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Introduction Medication nonadherence in patients with ulcerative colitis (UC) can result in frequent relapses, severe disease, and higher risk of colorectal cancer. Behavioral models relying on motivation and perceived competence, like the self-determination theory (SDT), have been implicated in nonadherence; however, the SDT has not been evaluated in the adult UC population. We sought to examine the association between adherence to oral medications in patients with UC and psychological distress, relationship with health care providers, motivation, and competence. Methods We performed a cross-sectional study within the Inflammatory Bowel Disease (IBD) Partners online registry in which participants completed a baseline survey including demographic information, IBD history, symptoms, medication adherence, and psychosocial factors. Members of the registry with a diagnosis of UC received an online follow-up survey that included baseline questionnaires and assessment of competence, motivation, and patient-physician relationship. Logistic regression models were performed to determine the relationship between psychosocial factors, adherence modifiers, and medication adherence. Results Of the 410 UC patients included, 29% had low adherence to their medications, 36% had medium adherence, and 34% had high adherence. In the multivariable analysis, younger patients, those with a lower perceived competence, and those with worse relationship with their providers were more likely to have lower adherence to their medications. Conclusions Poor adherence to oral medications in UC was associated with lower perceived competence and worse relationship with providers. Further interventions based on the SDT can potentially improve adherence and optimize patient care.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are often co-transmitted. Viral coinfection results in worse outcomes. Persons who inject drugs (PWIDs) face barriers to medical treatment, but HCV treatment is indicated and effective even with ongoing active drug use. We aimed to assess access to HCV care and treatment results in patients coinfected with HIV-HCV. This is a real-world retrospective single-center study of patients followed in the HIV clinic between 2002 and 2018. Linkage to care was defined as achieving care cascade steps: (1) hepatology clinic visit, (2) receiving prescription of anti-HCV treatment, and (3) documentation of sustained virologic response (SVR). Of 1660 patients with HIV, 254 with HIV-HCV coinfection were included. Only 39% of them achieved SVR. The rate limiting step was the engagement into hepatology care. Being a PWID was associated with ~50% reduced odds of achieving study outcomes, active drug use was associated with ~90% reduced odds. Older age was found to facilitate treatment success. Once treated, the rate of SVR was high in all populations. HCV is undertreated in coinfected young PWIDs. Further efforts should be directed to improve access to care in this marginalized population.

Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a developing therapeutic approach for premalignant pancreatic-cystic neoplasms (PCNs) and small pancreatic neuroendocrine tumors (PNETs). The safety and efficacy of pancreatic EUS-RFA were previously reported in small series. Herein we report our initial experience with RFA of PCNs and small PNETs.This is a prospective single-center study including 12 patients with a median follow-up of 7 months, with either PCN or PNETamp;lt;2 cm. Eligible PCNs were either intraductal papillary mucinous neoplasms (IPMN) with worrisome features or mucinous cystic neoplasms (MCN) that were not eligible or refused surgery. Ablation was performed using a 19-gauge dedicated needle.Twelve patients were treated, five had PCNs (four IPMNs, one MCN; median size of 36 mm, range 12-60) and seven had PNETs (median size 8.9 mm, range 6-18). Among patients with PCNs, the complete radiologic response was achieved in 3/5 (60%), partial response in 1/5 (20%) and failure in 1/5 (20%). Among six patients with nonfunctioning PNETs, the complete radiologic response was achieved in 4/6 (66.7%), partial radiologic response in 0/6 (0%) and failure in 2/6 (33.3%). Following a median follow-up of 7 months. One patient with insulinoma showed complete resolution of hypoglycemia-related symptoms. Three postprocedural adverse events occurred, including one case (1/12, 8.3%) of mild acute pancreatitis and two cases (2/12, 16.7%) of abdominal pain.EUS-guided RFA for premalignant PCNs and PNETs is feasible and well-tolerated. Efficacy would be further evaluated with continued follow-up of patients.

Context The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. Objective To assess type 2 diabetes risk among adolescents with NAFLD. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997–2011 and were followed until December 31, 2016. Participants A total of 1 025 796 normoglycemic adolescents were included. Interventions Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47–4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). Conclusions Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

Background Endoscopic ultrasound-guided liver biopsy (EUS-LB) using a 19-gauge (19-G) EUS needle is becoming increasingly popular. We evaluated the efficacy and safety of a 22-G EUS fine needle biopsy (FNB) needle for performing EUS-LB. Methods Patients referred for evaluation of elevated liver enzymes and without obstructive disease requiring endoscopic retrograde cholangiopancreatography (ERCP) were included. Using a 22-G FNB needle, two passes were made from the left lobe and one from the right. The main outcome measure was adequacy of the specimen for histology interpretation, and the secondary outcome was the safety of EUS-guided liver biopsy with a 22-G FNB needle. Patients were followed for post-procedure complications for 30 days. Results 40 patients (median age 61 years; 26 women) underwent EUS-LB. Analyzing by needle passes, the median longest core fragment was 12 mm (1st quartile – 3rd quartile 10 mm – 16.25 mm, interquartile range [IQR] 6.25 mm) from the left lobe and 11 mm (10 mm – 15.75 mm, IQR 5.75 mm) from the right lobe. The median cumulative core length per patient was 55 mm (44.5 mm – 68 mm, IQR 23.5 mm). The median cumulative number of complete portal triads (CPTs) per patient was 42 (28.5 – 53, IQR 24.5). The specimen was considered adequate in all 40 patients (100 %). Self-limiting abdominal pain was reported in 6 patients (15 %). Conclusions EUS-LB using a 22-G FNB needle is a safe and viable alternative to the use of larger gauge needles, yielding adequate tissue for evaluation of parenchymal disease in 100 % of the patients.

