Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblastic leukemia.

ABSTRACT: Epidemiological studies report opposing influences of infection on childhood B-cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus (CMV) infection as a model early-life infection, we show that virus exposure within 1 week of birth induces profound depletion of transplanted E2A-PBX1 and hyperdiploid B-ALL cells in wild-type recipients and in situ-generated PLC in Eµ-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of interleukin (IL)-12p40-driven interferon (IFN)-γ production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for potential inhibitory effects of early-life infection on B-ALL progression and could inform novel therapeutic or preventive strategies.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Exposición al Dicloro Difenil Tricloroetano y perfil tiroideo durante el embarazo: revisión sistemática y meta-análisis / Dichlorodiphenyltrichloroethane pesticide exposure and thyroid profile during pregnancy: systematic review and meta-analysis

Resumen Objetivo: Evaluar la asociación entre la exposición al p,p´-DDT y p,p´-DDE con la disrupción tiroidea durante el embarazo a través de un metaanálisis. Material y métodos: Se realizó una revisión sistemática y un meta-análisis basado en la declaración PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalysis). El protocolo de esta revisión se registró ante el International Prospective Register of Systematic Reviews (PROSPERO) con el folio de identificación: CRD42022324797. Se llevó a cabo una búsqueda en las bases de datos electrónicas PubMed y Web of Science para identificar los estudios elegibles publicados en inglés y español hasta el 2 de enero de 2022. Mediante meta-análisis de efectos aleatorios, se estimó un coeficiente de regresión beta (β) combinado, por cada hormona del perfil tiroideo, a partir de los β publicados de cada estudio y sus intervalos de confianza del 95% (IC del 95%). Resultados: Se incluyeron ocho estudios de los cuales solamente tres reportaron biomarcadores de exposición a p,p'-DDT, por lo que no fue posible conducir metaanálisis para evaluar la relación entre este compuesto y las hormonas del perfil tiroideo. La exposición a p,p'-DDE se asoció con un ligero incremento en los niveles de TSH (β combinada= 0.05; IC95%= -0.01. 0.12) y T3 total (β combinada= 0.02; IC95%= -0.05, 0.09), pero inversamente con los niveles de la T4 total (β combinada= -0.003; IC 95%= -0.05, 0.05) y T4 libre (β combinada= -0.01; IC95%= -0.03, 0.01), aunque ninguno de estos hallazgos fue estadísticamente significativo. Conclusiones: La evidencia disponible a la fecha aún es limitada como para emitir una conclusión sobre la asociación entre las variables de interés. Dado que pequeños cambios en la homeóstasis tiroidea de mujeres embarazadas podrían tener consecuencias en el desarrollo fetal, es necesario seguir generando evidencia al respecto.

Abstract Objective: Evaluate the association between p,p´-DDT and p,p´-DDE exposure with thyroid disruption during pregnancy through meta-analysis. Material and methods: We performed a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The protocol of this review was registered in PROSPERO with the identification sheet: CRD42022324797. We conduct systematic searches in PubMed and Web of Science electronic databases to identify eligible studies published in English and Spanish up to January 2, 2022. Using random-effects meta-analysis, a beta regression coefficient was estimated (β) pooled, for each hormone of the thyroid profile, from the β published in each study and their 95% confidence intervals (95% CI). Results: Eight studies were included, of which only three reported biomarkers of exposure to p,p'-DDT, so it was not possible to conduct a meta-analysis to assess the relationship between this compound and hormones in the thyroid profile. Exposure to p,p'-DDE was associated with a slight increase in TSH (pooled β= 0.05; 95% CI= -0.01, 0.12) and total T3 (pooled β= 0.02; 95% CI= -0.05, 0.09) levels , but inversely with total T4 (β pooled= -0.003; 95% CI= -0.05, 0.05) and free T4 (β pooled= -0.01; 95% CI= -0.03, 0.01) levels, although neither of these findings was statistically significant. Conclusions: The evidence available to date is still limited to draw a conclusion on the association between the variables of interest. Since small changes in thyroid homeostasis in pregnant women could have consequences on fetal development, it is necessary to continue generating evidence in this regard.

