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Mira Y Friedman,1,2 Maya Leventer-Roberts,3 Joseph Rosenblum,4 Nir Zigman,4 Iris Goren,4 Vered Mourad,4 Natan Lederman,5 Nurit Cohen,5 Eran Matz,6 Doron Z Dushnitzky,6 Nirit Borovsky,6 Moshe B Hoshen,3 Gili Focht,1 Malka Avitzour,1 Yael Shachar,1 Yehuda Chowers,7 Rami Eliakim,8 Shomron Ben-Horin,8 Shmuel Odes,9 Doron Schwartz,9 Iris Dotan,10 Eran Israeli,11 Zohar Levi,10 Eric I Benchimol,12–14 Ran D Balicer,3 Dan Turner1 On behalf of the Israeli IBD Research Nucleus (IIRN) 1The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; 2Braun School of Public and Community Medicine, The Hebrew University – Hadassah Medical Center, Jerusalem, Israel; 3Clalit Research Institute, Chief’s Office, Clalit Health Services, Tel Aviv, Israel; 4Maccabi Healthcare Services, Tel Aviv, Israel; 5Meuhedet Health Services, Tel Aviv, Israel; 6Leumit Health Services, Tel Aviv, Israel; 7Department of Gastroenterology, Rambam Health Care Campus, Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel; 8Department of Gastroenterology, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 9Department of Gastroenterology and Hepatology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel; 10Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel; 11Institute of Gastroenterology and Liver Diseases, Hadassah Medical Center, Hebrew University, Jerusalem, Israel; 12CHEO Inflammatory Bowel Disease Centre, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada; 13Department of Pediatrics and School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada; 14Institute for Clinical Evaluative Sciences, Ottawa, ON, Canada Background: Before embarking on administrative research, validated case ascertainment algorithms must be developed. We aimed at developing algorithms for identifying inflammatory bowel disease (IBD) patients, date of disease onset, and IBD type (Crohn’s disease [CD] vs ulcerative colitis [UC]) in the databases of the four Israeli Health Maintenance Organizations (HMOs) covering 98% of the population. Methods: Algorithms were developed on 5,131 IBD patients and 2,072 controls, following independent chart review (60% CD and 39% UC). We reviewed 942 different combinations of clinical parameters aided by mathematical modeling. The algorithms were validated on an independent cohort of 160,000 random subjects. Results: The combination of the following variables achieved the highest diagnostic accuracy: IBD-related codes, alone if more than five to six codes or combined with purchases of IBD-related medications (at least three purchases or ≥3 months from the first to last purchase) (sensitivity 89%, specificity 99%, positive predictive value [PPV] 92%, negative predictive value [NPV] 99%). A look-back period of 2–5 years (depending on the HMO) without IBD-related codes or medications best determined the date of diagnosis (sensitivity 83%, specificity 68%, PPV 82%, NPV 70%). IBD type was determined by the majority of CD/UC codes of the three recent contacts or the most recent when less than three contacts were recorded (sensitivity 92%, specificity 97%, PPV 97%, NPV 92%). Applying these algorithms, a total of 38,291 IBD patients were residing in Israel, corresponding to a prevalence rate of 459/100,000 (0.46%). Conclusion: The application of the validated algorithms to Israel’s administrative databases will now create a large and accurate ongoing population-based cohort of IBD patients for future administrative studies. Keywords: inflammatory bowel diseases, Crohn’s disease, ulcerative colitis, search algorithms, validation, case ascertainment, Israel, administrative database research

The growth pattern of infants from birth to 2 years of age was studied in a homogenous Moslem semirural community near Jerusalem. The weight of the study population was compared with that of children from a western neighbourhood in Jerusalem and the National Centre of Health Statistics standard. The Abu Ghosh children are lighter than the Jerusalem and the National Centre of Health Statistics populations at birth and subsequently at 1, 6, 12, and 24 months of age. The percentage of weight gain between any two measurements at the various ages is slightly lower than that of the Jerusalem population. There is no decline in percentage of weight gain after weaning. Birthweight has accounted for a high percentage of explained variance of weight at 6 months (14.4%), but explained only 1.2% of variance at 24 months. The percentage of girls below the 10th centile was less than that of boys. The genetic and environmental effects on growth as well as the effect of the mother and child health services on the child rearing patterns of the populations are discussed. [ABSTRACT FROM PUBLISHER]

CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5'-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.