Celiac disease (CeD) is an immune-mediated enteropathy triggered by the ingestion of gluten, which is present in wheat, barley, and rye. The clinical manifestations of CeD are diverse, ranging from diarrhea, steatorrhea, weight loss, or growth failure, through constipation, fatigue, and abdominal pain, to anemia, early osteoporosis, and neuropathy, to state a few. This chapter discusses the wide range of presentations encountered by care providers and focuses on the non-classical ones, which need to be carefully considered to avoid misdiagnosis of CeD.

Helminths or their products can immunomodulate the host immune system, and this phenomenon may be applied as the basis of new anti-inflammatory treatments. Previously, we have shown the efficacy of tuftsin&ndash, phosphorylcholine (TPC), based on a helminth product, in four animal models of autoimmune diseases: arthritis, colitis, systemic lupus erythematosus, and experimental autoimmune encephalomyelitis. We demonstrated that TPC reduced inflammatory process ex vivo in peripheral blood lymphocytes (PBLs) and in biopsies from giant-cell arteritis. In the present study, we assessed the therapeutic potential of TPC treatment on a chronic colitis murine model. C57BL/6 mice with chronic colitis were treated with TPC after the third cycle of 2% dextran sodium sulfate (DSS). Oral TPC treatment resulted in amelioration of the colitis clinical manifestations exemplified by reduced disease activity index (DAI) score, expansion of mesenteric lymph nodes (MLN) T regulatory cells (shown by Fluorescence Activated Cell Sorting (FACS)), significant reduction in the expression of pro-inflammatory cytokines (IL-1&beta, IL17, IL-6, TNF&alpha, ), and elevation in the expression of anti-inflammatory cytokine IL-10 (shown by RT-PCR). This study demonstrated the potential immunomodulatory effects of oral administration of TPC in a chronic colitis murine model. Further clinical trials are needed in order to evaluate this novel approach for the treatment of patients with inflammatory bowel disease.

Fibromyalgia is a complex disorder, and its diagnosis often comprises a challenge for physicians. We aimed to assess the time from the appearance of early symptoms to the definite diagnosis of fibromyalgia and to delineate patient and physician factors associated with this delay. The database of a large healthcare services provider was searched for all fibromyalgia patients (age 21 years or more) diagnosed during 2008-2011. Patients with a diagnosis confirmed by a physician with a relevant specialization were compared with age- and sex-matched nonfibromyalgia controls to retrospectively identify an initial complaint pattern characteristic of fibromyalgia. The time from initial complaints to fibromyalgia diagnosis, as well as the fraction of time while the patient was treated continuously by the same primary physician as at time of diagnosis, was assessed among all eligible fibromyalgia patients. An initial complaint pattern was identified in 67.9% of 2,055 patients with confirmed fibromyalgia vs. 27.6% of 9,172 controls. Among 2,369 (69.0%) of all 3,434 eligible patients with fibromyalgia, mean (SD) total time to diagnosis was 6.42 (3.57) years and mean (SD) time while treated by the same primary physician as at diagnosis was 3.75 (3.26) years. Comorbidity, younger patient, and older physician age were associated with longer time to diagnosis. By analysis of "real-world" data, fibromyalgia remains a complex and elusive diagnosis, taking years to be properly diagnosed. There is a need to increase the awareness of this syndrome among physicians, especially of older age.

Objective.To assess 1-year persistence and adherence rates with drug therapy among patients with fibromyalgia (FM) and to identify factors associated with therapy discontinuation.Methods.This retrospective, cohort study included members ≥ 21 years old from the Maccabi Healthcare Services, a large health maintenance organization in Israel, who were diagnosed with FM from 2008 through 2011. Medications of interest included the anticonvulsant pregabalin, antidepressants [selective serotonin reuptake inhibitor (SSRI), serotonin/norepinephrine reuptake inhibitor (SNRI)], and tricyclic antidepressants (TCA). Time to treatment discontinuation and proportion of days covered (PDC) with FM-specific therapies during the year from first dispensed were analyzed. PDC < 20% was considered low adherence and PDC ≥ 80% was considered high adherence. Logistic regression models were constructed for multivariable analyses.Results.Overall, 3932 patients with FM were included; 88.7% were female. Pre-diagnosis use of medication of interest was documented in 41% of the study population. Of the remaining 2312 patients, 56.1% were issued a prescription, 45.0% were dispensed at least 1 medication in the year following diagnosis, and only 28.8% had prescriptions filled twice within the first year from diagnosis. Among newly prescribed patients, 1-year discontinuation was highest for TCA (91.0%) and lowest for SSRI/SNRI antidepressants (73.7%). Over half of the patients (60.5%) had fewer than 20% of the days covered by any medication during the year and only 9.3% were very adherent (PDC ≥ 80%).Conclusion.This study clearly shows that in an Israeli “real-life” population of patients with FM, persistence and adherence with FM therapy in the year following diagnosis is remarkably low.