Interaction between Akkermansia muciniphila and Diet Is Associated with Proinflammatory Index in School-Aged Children.

BACKGROUND: Imbalance in the intestinal microbiota can lead to chronic low-grade inflammation. Diet may influence this association. In this study, we aimed to evaluate the interaction between Akkermansia muciniphila (A. muciniphila) and dietary patterns using a proinflammatory index. METHODS: We conducted a cross-sectional study with school-aged children. We quantified the relative abundance (RA) of A. muciniphila in feces using a polymerase chain reaction. We collected dietary information through employing a food frequency questionnaire and generated dietary patterns using principal component analysis. We generated a proinflammatory index from serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and adiponectin validated by receptor operating characteristic curves. We evaluated the association between A. muciniphila and the proinflammatory index using logistic regression, including an interaction term with dietary patterns. RESULTS: We found that children with a low RA of A. muciniphila and a high intake of simple carbohydrates and saturated fats had increased odds of being high on the proinflammatory index. However, when the consumption of this dietary pattern is low, children with a low RA of A. muciniphila had decreased odds of being high on the proinflammatory index. CONCLUSIONS: Our results suggest that the simultaneous presence of A. muciniphila and diet have a more significant impact on the presence of being high on the proinflammatory index compared to both factors separately.

Occupational exposure to pesticides: DNA damage in horticulturist from Nativitas, Tlaxcala in Mexico.

Mexico is a country where agricultural activity is of great importance, but biomonitoring data are still scarce. With more intensive pesticides use per unit area/surface in horticultural productivity, there is a higher impact on environmental contamination and workers' health. Considering that exposure to various pesticide and pesticide mixtures represents an additional genotoxic risk, the appropriate characterization of exposure, confounding factors and the risk itself are very much needed. We compared genetic damage in 42 horticulturists and 46 unexposed controls (Nativitas, Tlaxcala) using alkaline comet (whole blood) and micronucleus (MN) test with nuclear abnormalities (NA) (buccal epithelial cells). Workers demonstrated significantly higher levels of damage (TI%=14.02 ± 2.49 vs. 5.37 ± 0.46; MN=10.14 ± 5.15 vs. 2.40 ± 0.20), with more than 90% of them not using protective clothing nor gloves during application. Combined DNA damage techniques and periodic monitoring together with educational programs for safe pesticide application is the best strategy to assess and prevent workers' health risks.

Nursing training and its association with burnout syndrome among Mexican undergraduate students / Formación académica en enfermería y su asociación con el síndrome de burnout en estudiantes Mexicanos de pregrado

Abstract Introduction Previous data suggest that healthcare students, such as nursing students, might have a differential risk of presenting burnout syndrome caused by the stress they are subjected to. However, the evidence is still scarce and inconclusive. Objective To evaluate the association between nursing training and burnout syndrome among undergraduate students in Hidalgo, Mexico. Method A cross-sectional analytical study was conducted on 566 undergraduate students (56% were nursing students and the rest were non-healthcare students). Burnout syndrome was identified using the Spanish version of the Maslach Burnout Inventory-Student Survey, consisting of subscales: emotional exhaustion, depersonalization, and diminished academic efficacy. The association between the variables of interest was evaluated using logistic regression models adjusted for confounders. Results In the depersonalization subscale, nursing students, compared with non-healthcare students, had an adjusted Odds Ratio (aOR) of moderate/high burnout syndrome of 2.08 (95% confidence interval [CI] = [1.34, 3.22]). In addition, the association was stronger among students in the third and fourth school years (aOR = 3.58; 95% CI = [1.62, 7.89]) compared with those in the first and second school years (aOR = 1.20; 95% CI = [.71, 2.03]). Discussion and conclusion It is necessary that universities provide nursing students with tools that allow them to cope with stressful situations during their academic training and their future life as health professionals.

