Search

Physiological and psychological distress may accelerate cellular aging, manifested by shortening of telomere length (TL). The present study focused on TL shortening in anorexia nervosa (AN), an illness combining physiological and psychological distress. For that purpose, we measured TL in 44 female adolescents with AN at admission to inpatient treatment, in a subset of 18 patients also at discharge, and in 22 controls. No differences in TL were found between patients with AN and controls. At admission, patients with AN-binge/purge type (AN-B/P; n = 18) showed shorter TL compared with patients with AN-restricting type (AN-R; n = 26). No change in TL was found from admission to discharge, despite an improvement in body mass index standard deviation score (BMI-SDS) following inpatient treatment. Older age was the only parameter assessed to be correlated with greater TL shortening. Several methodological changes have to be undertaken to better understand the putative association of shorter TL with B/P behaviors, including increasing the sample size and the assessment of the relevant pathological eating disorder (ED) and non-ED psychological correlates in the two AN subtypes.

Background and ObjectivesTo explore the clinical characteristics and HLA associations of patients with anti–leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients.MethodsSeventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples.ResultsOur cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9p< 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1p< 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2p< 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9p< 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles.DiscussionOur cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

ObjectiveExploring the clinical characteristics and HLA associations of patients with anti-leucine–rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in IsraelBackgroundAnti-LGI1E is one of the most commonly diagnosed antibody-associated encephalitic syndromes in adults. Recent studies of various populations reveal significant associations with specific Human Leukocyte Antigen (HLA) genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients.Design/MethodsSeventeen consecutive anti-LGI1E patients diagnosed at Tel Aviv Sourasky Medical Center between the years 2011-2018 were included. HLA typing was performed using NGS methodology at the tissue typing laboratory of Sheba Medical Center and compared to data from the "Ezer Mizion" Bone Marrow Donor Registry, containing over 1,000,000 samples.ResultsOur cohort displayed a male predominance and median age of onset in the 7th decade, as previously reported. All patients responded to immunotherapy, though residual damage was not uncommon (23% with MRS >1). HLA analysis revealed overexpression of DRB1*07:01 (OR 13, CI 0.6 p < 1.e-10) and DRB1*04:02 (OR 12, CI-0.6 p < 1.e-10), as previously reported, as well as of the DQ alleles DQB1*02:02 (OR 12, CI 0.6 p < 1.e-10), DQB1*03:03 (OR 27, CI 0.9 p < 1.e-10), previously attributed to linkage disequilibrium (LD) with the mentioned DR alleles. An additional allele overexpressed among our patients was the DQB1*03:02 allele (OR 12, CI 0.6 p < 1.e-10), which appeared in complete LD with DRB1*04:02. Linkage disequilibrium analysis performed on patients and controls suggests these DR-DQ associations are unique to anti-LGI1E patients. In silico predictions performed for the overexpressed DQ alleles reveal them to be strong binders of LGI1 derived peptides, and suggest a correlation between peptide binding sites of paired DR-DQ alleles.ConclusionsOur findings shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying the possible relevance of certain DQ alleles as well as DR-DQ interactions.

A comprehensive study of unusual cases of placental pathology may provide insight into mechanisms of normal human fertilization and early embryonic development by examining the exception to the rule. A gravida three para two 39-year-old woman was monitored by ultrasound from 16 weeks of gestation for cystic placenta. A female newborn was born at 36 weeks gestation. Pathologic examination of the partially cystic placenta revealed a singleton placenta comprised of 2/3 normal placenta and 1/3 complete hydatidiform mole, largely degenerated. Immunostaining for p57 was negative in stromal cells of the molar villi. Chromogenic in-situ hybridization revealed diploidy in both normal and molar parts. A total of 16 microsatellites were studied by short tandem repeat analysis, 11 of which were informative. The analysis revealed bipaternal molar tissue of dispermic origin. The paternal monospermic contribution to the normal part was different from that in the molar part, thus resulting in tripaternal contribution to the conceptus. A chimera is a single organism composed of two or more different populations of genetically distinct cells that originated from different zygotes (tetragametic) whereas mosaic is a mixture of two cell lines in one organism originating from one zygote. The possible mechanisms leading to the formation of chimeric/mosaic placenta in our case (one of the components being complete hydatidiform mole), including twinning, fusion at an early embryonic stage and diploidization of triploids, are discussed.

Background Ethnicity may affect graft longevity and recipient mortality after heart transplantation (HTx). We hypothesized that differences in ethnic origin between Arabs and Jews undergoing HTx in Israel may contribute to differences in long-term outcomes. Methods The study population comprised all 254 patients who underwent HTx between 1991 and 2017 in a tertiary medical center located in the center of Israel. Patients were categorized as either Jews (226 patients, 89%) or Arabs (28 patients, 11%). The primary end point was cardiac allograft vasculopathy (CAV), secondary end points were cardiovascular (CV) mortality and the combined end point of CAV/CV mortality. Results In comparison with Jews, Arab patients were significantly younger (ave. age 42 vs. 50) and had shorter in-hospital stay (45 vs. 80 days). However, Kaplan-Meier survival analysis showed that at 10 years of follow-up CAV rates were significantly higher among Arabs (58%) compared with Jews (23%; log-rank P = 0.01) for the overall difference during follow-up. Similar results were shown for the separate end point of CV mortality and the combined end point of CAV/CV mortality. Multivariate analysis, which controlled for age, gender, statin treatment, and other potential confounders, showed that Arab recipient ethnic origin was associated with a significant > 2.5-fold (p = 0.01) increase in the risk for CAV; a > 4-fold increase in the risk for CV mortality (p = 0.001); and approximately 4-fold increase in the risk for the combined end point (p = 0.001). These findings were validated by propensity score analysis. Conclusions Our data suggest that Arab ethnic origin is associated with a significantly increased risk for CAV and mortality following HTx. Suggested explanations contributing to ethnic disparities in Israel include socioeconomic, environmental and genetic factors. Further studies are required to evaluate whether more aggressive risk factor management in the Israeli Arab population following HTx would reduce CAV and CV mortality in this high-risk population. Increased awareness and early intervention of the Israeli healthcare system and cooperation with the Arab community is of paramount importance.

