The Task Force for the Promotion of the Status of Women in Medicine in Israel.

BACKGROUND: In this article, we offer a brief summary of the report from the Task Force for the Promotion of the Status of Women in Medicine in Israel. The task force, formed by the Israel Medical Association in 2013, published a comprehensive report in May 2015 dedicated to the promotion of equal opportunities for female doctors in the Israeli healthcare system and in the academic world. The aim of this paper is to present the work of the task force and to highlight its main principles and recommendations against the backdrop of the gender revolution in the Israeli healthcare system and worldwide.

Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia.

Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion.

Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome.

Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance.

Population history and infrequent mutations: how old is a rare mutation? GUCY2D as a worked example.

The mosaic pattern of haplotypes observed around a single mutation results from one or several founder events. The difficulties involved in calculating the age of the variant are greatly reduced by assuming a single event, but this simplification may bias analysis of the genealogy of the mutation. However, if it is assumed that more than one founder event occurred, the number of genealogies is very large and the likelihood of every possible tree could not be realistically calculated. A multipoint approach is required, given the number of independent variables needed to describe a complex bifurcating genealogy. Starting from the observation that a limited number of parameters is needed for calculation of the simplest models of bifurcating genealogies, we show that the probability density of a two-ancestor model genealogy can be simply described as an algebraic function in a closed form, two coalescence times being calculated simultaneously without compromising accuracy. Implementation in a Bayesian framework is facilitated by the simplicity of the function, which describes the reciprocal relationship between the region of complete linkage disequilibrium and the branch length of the tree. We illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations.

Homozygous CRYBB1 deletion mutation underlies autosomal recessive congenital cataract.

PURPOSE: Some 30% of cases of congenital cataract are genetic in origin, usually transmitted as an autosomal dominant trait. The molecular defects underlying some of these autosomal dominant cases have been identified and were demonstrated to be mostly mutations in crystallin genes. The autosomal recessive form of the disease is less frequent. To date, only four genes and three loci have been associated with autosomal recessive congenital cataract. Two extended unrelated consanguineous inbred Bedouin families from southern Israel presenting with autosomal recessive congenital nuclear cataract were studied. METHODS: Assuming a founder effect, homozygosity testing was performed using polymorphic microsatellite markers adjacent to each of 32 candidate genes. RESULTS: A locus on chromosome 22 surrounding marker D22S1167 demonstrated homozygosity only in affected individuals (lod score > 6.57 at theta = 0 for D22S1167). Two crystallin genes (CRYBB1 and CRYBA4) located within 0.1 cM on each side of this marker were sequenced. No mutations were found in CRYBA4. However, an identical homozygous delG168 mutation in exon 2 of CRYBB1 was discovered in affected individuals of both families, generating a frameshift leading to a missense protein sequence at amino acid 57 and truncation at amino acid 107 of the 252-amino-acid CRYBB1 protein. Denaturing [d]HPLC analysis of 100 Bedouin individuals unrelated to the affected families demonstrated no CRYBB1 mutations. CONCLUSIONS: CRYBB1 mutations have been shown to underlie autosomal dominant congenital cataract. The current study showed that a different mutation in the same gene causes an autosomal recessive form of the disease.

Different perceptions and attitudes regarding prenatal testing among service providers and consumers in Israel.

INTRODUCTION: The increasing number of prenatal tests for fetal abnormalities calls for a prenatal care policy which will reflect not only medical values, but also the needs and attitudes of the services' consumers. OBJECTIVES: To compare attitudes of prenatal service consumers and providers regarding extent of prenatal testing and to evaluate these attitudes in relation to sociodemographic and professional characteristics. METHODS: Women were interviewed by phone 5-8 weeks postpartum (n = 596) using a structured questionnaire. Health professionals (n = 351) completed a parallel questionnaire. RESULTS: Health professionals were significantly more supportive of comprehensive prenatal testing than women (61.1 vs. 34.1%, respectively). In a multivariable analysis, age over 35, Ashkenazi origin and being better informed regarding tests, predicted a preference for comprehensive testing among women. Among health professionals, predictors of that attitude were secularism and a paramedical profession. CONCLUSIONS: Providers and consumers of prenatal services differ in their perceptions and opinions. Policy makers should have mechanisms in place to properly represent this diversity.

