis. All patients described seizure reduction during the first week of carbamazepine, and seizure freedom was obtained at a median of 13 days (range 7-22), sustained after the initiation of immunosuppression. Median time from symptom onset to carbamazepine initiation was 164 days (range 38-206 days). We discuss the particular seizure response to sodium channel blocking antiepileptic drugs, alone or associated with immunosuppression in this antibody mediated seizures.

Fluorescence enhanced BA-LIFT for single cell detection and isolation.

Laser bioprinting is a term that refers to a group of laser-based techniques for printing living cells with high precision and good viability. Most of these techniques are based on modifications of the standard laser induced forward transfer technique (LIFT). When it comes to printing living material, direct laser irradiation should be avoided, therefore an indirect LIFT technique comprising an energy absorption layer should be used. This work presents a blister actuated-LIFT (BA-LIFT) technique which uses a commercial polyimide tape as a uniform energy absorption layer. To increase the potential of the technique for cell selection and printing accuracy, we take advantage of the high optical transmission of the polyimide layer to implement an in-line fluorescence and conventional imaging vision system coaxial with the laser path. With this system and using the appropriate staining methodology it is possible to track and identify different cell types, selecting those to be transferred and tracking cell survival both in the donor and acceptor substrates. We studied the BA-LIFT printability map for sodium alginate and methylcellulose hydrogels in the fluence range from 6.1 to 2.0 J cm-2 together with the cell viability assessment measured by our fluorescence system. The study has revealed that less concentrated, therefore less viscose hydrogel shows better results with lower fluences, whereas hydrogels with higher concentrations present better results at higher fluences. Also, at low fluences 98 % of cell viability was obtained, besides both primary cells and cell lines keep their integrity, proliferating and functional activity. The technique was tested by tracking and targeting mouse hematopoietic progenitor stem cells transferred to assess colony forming units; moreover, natural killer cells were isolated and its activation in a stimulation media was tracked with the fluorescence system.

Decanethiol functionalized silver nanoparticles are new powerful leishmanicidals in vitro.

We evaluated, for the first time, the leishmanicidal potential of decanethiol functionalized silver nanoparticles (AgNps-SCH) on promastigotes and amastigotes of different strains and species of Leishmania: L. mexicana and L. major isolated from different patients suffering from localized cutaneous leishmaniasis (CL) and L. mexicana isolated from a patient suffering from diffuse cutaneous leishmaniasis (DCL). We recorded the kinetics of promastigote growth by daily parasite counting for 5 days, promastigote mobility, parasite reproduction by CFSE staining's protocol and promastigote killing using the propidium iodide assay. We also recorded IC50's of promastigotes and amastigotes, therapeutic index, and cytotoxicity by co-culturing macrophages with AgNps-SCH or sodium stibogluconate (Sb) used as reference drug. We used Sb as a reference drug since it is used as the first line treatment for all different types of leishmaniasis. At concentrations 10,000 times lower than those used with Sb, AgNps-SCH had a remarkable leishmanicidal effect in all tested strains of parasites and there was no toxicity to J774A.1 macrophages since > 85% were viable at the concentrations used. Therapeutic index was about 20,000 fold greater than the corresponding one for Sb treated cells. AgNps-SCH inhibited > 80% promastigote proliferation in all tested parasites. These results demonstrate there is a high leishmanicidal potential of AgNps-SCH at concentrations of 0.04 µM. Although more studies are needed, including in vivo testing of AgNps-SCH against different types of leishmaniasis, they can be considered a potential new treatment alternative.

Treating murine Kala-azar with a Mayan plant induces immunochemical changes.

Pentalinon andrieuxii Muell Arg is a Mexican-Central American plant anciently used by local people to treat cutaneous leishmaniasis. We evaluated a hexane extract of the root we called PAE for its chemical content and for its immunochemical and in vitro activity against Leishmania donovani and healing of experimental Kala-azar. Chemical analysis using gas chromatography coupled to mass spectrometry (GC-MS) identified hexadecanoic acid, hexadecanoic acid ethyl ester, 9, 12-octadecadienoic acid ethyl ester, octadecanoic acid ethyl ester, 9-octadecenoic acid ethyl ester and diethyl phthalate as the main compounds present in PAE. We also demonstrated PAE kills promastigotes and amastigotes in vitro and significantly reduces parasite loads in liver and spleen of infected Balb/c mice. PAE induces expression of NFkB/AP-1 transcription factors and production of IL-2 and IFN-γ by spleen cells of PAE treated but not in the untreated control mice. Furthermore, there were not IL-6, IL-10 nor TNF production in macrophages treated in vitro with PAE. We developed an affordable extract of P. andrieuxii effective to treat experimental Kala-azar in Balb/c mice.