Resumen Introducción Datos previos sugieren que los estudiantes del cuidado a la salud, como es el caso de enfermería, podrían tener un riesgo diferencial de presentar síndrome de burnout debido al estrés al que están sometidos, no obstante, la evidencia aun es escaza y no concluyente. Objetivo Evaluar la asociación entre la formación académica en enfermería con el síndrome de burnout en estudiantes universitarios de Hidalgo, México. Método Estudio trasversal analítico realizado en una muestra de 566 estudiantes universitarios (56% eran estudiantes de enfermería y el resto de las áreas diferentes a la salud). Para determinar la presencia de síndrome de burnout se utilizó la versión en español de la escala Maslach Burnout Inventory-Student Survey, conformada por las subescalas: agotamiento, eficacia académica y despersonalización. La asociación entre las variables de interés se evalúo mediante modelos de regresión logística ajustados por confusores. Resultados En la subescala de despersonalización los estudiantes de enfermería tuvieron mayores posibilidades de presentar síndrome de burnout medio/alto en comparación con los de las otras formaciones académicas (razón de momios ajustada [RMa] = 2.08; intervalo de confianza [IC] al 95% = [1.34, 3.22]). Además, la asociación fue más fuerte entre aquellos que cursaban el tercer y cuarto año escolar (RMa = 3.58; IC 95% = [1.62, 7.89]) a diferencia de los que cursaban los primeros dos años escolares (RMa = 1.20; IC 95% = [.71, 2.03]). Discusión y conclusión Es importante que las universidades brinden a los estudiantes de enfermería herramientas que les permitan sobrellevar las situaciones estresantes durante su formación académica y su futura vida profesional.

Management of Suprachoroidal Hemorrhage during Phacoemulsification: A Comprehensive Review.

Suprachoroidal hemorrhage (SCH) is a rare and sight-threatening complication of various intraocular surgeries, including cataract surgery. Although the rate of SCH complicating cataract surgery has decreased in the era of phacoemulsification, most likely due to smaller self-sealing incisions and modern equipment, it remains a challenging complication to manage. The aim of this review is to summarize the current evidence of the pathophysiology and management of SCH complicating phaco surgery. A literature review was performed using the PubMed database searching for diagnosis, therapy, and management of SCH during phacoemulsification. The evidence available on the optimal management of this condition is low, and there is no consensus so far. An early diagnosis is thought to be essential to avoid progression to the devastating stage of expulsion of intraocular contents (expulsive hemorrhage). Sudden intraoperative anterior chamber shallowing, red reflex loss, and a significant increase in intraocular pressure are highly suspicious for this severe complication. A fundus examination and ocular ultrasound are crucial to confirm the diagnosis and, if it is confirmed, stabilize the globe immediately. The initial therapeutic approach includes aggressive topical and systemic medication focused on controlling ocular inflammation and intraocular pressure, whereas the timing and the indications of surgical intervention remain controversial.

A low-protein maternal diet during gestation affects the expression of key pancreatic ß-cell genes and the methylation status of the regulatory region of the MafA gene in the offspring of Wistar rats.

