Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis.

OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA. METHODS: We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA. RESULTS: We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs. CONCLUSION: These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.

The Emergence of Different Functionally Equivalent PAH Degrading Microbial Communities from a Single Soil in Liquid PAH Enrichment Cultures and Soil Microcosms Receiving PAHs with and without Bioaugmentation.

Polycyclic aromatic hydrocarbon (PAHs) are common soil contaminants of concern due to their toxicity toward plants, animals and microorganisms. The use of indigenous or added microbes (bioaugmentation) is commonly used for bioremediation of PAHs. In this work, the biodegradation rates and changes in the bacterial community structure were evaluated. The enrichment culture was useful for unambiguously identifying members of the soil bacterial community associated with PAH degradation and yielded a low diversity community. No significant difference in the rate of PAH degradation was observed between the microcosm receiving only PAHs or PAHs and bioaugmentation. Moreover, identical matches to the bioaugmentation inoculum were only observed at the initial stages of PAH degradation on day 8. After 22 days of incubation, the substantial degradation of all PAHs had occurred in both microcosms and the PAH contaminated soil had statistically significant increases in Alphaproteobacteria. There were also increases in Betaproteobacteria. In contrast, the PAH contaminated and bioaugmented soil was not enriched in PAH degrading Proteobacteria genera and, instead, an increase from 1.6% to 8% of the population occurred in the phylum Bacteroidetes class Flavobacteria, with Flavobacterium being the only identified genus. In addition, the newly discovered genus Ohtaekwangia increased from 0% to 3.2% of the total clones. These results indicate that the same soil microbial community can give rise to different PAH degrading consortia that are equally effective in PAH degradation efficiency. Moreover, these results suggest that the lack of efficacy of bioaugmentation in soils can be attributed to a lack of persistence of the introduced microbes, yet nonetheless may alter the microbial community that arises in response to PAH contamination in unexpected ways.

A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk.

OBJECTIVE: Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. METHODS: A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ(2) test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). RESULTS: A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). CONCLUSIONS: The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk.

Pagetoid dyskeratosis in dermatopathology.

Pagetoid dyskeratosis (PD) is an incidental pathologic finding that appears in several skin conditions. In an attempt to better understand PD and its incidence in dermatopathology, the authors have analyzed all skin biopsies performed over the period of 1 year in our Department of Dermatology and examined their clinical and dermatopathological variables. The criteria used for a keratinocyte to be considered a PD cell were: (1) a size larger than normal, (2) the presence of pycnotic nucleus, (3) a clear halo surrounding the nucleus, and (4) a pale eosinophilic cytoplasm. A total of 3565 biopsies were analyzed, PD cells being found in 80 cases (2.24%). Melanocytic nevi were the commonest skin lesions in which PD was observed, followed by soft fibromas, angiofibromas, and acrochordons. Most lesions were located on the head, neck, and trunk. Most cases displayed fewer than 15 PD cells per field. PD cells were normally located in the mid epidermis (frequently in clusters). The biopsies usually revealed indirect signs of rubbing, although PD cells were also found in places where rubbing was unlikely. Here, the authors report the largest series of PD analyzed to date, expanding our understanding of this striking pathological observation.

Striated muscle hamartoma in a newborn.

Striated muscle hamartoma (SMH) is an uncommon benign lesion, that is usually congenital, polypoid, and primarily located on the head and neck. The key histopathologic sign is the existence of individualized fascicles of striated muscle affecting the dermis and subcutaneous fat tissue. Here we report the case of a newborn girl with an SMH, who presented with a congenital infiltrated plaque on her chin without any other associations.

[Effect of gestational weight gain in a cohort of pregnancy women with obesity operated and not operated for bariatric surgery]. / Efecto de la ganancia ponderal gestacional en una cohorte de gestantes con obesidad operadas y no operadas de cirugía bariátrica.