Background: Explosion injuries to the upper extremity have specific clinical characteristics that differ from injuries due to other mechanisms., Objectives: To evaluate the upper extremity injury pattern of attacks on civilian targets, comparing bomb explosion injuries to gunshot injuries and their functional recovery using standard outcome measures., Methods: Of 157 patients admitted to the hospital between 2000 and 2004, 72 (46%) sustained explosion injuries and 85 (54%) gunshot injuries. The trauma registry files were reviewed and the patients completed the DASH Questionnaire (Disabilities of Arm, Shoulder and Hand) and SF-12 (Short Form-12) after a minimum period of 1 year., Results: Of the 157 patients, 72 (46%) had blast injuries and 85 (54%) had shooting injuries. The blast casualties had higher Injury Severity Scores (47% vs. 22% with a score of > 16, P = 0.02) and higher percent of patients treated in intensive care units (47% vs. 28%, P = 0.02). Although the Abbreviated Injury Scale score of the upper extremity injury was similar in the two groups, the blast casualties were found to have more bilateral and complex soft tissue injuries and were treated surgically more often. No difference was found in the SF-12 or DASH scores between the groups at follow up., Conclusions: The casualties with upper extremity blast injuries were more severely injured and sustained more bilateral and complex soft tissue injuries to the upper extremity. However, the rating of the local injury to the isolated limb is similar, as was the subjective functional recovery.

Background: Trauma management includes the care provided both in hospital and by emergency medical systems in the community. In many cases it is the parents who decide where to take an injured child for care, depending on the circumstances and severity of the injury, the personal characteristics of the injured or the carer and the availability and accessibility of services., Objectives: To examine the use of pre-hospitalization services and reasons for their use by children and adolescents according to the injury and personal characteristics., Methods: The study group comprised 924 Israeli citizens aged 0-17 years hospitalized for injuries in six hospitals across Israel. Carers were interviewed in the hospital regarding the circumstances of the injury event, the use of pre-hospitalization services, and sociodemographic characteristics. Data on the cause and nature of the injury were obtained from the hospital records., Results: The proportion of severe injuries (Injury Severity Score 16+) was higher in Arab children than Jewish children (15% and 9% respectively). Sixty-three percent of the Arab children and 39% of the Jewish children used community services prior to hospitalization. The odds ratio of proceeding directly to the hospital was 0.44, 95% confidence interval 0.29-0.69, for the Arab compared to the Jewish children, controlling for severity, cause and nature of the injury, sociodemographic characteristics, and the reported availability of ambulance services., Conclusions: More Arab than Jewish carers tended to seek care in the community for an injured child, but the effect of personal characteristics on seeking care was similar in both population groups. Issues of availability and accessibility of services may explain the differences.

Background: Head injuries, especially in young children, are frequent and may cause long-lasting impairments., Objectives: To investigate the outcome of head and other injuries caused by diverse mechanisms and of varied severity., Methods: The study population consisted of Jews and Arabs (n=792), aged 0-17 years old, hospitalized for injuries in six hospitals in Israel. Caregivers were interviewed during hospitalization regarding circumstances of the injury and sociodemographic variables. Information on injury mechanism, profile and severity, and length of hospitalization was gathered from the medical files. Five months post-injury the caregivers were interviewed by phone regarding physical limitations and stress symptoms., Results: Head injuries occurred in 60% of the children, and of these, 22.2% suffered traumatic brain injury with loss of consciousness (type 1). Among the rest, 22% of Jewish children and 28% of Arab children remained with at least one activity limitation, and no statistically significant differences were found among those with head or other injuries. The odds ratio for at least two stress symptoms was higher for children involved in transport-related injuries (OR 2.70, 95% confidence interval 1.38-5.28) than for other mechanisms, controlling for injury profile. No association was found between stress symptoms and injury severity., Conclusions: Most children had recovered by 5 months after the injury. Residual activity limitations were no different between those with head or with other injuries. Stress symptoms were related to transport-related injuries, but not to the presence of TBI or injury severity.

The p38 mitogen-activated protein kinases are activated in response to various extracellular signals in eukaryotic cells and play a critical role in the cellular responses to these signals. The four mammalian isoforms (p38alpha, p38beta, p38gamma, and p38delta) are coexpressed and coactivated in the same cells. The exact role of each p38 isoform has not been entirely identified, in part due to the inability to activate each member individually. This could be resolved by the use of intrinsically active mutants. Based on previous studies on yeast p38/Hog1 [Bell M, Capone R, Pashtan I, Levitzki A & Engelberg D (2001) J Biol Chem276, 25351-2538] and human p38alpha[Diskin R, Askari N, Capone R, Engelberg D & Livnah O (2004) J Biol Chem279, 47040-47049] we have generated intrinsically active p38beta, p38gamma and p38delta mutants. In addition, we have identified a new activating mutation site in p38alpha. Most of the activating mutations are located in the L16 loop, in which conformational changes were shown to induce activation. We show that these changes impose substantial autophosphorylation activity, providing a mechanistic explanation for the intrinsic activity of the mutants. The new active variants maintain specificity towards substrates and inhibitors similar to that of the parental wild-type proteins, and are phosphorylated by mitogen-activated protein kinase kinase 6, their upstream activator. Thus, we have completed the development of a series of intrinsically active mutants of all p38 isoforms. These active variants could now become powerful tools for the elucidating the activation mechanism and specific biological roles of each p38 isoform.