Predictors of Poor Prognosis in Recurrent Hepatitis C After Liver Transplantation.

BACKGROUND: Hepatitis C is a common indication for liver transplantation (LT). Hepatitis C virus (HCV) recurrence is universal in viremic patients. This recurrence is frequently very aggressive, with graft loss in less than 5 years. Our aim is to detect which factors are related to worse fibrosis at 1 year post-LT. PATIENTS AND METHODS: Records of all HCV-positive transplanted patients in Hospital Universitario Nuestra Señora de la Candelaria from 1996 to 2014 were collected. The variables analyzed were donor and recipient age and gender, hypertension, diabetes, viral genotype, viral load at LT, hepatocellular carcinoma in the explant, anticoagulation or antiplatelet treatment, year of transplantation, and mean levels of tacrolimus in the first month. Severe recurrence was defined as fibrosis F3 by biopsy, liver stiffness > 9.5 kPa by transient elastography, or hepatic venous pressure gradient > 5 mm Hg at 1 year post-LT. Univariate and multivariate analyses were performed. RESULTS: From a sample of 112 patients, 88 patients met inclusion criteria. Mean recipient age was 52.8 ± 8.0 years and 70.5% were men. Mean donor age was 46.4 ± 16.1 years and 59.1% were men. Severe recurrence occurred in 23.9%. Univariate analyses showed 3 variables were statistically significant: donor age (P = .03), recipient age (P = .008), and presence of hepatocellular carcinoma (P = .01). Only the 2 first variables remained significant in the multivariate model (P = .009 and P = .044 respectively). Hepatocellular carcinoma was probably related to older recipients becoming a confounding factor. CONCLUSIONS: In our study, donor and recipient age both conferred a worse prognosis in terms of fibrosis progression in patients with liver transplant due to HCV.

A New Antileishmanial Preparation of Combined Solamargine and Solasonine Heals Cutaneous Leishmaniasis through Different Immunochemical Pathways.

Little has been done during the past 100 years to develop new antileishmanial drugs. Most infected individuals live in poor countries and have a low cash income to be attractive targets to pharmaceutical corporations. Two heterosidic steroids, solamargine and solasonine, initially identified as major components of the Brazilian plant Solanum lycocarpum, were tested for leishmanicidal activity. Both alkaloids killed intracellular and extracellular Leishmania mexicana parasites more efficiently than the reference drug sodium stibogluconate. A total of 10 µM each individual alkaloid significantly reduced parasite counts in infected macrophages and dendritic cells. In vivo treatment of C57BL/6 mice with a standardized topical preparation containing solamargine (45.1%) and solasonine (44.4%) gave significant reductions in lesion sizes and parasite counts recovered from lesions. Alkaloids present different immunochemical pathways in macrophages and dendritic cells. We conclude that this topical preparation is effective and a potential new and inexpensive treatment for cutaneous leishmaniasis.

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Remediación de residuos sólidos contaminados con Cr(vi) por un hongo filamentoso / Remediation of waste contaminated with Cr (VI) by a filamentous fungus