Promoting Arab and Israeli cooperation: peacebuilding through health initiatives.

This article describes a positive experience in building Arab and Israeli cooperation through health initiatives. Over the past 10 years Israeli, Jordanian, and Palestinian health professionals have worked together through the Canada International Scientific Exchange Program (CISEPO). In the initial project, nearly 17,000 Arab and Israeli newborn babies were tested for early detection of hearing loss, an important health issue for the region. The network has grown to address additional needs, including mother-child health, nutrition, infectious diseases, and youth health. Our guiding model emphasises two goals: project-specific outcomes in health improvement, and broader effects on cross-border cooperation. Lessons learned from this experience and the model provide direction for ways that health professionals can contribute to peacebuilding.

Primary congenital glaucoma presenting within the first three months of life in a Bedouin population: prognostic factors.

OBJECTIVES: To analyze the final outcome of surgery in Arab-Bedouin children with primary congenital glaucoma (PCG) presenting within the first three months of life, and to search for prognostic factors for success. DESIGN: Retrospective study of all cases with follow-up of at least 24 months. PATIENTS: Twenty-five Arab-Bedouin children (45 eyes) with PCG presenting within the first three months of life who underwent surgical procedures at the Soroka University Medical Center from January 1988 to December 1998. METHODS: Patient's age, family history, main presenting features, data from examinations under anesthesia, including intraocular pressure (IOP), horizontal corneal diameter, and cup/disc (c/d) ratio, and the type of surgery performed were reviewed. MAIN OUTCOME MEASURES: Success of the first operation, defined as final IOP < 21 mm Hg achieved after only one surgical procedure without anti-glaucoma medication, and final outcome, defined as good when IOP was < 21 mm Hg and > 5 mm Hg at the end of a 24-month follow-up period without anti-glaucoma medication, irrespective of the number of procedures performed. RESULTS: At presentation mean IOP was 36.2 +/- 8.0 mm Hg, corneal diameter was 12.62 +/- 0.98 mm, and c/d ratio was 0.41 +/- 0.16. The mean age at first operation was 17 +/- 20 days, and median of 5 days. The mean follow-up period was 37.4 +/- 25.4 months. The success of the first operation performed was not related to the type of operation (P = 0.22), gender (P = 0.47), consanguinity (P = 1.0), family history (P = 0.12), clinical presentation (P = 0.81), or age at first operation (P = 0.38). Eyes with high initial IOP and greater c/d ratio were at a significantly higher risk for failure (P = 0.05, P = 0.04, respectively). A final outcome of IOP under 21 mm Hg and above 5 mm Hg was achieved in 39 eyes (86.5%). There was no statistical association between final outcome and the type of first surgical procedure performed, gender, consanguinity, clinical presentation, and age at first operation. Cases with no family history had a significantly better final outcome (P = 0.05). In multivariate analysis only initial IOP showed borderline significance as an independent risk factor for final outcome (P = 0.06). CONCLUSIONS: Initial high IOP and higher c/d ratio were found to be predictive factors for failure of the first procedure. Final outcome was significantly better in cases with no family history, yet initial IOP was the only independent predictive factor for failure at the final outcome in a multivariate model. Findings of this type have not been previously reported, and they may constitute an important tool in predicting the treatment outcome of very young children with PCG.

HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease.

Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1. Nineteen celiac disease patients had at least one DQA1*05 DQB1*02 genotype (= DQ2), 4 affecteds had the second most common genotype of DQA1*03 DQB1*0302 (= DQ8), 9 were DQ2 and DQ8, and 4 had at least one copy of DQB1*02 without the DQA1*05 genotype. Using transmission disequilibrium testing, we observed a significant over-representation in affecteds of the DQA1*05 DQB1*02 genotype (p = 0.0089), as well as over-representation of the DQA1*03 DQB1*0302 genotype (p = 0.078). The HLA DQA1 DQB1 high-risk genotypes associated with celiac disease are similar in these Bedouin families with CD to what is observed in Northern and Southern Europeans.

[A comprehensive program for prevention of genetic diseases among Arabs in Israel].