The p38 family of kinases is a subgroup of the mitogen-activated protein kinase family. It is composed of four isoforms and is involved in critical biological processes as well as in inflammatory diseases. The exact unique role of each p38 isoform in these processes is not understood well. To approach this question we have been developing intrinsically active variants of p38s. Recently we described a series of mutants of the human p38alpha, which were spontaneously active as recombinant proteins purified from Escherichia coli cells. We show here that some of these mutants are spontaneously active in several mammalian cells in culture. The spontaneous activity of some mutants is higher than the activity of the fully activated wild type counterpart. We further produced mutants of the other p38 isoforms and found that p38beta(D176A), p38gamma(D179A), p38delta(D176A), and p38delta(F324S) are spontaneously active in vivo. The active mutants are also spontaneously phosphorylated. To test whether the mutants actually fulfill downstream duties of p38 proteins, we tested their effect on activating protein 1(AP-1)-mediated transcription. Active mutants of p38alpha induced AP-1-driven reporter genes, as well as the c-jun and c-fos promoters. An active variant of p38gamma suppressed AP-1-mediated transcription. When active variants of p38alpha and p38gamma were co-expressed, AP-1 activity was not induced, showing that p38gamma is dominant over p38alpha with respect to AP-1 activation. Thus, intrinsically active variants that are spontaneously active in vivo have been obtained for all p38 isoforms. These variants have disclosed different effects of each isoform on AP-1 activity.

Background: Trauma systems were created in order to provide optimal care for trauma patients. Hence, patients transferred to level I trauma centers are assumed to be transferred due to medical reasons as a result of complex injuries., Objectives: To explore the reasons for transfer of patients from regional to level I trauma centers in Israel as a basis for establishing a national policy regarding transfers., Methods: The data on patients transferred to five level I trauma centers during a 6 month period were collected using a structured form., Results: The study population comprised 929 patients transferred from regional hospitals. Most transfers were due to the need for a specialty unavailable at the first hospital (65%) or for special diagnostic equipment (3% in Jews, 23% in Arabs). Only 3.6% of the transferred patients were transferred because of multi-system injury. Some casualties were transferred following their own request, 26% Jews and 3% Arabs., Conclusions: Most patient transfers concur with the recommendations of the Ministry of Health, namely, the absence of a certain specialty or equipment. The fact that many of the transfers reflect a lack of available resources at the first evacuation destination suggests that increasing the availability of these resources can help reduce secondary triage. It is recommended that a cost-benefit analysis be conducted.

Background: To determine whether there are inequalities in the incidence of fatal and non-fatal unintentional injuries among Jewish and Arab children in Israel., Methods: A nationwide random sample of injured children aged 0-17 attending emergency rooms (ER) during one year was selected (n = 11 058). The number of cases was weighted to 365 days and rates and odds ratios (OR) were calculated. Logistic regression was performed to study the OR of hospitalization in the total population and among Jews and Arabs controlling for independent variables., Results: The incidence of ER admissions among the Jews was 752.6/10 000 (95% CI: 738.1-767.1), 1.5 times higher than among the Arabs (492.8/10 000, 95% CI: 472.8-512.8). However, the rate of hospitalization was 1.1 times higher among Arabs than among Jews and the mortality rate was 3.2 times higher among Arabs than among Jews., Conclusions: The differences in injury rates for fatal and non-fatal injuries may be due to differences in the severity of injuries or in the use of services by the two populations. A study is underway to elucidate this point.

Background: Trauma is viewed by many as a global problem. The phenomenon of similar outcomes within differing healthcare delivery systems can illuminate the strengths and weaknesses of various trauma systems as well as the effects of these characteristics on patient outcome., Objectives: To compare and contrast demographic and injury characteristics as well as patient outcomes of two urban/suburban trauma centers, one in Israel and the other in the United States., Methods: Study data were obtained from the trauma registries of two trauma centers. Demographic variables, injury characteristics and outcomes were compared statistically between registries., Results: Significant differences between the registries were found in demographic variables (age), injury characteristics (Injury Severity Score and mechanism of injury), and outcome (mortality and length of stay). Age and Injury Severity Score were found to be significant predictors of outcome in both registries. The Glasgow Coma Score was found to contribute to patient outcomes more than the ISS. Differences were found in the relative impact of injury and demographic factors on outcomes between the registries. After including the influence of these factors on patient outcomes, significant differences still remained between the outcomes of the trauma centers., Conclusions: Despite possible explanations for these differences, true comparisons between centers are problematic.