Introduction Intravenous immunoglobulin (IVIG) has been widely used to treat various conditions, including inflammatory and autoimmune diseases. IVIG has been shown to have a direct influence on neutrophils, eosinophils and lymphocytes. However, many aspects IVIG's effect on neutrophils activation still remain unknown. Objective To evaluate the effect of IVIG on PMA-induced activation of neutrophils, with and without priming with TNF-α, in a series of in vitro experiments performed on whole blood. Results Our data coincided with well-known literature indicating that the effect of phorbol 12-myristate 13-acetate (PMA) on human leukocytes includes activation of neutrophils, monocytes and eosinophils, increase of chemiluminescence (CL) and induction of netosis, resulting in assembly of traps. In presence of IVIG (10 mg/mL), CL was reduced by 25% in response to PMA compared to PMA-induced leukocyte activation without IVIG. Decreasing IVIG concentration to 1 mg/mL and below did not inhibit PMA-induced activation of CL.PMA-induced activation after TNF-α priming resulted in approximately 50% increase of amplitude of CL response to PMA. Moreover, maximum CL was reached by minute 5, which was more rapid than in the absence of TNF-α-priming (in this case maximum CL was reached by minute 15).The IVIG concentrations did not affect morphological changes of leukocytes after sequential addition of TNF-α and PMA. IVIG had no effect on leukocyte content and on PMA-induced CL of primed leukocytes.Addition of IVIG under TNF-α priming significantly increased the number of traps in the smears in response to PMA activation. Of note, such an increase in the number of traps was depended on the IVIG concentration in plasma. Conclusion In conclusion, we suggest that IVIG is able to reduce the degradation of traps under priming with TNF-α. Moreover, IVIG might switch the activation of primed leukocytes to netosis.

The data regarding the association between inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) is mostly composed of case reports and case series indicating an infrequent association.To investigate the association between IBD and SLE.Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services.The study included 5018 patients with SLE and 25,090 age- and sex-matched controls. The prevalence of UC was significantly higher in patients with SLE than in controls in a univariate analysis (0.4% and 0.2%, respectively; p0.017). However, in a multivariate logistic regression model SLE was not associated with UC (OR 1.67, 95% CI 0.99-2.815, p0.052). The prevalence of CD was higher in patients with SLE than in controls in a univariate analysis (0.7% and 0.3%, respectively; p0.001). A multivariate logistic regression model confirmed this finding and corroborated that SLE was associated with comorbid CD (OR 2.23, 95% CI 1.46-3.4, p0.001).Patients with SLE have a greater prevalence of CD than matched controls. The distinction of IBD from SLE gastrointestinal involvement can be challenging as clinical manifestations, laboratory tests, and radiographic findings may appear similar between the two diseases. Therefore, physicians treating patients with rather IBD or SLE should consider this potential association.

Background:Matrix metalloproteinase-9 (MMP-9) is a novel marker of intestinal inflammation. The aim of this study was to assess if serum MMP-9 levels predict clinical flare in patients with quiescent Crohn’s disease (CD).Methods:This study was a post hoc analysis of a prospective observational study in which quiescent CD patients were included and followed until clinical relapse or the end of a 2-year follow-up period. Serial C-reactive protein (CRP) and fecal calprotectin (FC) levels were measured, and the patients underwent repeated capsule endoscopies (CEs) every 6 months. Small bowel inflammation was quantified by Lewis score (LS) for CE. A baseline magnetic resonance enterography was also performed, and MaRIA score was calculated. Serum MMP-9 levels in baseline blood samples were quantified by ELISA.Results:Out of 58 eligible enrolled patients, 16 had a flare. Higher levels of baseline MMP-9 were found in patients who developed subsequent symptomatic flare compared with patients who did not [median 661 ng/ml, 25–75 interquartile range (IQR; 478.2–1441.3) versus 525.5 ng/ ml (339–662.7), respectively, p = 0.01]. Patients with serum MMP-9 levels of 945 ng/ ml or higher were at increased risk for relapse within 24 months [area under the curve (AUC) of 0.72 [95% confidence interval (CI): 0.56–0.88]; hazard ratio 8.1 (95% CI 3.0–21.9, p Conclusions:Serum MMP-9 may be a promising biomarker for prediction of clinical flare in CD patients with quiescent disease.