Maternal nutrition during gestation has important effects on gene expression-mediated metabolic programming in offspring. To evaluate the effect of a protein-restricted maternal diet during gestation, pancreatic islets from male progeny of Wistar rats were studied at postnatal days (PND) 36 (juveniles) and 90 (young adults). The expression of key genes involved in ß-cell function and the DNA methylation pattern of the regulatory regions of two such genes, Pdx1 (pancreatic and duodenal homeobox 1) and MafA (musculoaponeurotic fibrosarcoma oncogene family, protein A), were investigated. Gene expression analysis in the pancreatic islets of restricted offspring showed significant differences compared with the control group at PND 36 (P < 0.05). The insulin 1 and 2 (Ins1 and Ins2), Glut2 (glucose transporter 2), Pdx1, MafA, and Atf2 (activating transcription factor 2), genes were upregulated, while glucokinase (Gck) and NeuroD1 (neuronal differentiation 1) were downregulated. Additionally, we studied whether the gene expression differences in Pdx1 and MafA between control and restricted offspring were associated with differential DNA methylation status in their regulatory regions. A decrease in the DNA methylation levels was found in the 5' flanking region between nucleotides -8118 to -7750 of the MafA regulatory region in restricted offspring compared with control pancreatic islets. In conclusion, low protein availability during gestation causes the upregulation of MafA gene expression in pancreatic ß-cells in the male juvenile offspring at least in part through DNA hypomethylation. This process may contribute to developmental dysregulation of ß-cell function and influence the long-term health of the offspring.

A novel biocompatible polymer derived from D-mannitol used as a vector in the field of genetic engineering of eukaryotic cells.

The design and preparation of new vectors to transport genetic material and increase the transfection efficiency continue being an important research line. Here, a novel biocompatible sugar-based polymer derived from D-mannitol has been synthesized to be used as a gene material nanocarrier in human (gene transfection) and microalga cells (transformation process). Its low toxicity allows its use in processes with both medical and industrial applications. A multidisciplinary study about the formation of polymer/p-DNA polyplexes has been carried out using techniques such as gel electrophoresis, zeta potential, dynamic light scattering, atomic force microscopy, and circular dichroism spectroscopy. The nucleic acids used were the eukaryotic expression plasmid pEGFP-C1 and the microalgal expression plasmid Phyco69, which showed different behaviors. The importance of DNA supercoiling in both transfection and transformation processes was demonstrated. Better results were obtained in microalga cells nuclear transformation than in human cells gene transfection. This was related to the plasmid's conformational changes, in particular to their superhelical structure. It is noteworthy that the same nanocarrier has been used with eukaryotic cells from both human and microalga.

Ventilatory Parameters in Obstetric Patients With COVID-19 and Impact of Delivery: A Multicenter Prospective Cohort Study.

BACKGROUND: Current evidence on obstetric patients requiring advanced ventilatory support and impact of delivery on ventilatory parameters is retrospective, scarce, and controversial. RESEARCH QUESTION: What are the ventilatory parameters for obstetric patients with COVID-19 and how does delivery impact them? What are the risk factors for invasive mechanical ventilation (IMV) and for maternal, fetal, and neonatal mortality? STUDY DESIGN AND METHODS: Prospective, multicenter, cohort study including pregnant and postpartum patients with COVID-19 requiring advanced ventilatory support in the ICU. RESULTS: Ninety-one patients were admitted to 21 ICUs at 29.2 ± 4.9 weeks; 63 patients (69%) delivered in ICU. Maximal ventilatory support was as follows: IMV, 69 patients (76%); high-flow nasal cannula, 20 patients (22%); and noninvasive mechanical ventilation, 2 patients (2%). Sequential Organ Failure Assessment during the first 24 h (SOFA24) score was the only risk factor for IMV (OR, 1.97; 95% CI, 1.29-2.99; P = .001). Respiratory parameters at IMV onset for pregnant patients were: mean ± SD plateau pressure (PP), 24.3 ± 4.5 cm H2O; mean ± SD driving pressure (DP), 12.5 ± 3.3 cm H2O; median static compliance (SC), 31 mL/cm H2O (interquartile range [IQR], 26-40 mL/cm H2O); and median Pao2 to Fio2 ratio, 142 (IQR, 110-176). Respiratory parameters before (< 2 h) and after (≤ 2 h and 24 h) delivery were, respectively: mean ± SD PP, 25.6 ± 6.6 cm H2O, 24 ± 6.7 cm H2O, and 24.6 ± 5.2 cm H2O (P = .59); mean ± SD DP, 13.6 ± 4.2 cm H2O, 12.9 ± 3.9 cm H2O, and 13 ± 4.4 cm H2O (P = .69); median SC, 28 mL/cm H2O (IQR, 22.5-39 mL/cm H2O), 30 mL/cm H2O (IQR, 24.5-44 mL/cm H2O), and 30 mL/cm H2O (IQR, 24.5-44 mL/cm H2O; P = .058); and Pao2 to Fio2 ratio, 134 (IQR, 100-230), 168 (IQR, 136-185), and 192 (IQR, 132-232.5; P = .022). Reasons for induced delivery were as follows: maternal, 43 of 71 patients (60.5%); maternal and fetal, 21 of 71 patients (29.5%); and fetal, 7 of 71 patients (9.9%). Fourteen patients (22.2%) continued pregnancy after ICU discharge. Risk factors for maternal mortality were BMI (OR, 1.10; 95% CI, 1.006-1.204; P = .037) and comorbidities (OR, 4.15; 95% CI, 1.212-14.20; P = .023). Risk factors for fetal or neonatal mortality were gestational age at delivery (OR, 0.67; 95% CI, 0.52-0.86; P = .002) and SOFA24 score (OR, 1.53; 95% CI, 1.13-2.08; P = .006). INTERPRETATION: Contrary to expectations, pregnant patient lung mechanics were similar to those of the general population with COVID-19 in the ICU. Delivery was induced mainly for maternal reasons, but did not change ventilatory parameters other than Pao2 to Fio2 ratio. SOFA24 score was the only risk factor for IMV. Maternal mortality was associated independently with BMI and comorbidities. Risk factors for fetal and neonatal mortality were SOFA24 score and gestational age at delivery.