Introduction: Objective: to determine the effect of gestational weight gain and perinatal outcomes in obese women who underwent and did not undergo bariatric surgery. Material and methods: a retrospective observational cohort study was conducted. The gestational weight gain was classified as insufficient, adequate or excessive according to the guidelines of the United States Institute of Medicine: 4.99-9.07 kg for body mass index (BMI) > 30 kg/m2. Weight gain was calculated as the difference between the weight at the first visit of the 1st trimester and the weight at the visit of the 3rd trimester. Outcomes examined included antepartum variables (gestational diabetes, gestational hypertension, preeclampsia, premature rupture of membranes, placenta previa, placental abruption, intrauterine growth retardation, chorioammionitis, spontaneous abortion), intrapartum variables (induced delivery, vaginal delivery, vacuum, forceps delivery, cesarean section, shoulder dystocia), postpartum variables (postpartum hemorrhage, need for postpartum transfusion, postpartum anemia, need for emergency care, maternal death, postpartum tear, postpartum thrombosis) and neonatal variables (preterm delivery, weight percentile > 90, weight percentile < 10, Apgar score < 7, malformations). Using the statistical package SPSS 22.0, a statistical analysis of the data was performed. Results: two hundred and fifty-six women were recruited; 38 (14.58 %) were pregnant after bariatric surgery and 218 (85.15 %) were pregnant women with obesity who had not been operated on. Of the pregnant women with obesity who had not been operated on, 119 (46.68 %) had grade 1 obesity (BMI 30-34.9), and 99 (38.67 %) had grade 2 and 3 obesity (BMI > 35). A global and subgroup analysis was performed. In the overall analysis, 78 (30.46 %) had insufficient gain, 117 (45.70 %) had adequate gain, and 61 (23.82 %) excessive gain. Overall, insufficient weight gain was associated with a lower probability of gestational hypertension (p < 0.015) and forceps delivery (p < 0.000) and large for gestational age newborn (p < 0.000). On the other hand, insufficient weight gain was associated with a higher probability of intrauterine growth retardation (p 0.044), peripartum infection (0.022), preterm delivery (0.006), and delivery < 35 weeks (p 0.016). Excessive weight gain was associated with a higher probability of gestational hypertension (p 0.025), induced labor (p 0.009), forceps delivery (p 0.011) and large for gestational age newborn (p 0.006). Pregnancies after bariatric surgery had fewer overall complications compared to the other groups. Conclusions: insufficient and excessive weight gain worsens perinatal outcomes. Adequate weight gain does not increase complications and produces some benefits.

Introducción: Objetivo: determinar el efecto de la ganancia de peso gestacional y los resultados perinatales en mujeres con obesidad operadas y no operadas de cirugía bariátrica. Material y métodos: se realizó un estudio retrospectivo observacional de cohortes. La ganancia ponderal gestacional fue clasificada como insuficiente, adecuada o excesiva según las guías del Instituto de Medicina de Estados Unidos: 4,99-9,07 kg para índice de masa corporal (IMC) > 30 kg/m2. La ganancia ponderal se calculó con la diferencia entre el peso de la primera visita del primer trimestre y el peso en la visita del tercer trimestre. Los resultados examinados incluyeron variables anteparto (diabetes gestacional, hipertensión gestacional, preeclampsia, ruptura prematura de membranas, placenta previa, desprendimiento prematuro de placenta, retraso de crecimiento intrauterino, corioamnionitis, aborto espontáneo), intraparto (parto inducido, parto vaginal, ventosa, fórceps, cesárea, distocia de hombros), posparto (hemorragia posparto, necesidad de trasfusión posparto, anemia posparto, necesidad de asistencia a Urgencias, muerte materna, desgarro posparto, trombosis posparto) y neonatales (parto pretérmino, percentil peso > 90, percentil peso < 10, puntuación Apgar < 7, malformaciones). Mediante el paquete estadístico SPSS 22.0 se realizó un análisis estadístico de los datos. Resultados: se reclutaron 256 mujeres; 38 (14,58 %) eran gestantes poscirugía bariátrica y las 218 (85,15 %) restantes eran gestantes con obesidad no operadas. De las gestantes con obesidad no operadas, 119 (46,68 %) tenían obesidad grado 1 (IMC 30-34,9) y 99 (38,67 %) tenían obesidad grados 2 y 3 (IMC > 35). Se realizó un análisis global y por subgrupos. En el análisis global tuvieron ganancia insuficiente 78 (30,46 %), ganancia adecuada 117 (45,70 %) y excesiva 61 (23,82 %). En conjunto, la ganancia ponderal insuficiente se asoció con menor probabilidad de hipertensión arterial (HTA) gestacional (p 0,015) y parto con fórceps (p 0,000) y grande para edad gestacional (p 0,000). Por otro lado, la ganancia ponderal insuficiente se asoció a mayor probabilidad de retraso de crecimiento intrauterino (p 0,044), infección periparto (0,022), parto pretérmino (0,006) y parto < 35 semanas (p 0,016). La ganancia ponderal excesiva se asoció a mayor probabilidad de HTA gestacional (p 0,025), parto inducido (p 0,009), parto por fórceps (p 0,011) y grande para edad gestacional (p 0,006). Las gestaciones poscirugía bariátrica tuvieron menos complicaciones globales respecto al resto de grupos. Conclusiones: la ganancia ponderal insuficiente y excesiva empeora los resultados perinatales. La ganancia ponderal adecuada no aumenta las complicaciones y produce algunos beneficios.