La biotecnología ambiental recurre a organismos capaces de reducir los niveles de metales pesados, entre ellos el Cr(VI), contenido en residuos y efluentes agroindustriales. El objetivo del trabajo fue estudiar la biorremediación de un residuo como pulpa de limón contaminada con Cr(VI) y el efecto del metal sobre el crecimiento fúngico. Se utilizaron tres hongos filamentosos como Aspergillus niger; Penicillium expansum y P. islandicum para remediar pulpa de limón (residuo) contaminada con Cr(VI) (50 mg/L) que se realizó en las siguientes condiciones de cultivo: la pulpa se suplementó con urea, 0,006; (NH4) 2SO4, 0,012; KH2PO4,0,003 y KCl, 0,001 g/ g; 105 conidios/g, a pH 2,5, 30°C y 96 h de incubación. Se estudió el efecto tóxico de diferentes concentraciones (5; 10; 20 y 50 mg/L) del metal sobre el desarrollo del hongo de mayor eficiencia de remediación (Ef. por ciento). Aspergillus niger; obtuvo mayor EF. de remediación (97 por ciento) respecto a Penicillium expansum (95 por ciento) y P. islandicum (94 por ciento), del residuo contaminado con 50 mg/L de Cr(VI). Se determinó que la presencia de Cr(VI) y no su concentración estimuló la maduración temprana (48 h) de los conidios (blancos a negros) de A. niger, sin que se observe alteraciones en el micelio con respecto al control (72h), desarrollado en la pulpa sin el metal. En conclusión, A. niger fue más resistente y presentó altas Ef. de remediación de Cr(VI) de residuos sólidos, este proceso es una alternativa a las tecnologías físico-químicas, debido que los microorganismos pueden remover selectivamente diferentes iones de zonas contaminadas.

Environmental biotechnology uses organisms capable of reducing levels of heavy metals, including the Cr (VI), contained in waste and agro-industrial effluents. The objective of this work was to study bioremediation of waste contaminated with Cr(VI) lemon pulp and the effect of the metal on the fungal growth. We used three filamentous fungi such as Aspergillus niger; Penicillium expansum and P. islandicum to remedy pulp from lemon (residue) contaminated with Cr(VI) (50 mg/L) that was conducted in the following conditions of cultivation: the pulp is supplemented with urea, 0.006; (NH4) 2SO4, 0.012; KH2PO4, 0.003 and KCl, 0.001 g / g; 105 conidia/g, at pH 2.5, 30 ° C and 96 h of incubation. We studied the toxic effect of different concentrations (5, 10, 20 and 50 mg/L) of the metal on the development of the fungus increased efficiency of remediation (Ef. percent). Aspergillus niger; obtained greater EF. remediation (97 percent) with respect to Penicillium expansum (95 percent) and P. islandicum (94 percent), 50 mg/L of Cr (VI)-contaminated waste. It was determined that the presence of Cr (VI) and not its concentration stimulated early maturation (48 h) of conidia (white on black) from A. niger, unless you observe alterations in the mycelium as compared to the control (72 h), developed in the pulp without the metal. In conclusion, A. niger was stronger and presented high Ef. remediation of Cr (VI) waste, this process is an alternative to physico-chemical technologies, due to the micro-organisms be removed selectively different ions from contaminated areas.

Mujeres violentadas durante el embarazo y el parto: experiencias de parteras en Jalisco, México / Abused women during pregnacy and childbirth : experience from midwives in Jalisco, Mexico

OBJETIVO: explorar la experiencia y perspectiva de parteras con mujeres violentadas durante el embarazo y el parto en Jalisco, México. METODOLOGIA: se llevó a cabo un estudio cualitativo en zona rural de Jalisco, México, entre mayo y octubre de 2011 con 24 parteras, utilizando la entrevista individual, modalidad historia de vida pautada y la asamblea participativa regional como técnicas de indagación; posteriormente, los discursos fueron analizados bajo el modelo actancial semiótico. RESULTADOS : familiaridad de las parteras con la violencia hacia la mujer durante el embarazo y el parto, atribuida principalmente a aspectos de género y ruralidad; señalan al binomio violencia-embarazo como factor de riesgo para presentar problemas obstétricos, siendo la violencia física la que más encuentran y a la pareja como principal agresor. Resalta su capacidad de diálogo y escucha activa en identificación de violencia. Refieren posibilidad de ser escuchadas en la generación de acciones frente a este problema. DISCUSION:necesidad de asumir una postura política estatal sobre la partería, que permita reconocer su papel en la sociedad y la posibilidad de incorporarlas en las acciones que hacen frente al problema de la violencia, y valorar los elementos propios de su ejercicio en la detección y manejo de estas mujeres.