Effects of a Clinical Exercise Program on Health-Related Fitness and Quality of Life in Spanish Cancer Patients Receiving Adjuvant Therapy.

OBJECTIVE: To report the feasibility and effectiveness of a newly developed clinical exercise program for improving maximal cardiorespiratory fitness in Spanish cancer patients receiving adjuvant chemotherapy or radiation. We also examined the effectiveness of the exercise program for improving maximal muscular strength, body composition, fatigue, and quality of life, and explored if the effectiveness varied based on selected patient characteristics. DESIGN: The study was a single group implementation feasibility study using a pre-posttest design. METHODS: Participants performed a 12-week, twice-weekly, supervised, multi-component exercise program during adjuvant therapy. Paired t-tests were used to assess pre-post changes, and analyses of covariance were used to compare effectiveness based on selected patient characteristics. RESULTS: We had 100 cancer patients referred to the clinical exercise program of which 85 (85%) initiated the exercise program and 76 (89%) completed the post-intervention fitness assessment. Exercise significantly improved VO2max by 4.8 mL/kg/minutes (P < .001, d = 0.74). Exercise also significantly improved chest strength (P < .001, d = 0.82), leg strength (P < .001, d = 1.27), lean body mass (P < .001, d = 0.11), skeletal muscle mass (P < .001; d = 0.09), fat mass (P < .001; d = 0.10), % body fat (P < .001; d = 0.17), quality of life (P = .0017; d = 0.41), and fatigue (P = .007; d = 0.46). Treatment modality, cancer type, and age affected some exercise responses, especially related to body composition changes. CONCLUSIONS: A 12-week, supervised, multi-component exercise program was effective for improving health-related fitness and quality of life in Spanish cancer patients receiving adjuvant therapy. Our results show the benefits of incorporating clinical exercise programming into the supportive care of cancer patients receiving treatments. REGISTRATION: The study protocol is registered at ClinicalTrials.gov (NCT05078216).

Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.

Influence of Type I Interferons in Gammaherpesvirus-68 and Its Influence on EAE Enhancement.