Genome-wide transcriptional analysis of T cell activation reveals differential gene expression associated with psoriasis.

BACKGROUND: Psoriasis is a chronic autoimmune disease in which T cells have a predominant role in initiating and perpetuating the chronic inflammation in skin. However, the mechanisms that regulate T cell activation in psoriasis are still incompletely understood. The objective of the present study was to characterize the main genetic pathways associated with T cell activation in psoriasis. RESULTS: Gene expression profiles from in vitro activated T cells were obtained from 17 psoriasis patients and 7 healthy controls using Illumina HT-12 v4 microarrays. From a total of 47,321 analyzed transcripts, 42 genes were found to be differentially expressed between psoriasis and controls (FDR p-value < 0.1, absolute fold-change > 1.2). Using an independent cohort of 8 patients and 8 healthy controls we validated the overexpression of SPATS2L (p-value =0.0009) and KLF6 (p-value =0.0012) genes in activated T cells from psoriasis patients. Using weighted correlation analysis we identified SPATS2L and KLF6 coexpression networks, which were also significantly associated with psoriasis (p-value < 0.05). Gene Ontology analysis allowed the identification of several biological processes associated with each coexpression network. Finally, using Gene Set Enrichment Analysis over the global T cell transcriptome we also found additional genetic pathways strongly associated with psoriasis (p-value < 0.0001). CONCLUSIONS: This study has identified two new genes, SPATS2L and KLF6, strongly associated with T cell activation in psoriasis. Functional analyses of the gene expression profiles also revealed new biological processes and genetic pathways associated with psoriasis. The results of this study provide an important insight into the biology of this common chronic inflammatory disease.

Detection of adverse drug reactions through the minimum basic data set.

OBJECTIVE: To analyze adverse drug reaction (ADR) detection using the Minimum Basic Data Set (MBDS) at hospital discharge and to compare the ADR reporting rate to the Pharmacovigilance Referral Centre with other similar hospitals that do not use this reporting system. Setting 650-bed University Hospital serving a population of 294,000 inhabitants in Spain. METHOD: A retrospective descriptive study was conducted between January 2006 and December 2007. All reports of ADRs gathered in MBDS (a tool that encodes all administrative and clinical information generated for each patient during a hospitalization episode) with International Classification Disease codes between E930 and E949.9 were analyzed to assess the appropriateness of their referral to the pharmacovigilance centre. Finally, we compared our reporting rate with other hospitals that do not use this system for ADR identification. MAIN OUTCOME MEASURE: The incidence of ADRs detected in hospitalized patients and the reporting rate (per thousand inhabitants) to the referral pharmacovigilance centre using the Yellow Card system. RESULTS: Out of 43,282 hospital discharges, 386 ADR were recorded (0.89% of hospitalized patients). The mean (+/-SD) age of patients with reported ADR was 61.9 years (+/-19.2), median age was 65 years, and 55.2% were female. The Department of Pharmacy reported 276 (71.5%) of ADR using the Yellow Card system. The most frequently reported drugs were anti-cancer agents (42.5%) and cardiovascular drugs (23.8%), with a high frequency of digitalis glycosides (18.4%). ADR were most frequently recorded by the Departments of Oncology (41.7%) and Internal Medicine (17.9%). CONCLUSION: The MBDS is a useful and accessible instrument to determine the incidence of ADR in a hospital, resulting in the notification of severe events that might otherwise not be reported. Its use also improves identification of the main drugs responsible for ADR and of the patient populations at greatest risk, facilitating the implementation of alert systems and the development of prevention and detection strategies.

Genetic variation associated with cardiovascular risk in autoimmune diseases.

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.