Pericardial biopsies are rarely performed during the diagnosis and management of pericardial diseases. The circumstances and clinical profile of patients undergoing pericardial biopsies are largely uncharacterized.To examine the circumstances in which pericardial biopsies are obtained and to evaluate their diagnostic yield.We studied a total of 100 cases (71% males, mean age 60.8 years, range 8.1-84.5 years) of surgically resected pericardium specimens obtained from 2000 to 2015 at Sheba Medical Center, the largest medical center in Israel. Patients were classified into groups according to four major histological etiologies: idiopathic pericarditis, constrictive pericarditis, malignant pericarditis, and post-cardiac injury syndrome (PCIS). The clinical history and course, laboratory, echocardiography, and histological results were reviewed retrospectively.Causes of pericarditis according to histological definitions included idiopathic pericarditis (29%), constrictive pericarditis (29%), PCIS (9%), and malignant pericarditis (26%). Overall sensitivity of the pericardial biopsy in patients with malignancy was 57.7%. During the study period, we found a trend toward an increased number of biopsies due to constrictive pericarditis and PCIS, along with a decrease in the number of biopsies performed in patients with malignant or idiopathic pericarditis. The diagnosis following biopsy did not change for any of the patients.Our findings suggest a low diagnostic yield from pericardial biopsies, especially in malignant pericarditis. This conclusion, along with novel therapies, resulted in the infrequent use of pericardial biopsy in recent years.

OBJECTIVE The sequelae of increasing childhood obesity are of major concern. We assessed the association of BMI in late adolescence with diabetes mortality in midlife. RESEARCH DESIGN AND METHODS The BMI values of 2,294,139 Israeli adolescents (age 17.4 ± 0.3 years), measured between 1967 and 2010, were grouped by U.S. Centers for Disease Control and Prevention age/sex percentiles and by ordinary BMI values. The outcome, obtained by linkage with official national records, was death attributed to diabetes mellitus (DM) as the underlying cause. Cox proportional hazards models were applied. RESULTS During 42,297,007 person-years of follow-up (median, 18.4 years; range CONCLUSIONS Adolescent BMI, including values within the currently accepted “normal” range, strongly predicts DM mortality up to the seventh decade. The increasing prevalence of childhood and adolescent overweight and obesity points to a substantially increased future adult DM burden.

BACKGROUND: Giant cell arteritis (GCA) is an inflammatory disease of unknown etiology affecting adults age > 50 years. GCA (also known as temporal arteritis) is a vasculitis of large and medium‐size vessels that involves the extracranial branches of the carotid artery. Common manifestations include constitutional symptoms, headache, jaw claudication, scalp tenderness, and vision loss. Cardiac involvement in GCA is considered to be as low as 5%, and

A novel small molecule named tuftsin-phosphorylcholine (TPC), which is linked to the biological activity of helminths, was constructed. The current study address the effect of TPC treatment in established collagen-induced arthritis (CIA) mice and propose TPC bi-functional activity. TPC treatment was initiated when clinical score was 2 to 4. Arthritis scores in TPC treated mice were lower compared to mice treated with vehicle (P < 0.001). Joint staining showed normal joint structure in TPC-treated mice compared to control groups treated with phosphate buffered saline (PBS), phosphorylcholine, or tuftsin, which exhibited severely inflamed joints. TPC enhanced anti-inflammatory response due to increased IL-10 secretion, and reduced pro-inflammatory cytokine secretion (IL-1-β, IL-6, TNF-αP < 0.001). Furthermore, TPC therapy increased expansion of CD4+CD25+FOXP3+T regulatory cells and IL-10+CD5+CD1d+B regulatory cells. We propose that the immunomodulatory activity of TPC can be a result of a bi-specific activity of TPC: (a) The tuftsin part of the TPC shifts RAW macrophage cells from pro-inflammatory macrophages M1 to anti-inflammatory M2-secreting IL-10 (P < 0.001) through neuropilin-1 and (b) TPC significantly reduce mouse TLR4 expression via NFkB pathway by HEKTM cells (P < 0.02) via the phosphorylcholine site of the molecule. Our results indicate that TPC, significantly ameliorated established CIA by its immunomodulatory activity. These data could lead to a novel self bi-functional small molecule for treating patients with progressive RA.

