Dana Ben-Ami Shor

Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).

Gluten Sensitivity in Multiple Sclerosis Experimental Myth or Clinical Truth

Patients with neurological disease of unknown etiology sometimes present with antigliadin and antitissue transglutaminase antibodies. The association between these antibodies and multiple sclerosis has been previously suggested. The purpose of this study was to determine the prevalence of these antibodies in multiple sclerosis patients. We determined the level of serum immunoglobulin A and immunoglobulin G antigliadin and antitissue transglutaminase antibodies in 98 patients with multiple sclerosis. We found a highly significant increase in titers of immunoglobulin G antibodies against gliadin and tissue transglutaminase in the multiple sclerosis patients. Seven patients had a positive IgG AGA, whereas only 2 controls presented positive titers (P= 0.03). Four patients had positive IgG anti‐tTG while all the controls tested negative (P= 0.02). However, immunoglobulin A antibodies against gliadin and tissue transglutaminase were not statistically higher in the multiple sclerosis group in comparison to the control group. Our findings support the associations between antibodies against gliadin and tissue transglutaminase to multiple sclerosis. The specific role of these antibodies in the pathogenesis of multiple sclerosis remains uncertain and requires additional research. A gluten free diet should be considered in specific cases of patients who present with gluten antibodies.

The mechanisms behind helminth's immunomodulation in autoimmunity

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 hosts 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 hosts 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.

BMI at Age 17 Years and Diabetes Mortality in Midlife: A Nationwide Cohort of 2.3 Million Adolescents

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 <1–44 years) there were 481 deaths from DM (mean age at death, 50.6 ± 6.6 years). There was a graded increase in DM mortality evident from the 25th to the 49th BMI percentile group onward and from a BMI of 20.0–22.4 kg/m2 onward. Overweight (85th to 94th percentiles) and obesity (the 95th percentile or higher), compared with the 5th to 24th percentiles, were associated with hazard ratios (HRs) of 8.0 (95% CI 5.7–11.3) and 17.2 (11.9–24.8) for DM mortality, respectively, after adjusting for sex, age, birth year, height, and sociodemographic variables. The HR for the 50th through 74th percentiles was 1.6 (95% CI 1.1–2.3). Findings persisted in a series of sensitivity analyses. The estimated population-attributable fraction for DM mortality, 31.2% (95% CI 26.6–36.1%) for the 1967–1977 prevalence of overweight and obesity at age 17, rose to a projected 52.1% (95% CI 46.4–57.4%) for the 2012–2014 prevalence. 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.

All disease begins in the gut: Celiac disease co-existence with SLE

BACKGROUND 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. METHODS 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. RESULTS 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, p<0.001). Also, SLE was associated with CD (OR 3.92, 95% CI 2.55-6.03, p<0.001) in a multivariate logistic regression model. CONCLUSIONS 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.

Anti-ribosomal-P antibodies accelerate lupus glomerulonephritis and induce lupus nephritis in naïve mice

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, naïve 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 naïve 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 naïve 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.

Cardiovascular and Metabolic Risk Factors in Inherited Autoinflammation

CONTEXT The natural progression of metabolic abnormalities among patients with inherited autoinflammation is unclear. OBJECTIVE The objective of the study was to assess the cardiometabolic risk of participants with familial Mediterranean fever (FMF). DESIGN AND SETTING This study included nationwide cross-sectional and longitudinal cohorts. PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOME MEASURES Abnormal BMI or BP (age 17 y) and Adult Treatment Panel III criteria of the metabolic syndrome were measured. RESULTS 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. CONCLUSIONS FMF is associated with lower rates of most components of the metabolic syndrome compared with normal subjects, unlike other inflammatory conditions.

Does inflammatory bowel disease coexist with systemic lupus erythematosus

BACKGROUND 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. OBJECTIVES To investigate the association between IBD and SLE. METHODS Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of ulcerative colitis (UC) and Crohns 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. RESULTS 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; p<0.017). However, in a multivariate logistic regression model SLE was not associated with UC (OR 1.67, 95% CI 0.99-2.815, p<0.052). The prevalence of CD was higher in patients with SLE than in controls in a univariate analysis (0.7% and 0.3%, respectively; p<0.001). 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, p<0.001). CONCLUSIONS 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.

Autoimmunity: Will worms cure rheumatoid arthritis?

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 effects of maternal vitamin D on neonatal growth parameters

AbstractVitamin 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). Conclusion: 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.