Epstein-Barr virus (EBV) has been identified as a putative trigger of multiple sclerosis (MS). Previously, we reported that mice latently infected with murine gammaherpesvirus 68 (γHV-68), the murine homolog to EBV, and induced for experimental autoimmune encephalomyelitis (EAE), developed an enhanced disease more reminiscent of MS. These prior results showed that expression of CD40 on CD11b+CD11c+ cells in latently infected mice was required to prime the strong Th1 response driving disease as well as decreasing Treg frequencies in the periphery and CNS. Subsequent work demonstrated that transfer of B cells from latently infected mice was sufficient to enhance disease. Herein, we show that B cells from infected mice do not need type I IFN signaling to drive a strong Th1 response, yet are important in driving infiltration of the CNS by CD8+ T cells. Given the importance of type I IFNs in MS, we used IFNARko mice in order to determine if type I IFN signaling was important in the enhancement of EAE in latently infected mice. We found that while type I IFNs are important for the control of γHV-68 infection and maintenance of latency, they do not have a direct effect in the development of enhanced EAE.

Safety, feasibility, and effectiveness of implementing supervised exercise into the clinical care of individuals with advanced cancer.

OBJECTIVE: To evaluate the safety, feasibility, and preliminary effectiveness of implementing supervised exercise programming into the clinical care of individuals with advanced cancer. DESIGN: Single group implementation feasibility study using a pre-posttest design. SETTING: Exercise Oncology Unit of the Spanish Cancer Association (a cancer-specific community facility outside the hospital setting). PARTICIPANTS: Adult individuals with advanced cancer profile involving advanced local cancer or distant metastases. INTERVENTION: A 12-week, twice-weekly, supervised, clinic-based multi-component exercise program. MAIN MEASURE: Paired t-tests were used to assess pre-post changes and analyses of covariance were used to compare effects based on selected participant characteristics. RESULTS: Eighty-four individuals with advanced cancer completed the baseline assessment, with six participants withdrawing prior to the start of the program. Of the 78 participants, 17 dropped out, thus, a total of 61 completed the final assessment. Mean adherence was 82.5%. No serious adverse events occurred. Exercise significantly improved VO2max by 5.2 mL·kg·min (p < 0.001), chest strength (p < 0.001), leg strength (p < 0.001), lean body mass (p = 0.003), skeletal muscle mass (p < 0.002), % body fat (p = 0.02), quality of life by 5.3 points (p = 0.009), fatigue by 3.2 points (p = 0.012), and physical activity by 1680 METs/week (p < 0.001). CONCLUSIONS: Our clinically supervised and tailored exercise program involving moderate to vigorous intensity exercise was found to be feasible, safe, and effective for individuals with advanced cancer. IMPLICATIONS FOR CANCER SURVIVORS: With proper screening and supervision, individuals with advanced cancer can benefit from tailored exercise oncology support as part of an overall therapeutic care plan.

Vascular endothelial growth factor haplotypes are associated with severe ischaemic complications in giant cell arteritis regardless of the disease phenotype.

OBJECTIVES: To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). METHODS: VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. CONCLUSIONS: VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.

High Relative Abundance of Staphylococcus aureus and Serum Cytokines Are Associated with Cardiometabolic Abnormalities in Children.

Background: The alteration in the composition of the gut microbiota has been associated with an increased risk of developing cardiovascular and metabolic diseases. The present study evaluated the association between the relative abundance (RA) of intestinal Staphylococcus aureus and the inflammatory response with cardiometabolic alterations in children. Methods: This cross-sectional study included 1142 children (age 6-12 years), which were classified by degree of adiposity. Anthropometry, cardiometabolic markers, and RA of intestinal S. aureus were measured. Cytokine concentrations were available in 626 children. Path coefficients (PC) were estimated by path analysis. Results: RA of S. aureus was positively associated with cholesterol PC = 24.98 (95% CI 10.76 to 39.21) and negatively with triglycerides PC = -13.10 (95% CI -22.73 to -3.48). Body mass index (BMI) Z-scores had significant mediation effects on the association between RA of S. aureus with waist circumference PC = 2.87 (95% CI 0.58 to 5.16), triglycerides PC = 6.63 (95% CI 1.29 to 11.98), low-density lipoproteins (LDL) PC = 1.73 (95% CI 0.27 to 3.18), and high-density lipoproteins PC = -1.20 (95% CI -2.19 to -0.22). Interleukin 6 (IL-6) was negatively associated with glucose PC = -3.01 (95% CI -5.85 to -0.17) and LDL PC = -8.65 (95% CI -16.54 to -0.77), and interleukin 10 (IL-10) was positively associated with glucose PC = 3.37 (95% CI 0.47 to 6.26). Conclusions: It is suggested that the RA of S. aureus, IL-6, and IL-10 are associated with cardiometabolic alterations in children, where BMI Z-scores have an important mediating effect for the development of these.