Influenza vaccines represent a major tool to contain the clinical and epidemiological burden generated by influenza. However, in spite of their effectiveness, vaccines are victims of prejudices and false myths, which contribute to the increasing phenomenon of vaccine hesitancy and loss of confidence. Media and, mainly, new media, and information and communication technologies play a major role in disseminating health-related information. While, on the one hand, they can be extremely promising in promoting disease prevention, on the other hand, they can also have a negative impact on population's health attitudes and behaviors when delivering information not based on scientific evidences. The “Fluad-case” is an excellent example of the crucial role of an adequate information campaign. Following the cluster of deaths allegedly related to the administration of the adjuvanted influenza vaccine “Fluad” during the 2014–2015 influenza campaign, the Italian health authorities and regulatory bodies decided the withdrawal of two potentially contaminated Fluad batches. This fostered a huge media coverage, with resulted in negatively impacting on influenza vaccination coverage. Monitoring and tracking the Fluad-related web searches, we showed that Liguria resulted the Italian region with the highest number of Fluad-related website searches and that, interestingly, Fluad was searched also in Regions in which this vaccine was not distributed. A positive moderate correlation between accessing Fluad-related websites and overall influenza vaccination coverage was found (r = 0.66 ([95%CI 0.29–0.86], p = 0.0026). Considering subjects ≥65 years, who are the subjects for which the Fluad vaccination is recommended, the correlation resulted r = 0.49 ([95%CI 0.03–0.78], p = 0.0397). As such, health authorities and decision-makers should promote high-quality communication campaigns in order to raise awareness of vaccination practices.

ObjectiveThe aim of this study was to assess coronary artery disease (CAD) risk among obese young men without metabolic risk factors.DesignA longitudinal study in a historical cohort.MethodsIncident CAD during a median follow-up of 6.1 years was assessed among 31 684 young men (mean age 31.2±5.7 years) of the Metabolic, Lifestyle and Nutrition Assessment in Young Adults (MELANY) cohort. Participants were categorized by BMI and the number of metabolic abnormalities (based on the Adult Treatment Panel-III). Metabolically healthy (MH) obesity was defined as BMI ≥30 kg/m2 in the presence of normal blood pressure (BP) and normal levels of fasting glucose, triglyceride, and HDL-cholesterol (HDL-c) levels (n=599; 1.9%). Cox proportional hazard models were applied.ResultsThere were 198 new cases of CAD that were diagnosed during 209 971 person-years of follow-up, of which six cases occurred among MH obese. The incidence of CAD among MH lean, overweight, and obese participants was 0.23, 0.45, and 1.0/1000 person-years respectively. In a multivariable model adjusted for clinical and biochemical CAD risk factors, a higher CAD risk was observed among MH-obese (hazard ratio=3.08; 95% CI=1.10–8.68, P=0.033), compared to MH-normal weight subjects. This risk persisted when BMI was treated as a time-dependent variable, or when fasting glucose, HDL-c, triglycerides, or BP were added to the model. Similar results were also obtained when a more permissive definition of MH was used.ConclusionsObesity may continue to contribute to increased risk for incident CAD in young men even in the presence of a healthy metabolic profile.

In areas where helminths infections are common, autoimmune diseases are rare. Treatment with helminths and ova from helminths, improved clinical findings of inflammatory bowel disease, multiple-sclerosis and rheumatoid-arthritis. The immunomodulatory functions of some helminths were attributed to the phosphorylcholine (PC) moiety. We aimed to decipher the tolerogenic potential of Tuftsin-PC (TPC) compound in mice genetically prone to develop lupus. Lupus prone NZBXW/F1 mice received subcutaneously TPC (5 μg/1 ml), 3 times a week starting at 14 weeks age. Autoantibodies were tested by ELISA, T-regulatory-cells by FACS, cytokines profile by RT-PCR and cytokines protein levels by DuoSet ELISA. Glomerulonephritis was addressed by detection of proteinuria, and immunoglobulin complex deposition in the mesangium of the kidneys of the mice by immunofluorescence. Our results show that TPC attenuated the development of glomerulonephritis in lupus prone mice, in particular, it ameliorated proteinuria (p 0.02), and reduced immunoglobulin deposition in the kidney mesangium. TPC also enhanced the expression of TGFβ and IL-10 (p 0.001), and inhibited the production of IFNγ and IL-17 (p 0.03). TPC Significantly enhanced the expansion of CD4+CD25+FOXP3+ T-regulatory cells (Tregs) phenotype in the treated mice. These data indicate that TPC hampered lupus development in genetically lupus prone mice which was exemplified by moderate glomerulonephritis, attenuation of pro-inflammatory cytokines and enhancement of anti-inflammatory cytokines expression, as well as Tregs expansion. Our results propose harnessing novel natural therapy for lupus patients.

Vitamin D facilitates calcium absorption and bone building. Presence of vitamin D is highly important in pregnant women due to its effect on the development of the fetal skeleton. The study population comprised 208 low-risk pregnant women of a heterogeneous population. Maternal and fetal serum concentrations of vitamin D were measured using the Liaison 25(OH)D Assay (DiaSorin, Italy).Maternal vitamin D serum concentrations correlate with neonatal vitamin D serum concentrations but do not affect neonatal weight and/or head circumference. WHAT IS KNOWN? • Vitamin D is known to be also involved in immunomodulation and cellular proliferation and differentiation. • Vitamin D is highly important in pregnant women for its effect on fetal musculoskeletal and neurological development. WHAT IS NEW? • No association was detected between maternal or neonatal vitamin D concentration with neonatal growth parameters or obstetrical complications, and no association was found between maternal vitamin D serum concentrations and maternal obstetrical complication rate. • A strong correlation was demonstrated between maternal and neonatal serum vitamin D concentrations.