Genetic diseases are relatively prevalent among the Arab population, and are a significant cause of morbidity and mortality in this population. The relative high rate of genetic diseases among the Arabs in Israel is a direct result of very high rates of consanguinity. In order to reduce the frequency of congenital malformations/inherited diseases, it is important to choose combined strategies, including efforts focused on health education and health promotion, with an emphasis on the medical consequences of marriages within the family. Primary prevention is conducted by genetic counseling prior to marriage or prior to the first pregnancy and secondary prevention focuses on early genetic screening during the pregnancy. In order to provide the necessary tools for such a program, genetic research must first characterize the common genetic diseases in the small communities, and identify their responsible mutations.

Congenital glaucoma: CYP1B1 mutations in Israeli Bedouin kindreds.

PURPOSE: To investigate CYP1B1 gene mutations in Arab-Bedouin Israeli patients with primary congenital glaucoma (PCG). METHODS: Testing linkage to candidate genes using adjacent polymorphic markers and sequencing of genomic DNA samples by standard methods. RESULTS: In 9 of 11 unrelated affected Israeli Bedouin families, PCG was associated with homozygosity of 3 different CYP1B1 mutations. As in Saudi Arabian families, the 3987G>A CYP1B1 substitution accounted for approximately 50% of cases. A novel CYP1B1 mutation, 8405G>A, was found in 2 unrelated families. In 2 consanguineous families, there was no evidence of homozygosity or mutations in CYP1B1. CONCLUSIONS: CYP1B1 mutations account for the majority of cases of PCG in the Israeli Bedouin population. The most frequently found CYP1B1 mutation (3987G>A) in our study is also the commonest CYP1B1 mutation in the Saudi Arabian population, in line with the common genetic background of both populations. The absence of homozygosity in the CYP1B1 locus in the affected individuals in 2 consanguineous inbred families, suggests that other genes take part in the causation of congenital glaucomas. This is the first study describing the genetic basis of PCG among Israeli Arab-Bedouin individuals, in whom the frequency of the disease is the highest in the world. Further similar studies based on new diagnosed patients are needed to possibly prevent, screen, and treat (antenatal and postnatal) this sight-devastating childhood disease.

A targeted population carrier screening program for severe and frequent genetic diseases in Israel.

A national carrier screening program targeted at communities in which severe genetic diseases are present with a frequency higher than 1/1000 live births, has been in existence in Israel since 2002. Within the communities at risk, carrier screening is voluntary whereas genetic counseling and testing is provided free of charge. During the first 5 years of the program more than 13 000 tests were performed, and at the end of 2007 it was offered in 35 different localities/communities for a total of 36 diseases. Many of the couples identified to be at risk opted for prenatal diagnosis and in two cases an affected pregnancy was terminated. In some cases the couples declined prenatal diagnosis and two of those families gave birth to an affected child. Based on the experience learnt from this targeted screening program it appears that a knowledge-based, voluntary screening program operated within the community is an effective way to provide genetic services and test referrals. The community program directed toward couples in their reproductive period does not seem to have led to stigmatization at either the individual or the community level.

Attitudes toward the acceptability of reasons for pregnancy termination due to fetal abnormalities among prenatal care providers and consumers in Israel.

OBJECTIVES/BACKGROUND: Current prenatal diagnostic abilities confront parents and health professionals with complicated issues regarding termination of pregnancy (TOP) due to fetal abnormalities. 1. To assess and compare attitudes of consumers (women) and providers (health professionals) of prenatal care regarding TOP due to fetal abnormality.2. To identify factors related to these attitudes. METHODS: The study was conducted in southern Israel. Consumers (596) were interviewed by phone 5-8 weeks postpartum. Health professionals (351) filled out a self-administrated questionnaire. RESULTS: More than half of the interviewees approved of TOP due to mental retardation, death during infancy, severe physical disability and very low quality of life (in descending order). For each condition, care providers were significantly more supportive of TOP than women, and had far fewer hesitations. The hierarchy of 'TOP acceptability' was similar in both populations. Factors associated with women's attitudes were degree of religiosity, Ashkenazi origin and country of birth. Two approaches toward TOP were identified: 'consistent' versus 'ad hoc'. CONCLUSIONS: Prenatal care providers and consumers differ in their attitudes regarding acceptability of reasons for TOP. Care providers offering prenatal tests should be aware of their patients' attitudes, in order to guide informed decisions regarding the tests.