OBJECTIVE:to explore the experiences and perspectives that a group of midwives from Jalisco, Mexico had with women who were abused during pregnancy and childbirth . METHODOLOGY: a qualitative study was conducted in a rural zone of Jalisco, Mexico, between May and October 2011 with 24 midwives. The techniques used to obtain the data were: individual interviews, life history, and the participatory regional assembly. After collecting the discourses, these were analyzed using the semiotic actantial model. RESULTS:the midwives are familiar with the violence exercised against women during the pregnancy and birth process; this is mainly attributed tolocation- and sex-related aspects,which in turn shows the combination of pregnancy and violence as a risk factor for obstetrical problems. In addition, physical violence was the most common type of abuse, and the woman’s partner was the main aggressor. Finally, the midwives’ ability to speak, listen and identify the cases of violence is worth mentioning. CONCLUSION: it is necessary to assume a political stance on midwives that would help recognize their goal in society and incorporate them into any actions taken to stop domestic violence while valuing the midwives’ efforts to identify and aid thesemothers.

Disfunción diafragmática inducida por ventilación mecánica / Ventilator-induced diaphragmatic dysfunction

The ventilator-induced diaphragmatic dysfunction is a group of disorders caused by the inactivity of the diaphragm muscle during controlled mechanical ventilation. From a structural point of view, the diaphragm subjected to mechanical ventilation undergoes an atrophy process, in which decreased synthesis and increased muscle protein degradation are observed. Recent research has identified different molecular signaling pathways that link both processes in the diaphragm, describing compelling evidence that shows that oxidative stress contributes to this phenomenon. Also, functional changes characterized by a reduction in stress and fatigue resistance, associated with an increase in the maximum shortening velocity are observed. The purpose of the present review is to analyze the impact of mechanical ventilation on the structure and function of the diaphragm muscle. Clinical implications and potential preventive steps are discussed. Since the duration of mechanical ventilation is the primary responsible for the absence of mechanical stimulation on the diaphragm, the use of ventilatory strategies for successful early weaning and early use of partial modalities should be the main pillars in the prevention of this condition.

La disfunción diafragmática inducida por ventilación mecánica consiste en un conjunto de alteraciones producidas por la inactividad del músculo diafragma durante la ventilación mecánica controlada. A nivel estructural, el diafragma sometido a ventilación mecánica experimenta un proceso de atrofia por desuso, en el que se observa una disminución de la síntesis y aumento en la degradación de proteínas musculares. Recientemente se han identificado diferentes rutas de señalización molecular que vinculan ambos procesos en el diafragma, existiendo evidencia fehaciente que el estrés oxidativo contribuye a este fenómeno. Concomitantemente, se han observado cambios funcionales caracterizados por una reducción de la fuerza y resistencia a la fatiga, asociado a un incremento en la velocidad máxima de acortamiento. El objetivo principal de esta revisión es analizar el impacto de la ventilación mecánica sobre la estructura y función del músculo diafragma. Además se discuten implicancias clínicas y potenciales intervenciones preventivas para esta emergente entidad. Dado que el tiempo de permanencia en ventilación mecánica controlada es el principal factor responsable de la ausencia de estímulo mecánico sobre el diafragma, el empleo de estrategias de destete ventilatorio precoz y el uso temprano de modalidades parciales, debieran constituir los pilares de su prevención.

Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

Role of TNFRSF1B polymorphisms in the response of Crohn's disease patients to infliximab.

Infliximab (IFX) is a valid treatment for Crohn's disease (CD), but a relevant percentage of patients do not benefit from this therapy. In the Japanese population, the response to IFX was associated with markers in the TNF receptor superfamily 1A (TNFRSF1A) and 1B (TNFRSF1B) genes. We aimed to replicate the association previously described in the Japanese population and to ascertain the role of TNF receptors as modulators of the response to IFX. We studied 297 white Spanish CD patients with a known response to IFX: 238 responders and 59 primary nonresponders. Four single nucleotide polymorphisms (SNPs) were analyzed: rs767455 in TNFRSF1A and rs1061622, rs1061624, and rs3397 in TNFRSF1B. Comparisons between groups were performed with chi-square tests or the Fisher's exact test. Different features (sex, age, disease duration, smoking among others) were evaluated as possible confounding factors. No significant association was found between the studied TNFRSF1A polymorphisms and response to IFX. In the TNFRSF1B gene, the haplotype rs1061624_A-rs3397_T was significantly increased in nonresponders: p = 0.015, OR = 1.78, 95% CI 1.09-2.90; and an increased frequency of rs1061622_G carriers was observed in patients with remission: p = 0.033 vs nonresponders and p = 0.023 vs patients with a partial response. Our results support a role of TNFRSF1B gene variants in the response to IFX in CD patients.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.