Recent research in systemic lupus erythematosus (SLE) yielded new antigens and antibodies in SLE patients. We describe the various autoantibodies that can be detected in patients with SLE. A literature review, using the terms “autoantibody” and “systemic lupus erythematosus”, was conducted to search for articles on autoantibodies in SLE, their target antigens, association with disease activity and other clinical manifestations. One hundred and eighty autoantibodies were so far described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of an autoantibody, the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 180 autoantibodies. SLE is so far the autoimmune disease with the largest number of detectable autoantibodies. Their production could be antigen-driven, the result of a polyclonal B cell activation, impaired apoptotic pathways, or the outcome of an idiotypic network dysregulation.

Improved clinical findings of inflammatory bowel disease (IBD) upon treatment with helminthes and their ova were proven in animal models of IBD and in human clinical studies. The immunomodulatory properties of several helminthes were attributed to the phosphorylcholine (PC) molecule. We assessed the therapeutic potential of tuftsin-PC conjugate (TPC) to attenuate murine colitis. Colitis was induced by Dextransulfate-Sodium-Salt (DSS) in drinking water. TPC was given by daily oral ingestion (50 μg/0.1 ml/mouse or PBS) starting at day −2. Disease activity index (DAI) score was followed daily and histology of the colon was performed by H&E staining. Analysis of the cytokines profile in distal colon lysates was performed by immunoblot. Treatment of DSS induced colitis with TPC prevented the severity of colitis, including a reduction in the DAI score, less shortening of the colon and less inflammatory activity in histology. The immunoblot showed that the colitis preventive activity of TPC was associated with downregulation of colon pro-inflammatory IL-1β, TNFα and IL-17 cytokines expression, and enhancement of anti-inflammatory IL-10 cytokine expression. In the current study, we demonstrated that TPC treatment can prevent significantly experimental colitis induction in naive mice. We propose the TPC as a novel potential small synthetic molecule to treat colitis.

Context As opposed to coronary heart disease (CHD) mortality, cardiovascular mortality attributed to non-CHD causes has increased. Objective To evaluate the association of body mass index (BMI) in late adolescence with mortality attributed to non-CHD cardiovascular sequelae. Design and Setting A nationwide cohort. Participants A total of 2,294,139 adolescents examined between 1967 and 2010. Interventions Height and weight were measured at age 17. All cardiovascular disease-specific outcomes, coded by the Central Bureau of Statistics from death notifications as the underlying cause of death, were obtained by linkage. Cox hazards models were applied. Main Outcome Measurements Death attributed to fatal arrhythmias, hypertensive heart disease, cardiomyopathies, arterial disease, heart failure, and pulmonary embolism. Results During 42,297,007 person-years of follow-up, there were 3178 deaths due to cardiovascular causes, of which 279, 122, 121, 114, 94, and 70 were attributed to the main outcomes, respectively. BMI was positively associated with all study outcomes with hazard ratios (HRs) per unit increment in BMI ranging from 1.09 [95% confidence interval (CI): 1.03 to 1.16] for arterial disease to 1.16 (95% CI: 1.11 to 1.21) for hypertensive heart disease. When BMI was treated as a categorical variable, a graded increase in risk was evident from the high-normal (22.0 to

The natural progression of metabolic abnormalities among patients with inherited autoinflammation is unclear.The objective of the study was to assess the cardiometabolic risk of participants with familial Mediterranean fever (FMF).This study included nationwide cross-sectional and longitudinal cohorts.The prevalence of components of the metabolic syndrome at age 17 years was assessed from the medical database of the Israeli Defense Force from 1973 through 1997. Included were 745 males with FMF, 902 healthy male siblings, and a control group of 787,714 participants. A prospective follow-up study traced the incidence of components of the metabolic syndrome to age 45 years among 57 FMF and 1568 control army personnel participants.Body mass index (BMI) and blood pressure (BP) were measured at age 17 years (cross-sectional); lifestyle, anthropometric, and biochemical data were periodically recorded from age 25 years.Abnormal BMI or BP (age 17 y) and Adult Treatment Panel III criteria of the metabolic syndrome were measured.In multivariable regression analysis adjusted for known confounders of obesity, FMF participants had an odds ratio of 0.65 for the occurrence of overweight [95% confidence interval (CI) 0.44-0.96, P = .03] and 0.66 (95% CI 0.48-0.92, P = .012) for hypertension-range BP; their siblings tended to obesity (odds ratio 1.48; 95% CI 1.04-2.11, P = .008). In the follow-up arm, a multivariable analysis adjusted for age, birth year, BMI, education, socioeconomic status, ethnicity, and physical activity yielded hazard ratios of 0.32 (95% CI 0.10-0.82, P = .002) for incident obesity, 0.49 (95% CI 0.25-0.95, P = .037) for incident triglycerides 150 mg/dL or greater, 0.56 (95% CI 0.31-0.98, P = .048) for low-density lipoprotein cholesterol 130 mg/dL or greater, and 2.14 (1.368-3.359, P = .001) for high-density lipoprotein cholesterol less than 40 mg/dL for FMF participants compared with controls. Incident elevated BP was lower among FMF participants (hazard ratio 0.49; 95% CI 0.23-1.00, P = .05), whereas dysglycemia incidence was comparable.FMF is associated with lower rates of most components of the metabolic syndrome compared with normal subjects, unlike other inflammatory conditions.