HLA association with the susceptibility to anti-synthetase syndrome.

OBJECTIVE: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). METHODS: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. RESULTS: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P=1.56E-09, odds ratio-OR [95% confidence interval-CI]=2.54 [1.84-3.50] and 21.4% versus 5.5%, P=18.95E-18, OR [95% CI]=4.73 [3.18-7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P=0.0003, OR [95% CI]=0.48 [0.31-0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P=0.001, OR [95% CI]=2.54 [1.39-4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. CONCLUSIONS: Our results support the association of the HLA complex with the susceptibility to ASSD.

Multiple Sclerosis-Like Symptoms in Mice Are Driven by Latent γHerpesvirus-68 Infected B Cells.

Multiple sclerosis (MS) is caused by a combination of genetic and environmental factors. It is believed that previous infection with Epstein Barr Virus (EBV) plays an important role in the development of MS. Previously, we developed a murine model where latent infection with gamma herpesvirus 68 (γHV-68), a murine homolog to EBV, enhanced the symptoms of experimental autoimmune encephalomyelitis (EAE), resulting in disease that more closely resembles MS in humans. Here, we explored the conditions that were necessary for EAE enhancement. We showed that latently infected CD19+IgD- B cells were capable of enhancing EAE symptoms when transferred from mice previously infected with γHV-68 into uninfected mice. We also observed a prevention of enhancement when B cells were depleted before infection. However, depletion after the establishment of latency only partially reduced EAE. This indicated the existence of a mechanism where B cells play an important role as antigen presenting cells (APCs) prior to EAE induction for the priming of Th1 cells. It is possible that these signals persist even after B cell depletion, strongly suggesting a paracrine signaling modulation of non-B cell APCs. These results strongly support the concept that EBV contributes to the development of autoimmunity and highlights the need for a vaccine against EBV that could limit or prevent multiple sclerosis development.

A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease.

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn's disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

Mutation of ten-eleven translocation-2 is associated with increased risk of autoimmune disease in patients with myelodysplastic syndrome.

BACKGROUND/AIMS: Myelodysplastic syndrome (MDS) is caused by genetic and epigenetic alteration of hematopoietic precursors and immune dysregulation. Approximately 20% of patients with MDS develop an autoimmune disease (AID). Here, we investigated whether particular genetic mutations are associated with AID in patients with MDS. METHODS: Eighty-eight genetic mutations associated with myeloid malignancy were sequenced in 73 MDS patients. The association between these mutations and AID was then analyzed. RESULTS: The median age of the 73 MDS patients was 70 years (interquartile range, 56 to 75), and 49 (67.1%) were male. AID was observed in 16 of 73 patients (21.9%). Mutations were detected in 57 (78.1%) patients. The percentage (68.8% vs. 80.7%, p = 0.32) and the mean number of mutations (1.8 ± 1.6 vs. 2.2 ± 1.8, p = 0.34) in MDS patients with or without AID were similar. However, the ten-eleven translocation- 2 (TET2) mutation rate was significantly higher in patients with AID than in those without (31.3% vs. 5.3%, respectively; p = 0.001). All TET2 mutations were variants of strong clinical significance. CONCLUSION: Mutation of TET2 in patients with MDS may be associated with increased risk of developing AID.