The incidence of autoimmune diseases is increasing in Western countries, possibly due to the improved sanitary conditions and reduced exposure to infections in childhood (the hygiene hypothesis). There is an ongoing debate whether infection prevents or precipitates autoimmune diseases. Various helminths species used in several animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. At present the scientific data is based mostly on experimental animal models; however, there is an increasing body of evidence in a number of clinical trials being conducted. Herein we review several clinical trials evaluating the anti-inflammatory effects of helminths and assessing their association with different autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and autoimmune liver diseases. We also describe the common pathways by which helminths induce immune modulation and the key changes observed in the host immune system following exposure to helminths. These common pathways include the inhibition of IFN-γ and IL-17 production, promotion of IL-4, IL-10 and TGF-β release, induction of CD4(+) T cell FoxP3(+) expression, and generation of regulatory macrophages, dendritic cells, and B cells. Helminths products are becoming significant candidates for anti-inflammatory agents in this context. However, further research is needed for synthetic analogues of helminths' potent products that mimic the parasite-mediated immunomodulation effect.

Case reports and case series have indicated a possible association between celiac disease (CD) and systemic lupus erythematosus (SLE), but additional population-based studies are required. The true prevalence of CD in SLE patients is still unknown, but is indeed an important factor when considering the clinical implications, notably the necessity of screening strategies in SLE patients. Our objective was to investigate the association between CD and SLE using a community-based approach in a real-life population database.Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of CD in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services.The study included 5018 patients with SLE and 25,090 age- and sex-matched controls. The prevalence of CD was significantly higher in patients with SLE than in controls in univariate analysis (0.8% and 0.2%, respectively, p0.001). Also, SLE was associated with CD (OR 3.92, 95% CI 2.55-6.03, p0.001) in a multivariate logistic regression model.Patients with SLE had a greater prevalence of CD than matched controls in a large case-control study. A complex combination of genetic, immunological and novel environmental factors may explain this positive association. Physicians should keep in mind that CD can be a tricky diagnosis in SLE patients, yet a treatable condition, probably more common in this population than we used to think.

In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood.We grouped data on BMI, as measured from 1967 through 2010 in 2.3 million Israeli adolescents (mean age, 17.3±0.4 years), according to age- and sex-specific percentiles from the U.S. Centers for Disease Control and Prevention. Primary outcomes were the number of deaths attributed to coronary heart disease, stroke, sudden death from an unknown cause, or a combination of all three categories (total cardiovascular causes) by mid-2011. Cox proportional-hazards models were used.During 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from cardiovascular causes, including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death. On multivariable analysis, there was a graded increase in the risk of death from cardiovascular causes and all causes that started among participants in the group that was in the 50th to 74th percentiles of BMI (i.e., within the accepted normal range). Hazard ratios in the obese group (≥95th percentile for BMI), as compared with the reference group in the 5th to 24th percentiles, were 4.9 (95% confidence interval [CI], 3.9 to 6.1) for death from coronary heart disease, 2.6 (95% CI, 1.7 to 4.1) for death from stroke, 2.1 (95% CI, 1.5 to 2.9) for sudden death, and 3.5 (95% CI, 2.9 to 4.1) for death from total cardiovascular causes, after adjustment for sex, age, birth year, sociodemographic characteristics, and height. Hazard ratios for death from cardiovascular causes in the same percentile groups increased from 2.0 (95% CI, 1.1 to 3.9) during follow-up for 0 to 10 years to 4.1 (95% CI, 3.1 to 5.4) during follow-up for 30 to 40 years; during both periods, hazard ratios were consistently high for death from coronary heart disease. Findings persisted in extensive sensitivity analyses.A BMI in the 50th to 74th percentiles, within the accepted normal range, during adolescence was associated with increased cardiovascular and all-cause mortality during 40 years of follow-up. Overweight and obesity were strongly associated with increased cardiovascular mortality in adulthood. (Funded by the Environment and Health Fund.).

The association between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) has been suggested previously, but prior studies provided contradicting findings.To characterize the expression profile of eight classic and non-classic aPL in patients diagnosed with MS.Using the BioPlex 2200 immunoassay, we measured the levels of serum immunoglobulin (Ig)M and IgG isotypes of three classic aPL and five non-classic aPL in 98 subjects with MS and 237 healthy controls.Three non-classic aPL were significantly more prevalent among MS patients in comparison to the control group. These antibodies included IgM and IgG against phosphatidylserine-β2GPI (PS-B2), IgG prothrombin complex (PT-PT) and IgM prothrombin (PT). The positive results according to Bonferroni correction are PS-B2 IgG and PT-PT IgG. The remaining aPL profiles did not differ significantly between the two groups.An association between certain non-classic aPL and MS has been established. The specific role of these autoantibodies in the pathogenesis of the condition remains uncertain.

Reduced bone mineral density is frequently found especially in adult celiac disease (CD) and dietary guidelines favor vitamin D supplementation in adults and children with CD. Vitamin D serum levels were investigated in CD populations in order to challenge its routine supplementation. Israeli (61), Spanish (59), CD children (groups 1 and 5, respectively) were compared to children with nonspecific abdominal pain (56), their parents (84) and Spanish adult CD patients (22) (group 2, 3, 4, respectively). 25(OH)-vitamin D was checked by LIAISON chemiluminescent immunoassays. Groups 5 and 1 had the highest levels compared to groups 4 and 3 with the lowest levels. The levels in groups 1 and 2 were comparable. Concerning 25(OH)-vitamin D sera levels, only the difference between group 5 and 4 was statistically significant (30.3 ± 12.3 and 20.2 ± 10.5 ng/ml, respectively p = 0.003). When vitamin D was splitted above and below 20 ng/ml level, 54.5% of Spanish adult CD had vitamin D deficiency compared to 16.9% of the local CD children (p = 0.001). 29.6% of group 2 had deficient levels compared to their parents with 50% (p = 0.019). In conclusion, Vitamin D sera levels negatively correlate with age. Thus, mainly adult CD population should be assessed for vitamin D levels and supplemented accordingly.

Evolving understanding of the role of helminths in the pathogenesis of autoimmunity has led to the development of novel therapeutic interventions that are showing promise in patients with immune-mediated diseases. Meanwhile, studies in animal models of arthritis suggest that these new products might also be applicable in autoimmune rheumatic disease.

The incidence of autoimmune diseases has risen throughout the last half a century, mostly in the industrialized world. Helminths and their derivatives were found to have a protective role in autoimmunity and inflammatory conditions, as they manipulate the immune network, attenuating the host's cellular and humoral responses. Indeed, various helminth species used in several human and animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Our review will focus on the main mechanisms by which helminths and their secreted molecules modulate the host's immune system. The main pathways induce a shift from Th1 to Th2 phenotype, accelerate T regulatory and B regulatory phenotypes, and attenuate the levels of the inflammatory cytokines, leading to a tolerable scenario.

Background Lupus nephritis is known to be associated with several antibodies including autoantibodies that target the DNA, C1q and histone, α-actinin, and the nucleosome. In addition, circulating anti-phosphoribosomal protein antibodies (anti-Ribos.P) were found to be associated with lupus nephritis. Study objective We have assessed the direct role of anti-Ribos.P in the development of glomerulonephritis in-vitro and in animal models. Study design NZBxW/F1 lupus prone mice were immunized with recombinant Ribos.P0 (rRibos.P). Evaluation of renal disease included mice evaluation for proteinuria and histologic analysis of the kidneys. Anti-Ribos.P monoclonal Ab was prepared from the rRibos.P immunized NZBxW/F1 mice by hybridoma technology. MAPKs expression was analyzed by MAPKs protein array and confirmed by real-time PCR and western blot. To elucidate whether anti-Ribos.P induce glomerulonephritis, naive C3H mice were immunized with recombinant rRibos.P and the glomerulonephritis was followed up as described above. Results The immunized NZBxW/F1 lupus prone mice developed anti-Ribos.P which was cross reactive with Sm and not dsDNA. The mice developed accelerated glomerulonephritis manifested by early proteinuria and immunoglobulin deposites in the mesangium of the kidneys. Anti-Ribos.P deposited in the glomerular mesangium were eluted from the kidney. The Ribos.P immunized naive C3H/Hen mice developed glomerulonephritis manifested by circulating autoantibodies directed to Ribos.P, dsDNA and Sm. The anti Ribos.P were cross reactive with Sm but not with dsDNA, and were deposited in the glomeruli. Interestingly these mice developed alopecia. In vitro. Primary mesangial cells exposed to mouse anti-Ribos.P mAb originated from the immunized lupus mice and to human anti-Ribos.P Abs, induced activation of mesangial cells via p38α, JNK, AKT and HSP27 MAPKs expression pathway. Conclusions Our data show for the first time that anti-Ribos.P are nephritogenic autoantibodies, as illustrated by in-vitro and in-vivo experiments: a) They accelerate the development of glomerulonephritis in lupus prone mice; b) They induce nephritis in naive mice. c) Anti-Ribos.P Abs trigger MAPKs expression in primary mesangial cells. These data contribute a direct mechanistic link between anti-Ribos.P and nephritis in lupus mice.