BACKGROUND The impact of donor-recipient ethnic matching on heart transplantation (HT) has been poorly studied with inconclusive results. We aimed to investigate the impact of ethnic matching on HT outcomes in Israeli multiethnic patients. METHODS The study comprised 168 patients who underwent HT from 1990-2017. Patients and their donors were ethnically categorized to Jews and Arabs. Primary end points were all-cause in-hospital and late mortality; secondary end points included primary graft dysfunction (PGD), rejections, and vasculopathy. RESULTS Donor-recipient ethnic matching was found in 111 patients, while 57 were ethnically mismatched. Baseline characteristics were similar in both groups. Ethnic mismatching was associated with >7-fold (P = 0.018) increased risk for in-hospital mortality and >8-fold (P

Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies.

BACKGROUND: Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder in the fetus or neonate caused by maternal alloantibodies directed against fetal platelet (PLT) antigens inherited from the father. The immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs), usually DRB3*0101 leading to an immune response. STUDY DESIGN AND METHODS: In this study our aims were to find whether other allele variants of the β subunit of the HLA-DR family specifically focused on the HLA residues that bind Position 33 of the HPA-1 integrin contribute to FNAIT development and affect response to treatment and whether coexistence of both anti-HPA-1a and anti-HLA Class I specific against the father's antigens leads to a more severe thrombocytopenia in the newborn. We examine the genotype of 23 mothers to newborns with FNAIT compared to a control group. RESULTS: Our results suggested that, when HPA-1 incompatibility with the husband is found, the presence of two HLA alleles (DRB3*01:01 and DRB4*01:01) in the mother increases the risk and severity of FNAIT and reduces the success of a preventive immunoglobulin G treatment. We provide a structural model for the molecular basis of the rational effects of the different HLA alleles. In addition, we found that the presence of both anti-HPA-1 and anti-HLAs did not aggravate FNAIT in comparison to mothers harboring only anti-HPA-1. CONCLUSION: Overall, we suggest that a specific genotyping of the mother in relation to HLA-DRB as well as HPA-1 can serve as an antenatal diagnostic tool, particularly in siblings of women who gave birth to neonates with FNAIT.

JAK2 V617F mutation is found in a high proportion of MPD patients. We developed a quantitative assay for the detection of the JAK2 mutation and demonstrated its clinical utility in MPD patients who underwent SCT. Sixty percent of the patients were JAK2 V617F positive prior to the SCT (mean mutation levels 74%, range 16-98%). After the procedure, the mutation levels progressively decreased and were in correlation with the donor-recipient chimerism status (r=0.97, p

The aims of our research were to define the genotype-phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype-phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-L: -erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.

Human leukocyte antigen-G (HLA-G) belongs to the nonclassical HLA class I family of genes presently designated as class Ib genes. It was found to be expressed mainly in placental tissue and in the thymus. Expression of HLA-G is induced by lymphokines such as interleukin-10 and has been associated with the escape of tumor cells from immune surveillance or with inhibition of graft rejection. In this report, Epstein-Barr virus-transformed B-cell lines established from peripheral blood lymphocytes from healthy volunteers were studied. Our results show that EBV-transformed B-cell lines, but not freshly separated peripheral blood lymphocytes, can be induced to express HLA-G either by subjecting the cultures to nutrient deficiency to hypoxia or to both, however, not all cell lines responded equally to stress conditions. The association of HLA-G with certain cancer transformations may suggest that the resistance to HLA-G expression could be related to susceptibility to the development of malignancy.

Context: Several studies assessed adiponectin levels in anorexia nervosa (AN) patients, however, data regarding the dynamics of changes in adiponectin levels during refeeding of these patients is limited and contradicting. Objective: Our objective was to assess adiponectin levels and the distribution of its different isoforms in AN patients before and after long-term refeeding, and to relate them to alterations in body mass index, leptin, insulin sensitivity, and additional endocrine parameters. Design, Setting, and Participants: We conducted a longitudinal controlled study of 38 female adolescent malnourished AN inpatients, with 13 young, lean, healthy women serving as controls. Blood samples were obtained upon admission and thereafter at 1, 3, and 5 months (at target weight). Main Outcome Measures: Changes in body mass index, leptin, adiponectin, insulin sensitivity, and adiponectin multimeric forms were measured. Results: At admission, leptin levels of AN patients were significantly lower, whereas insulin sensitivity (assessed by homeostasis model assessment-insulin resistance), adiponectin levels, and the ratio of high molecular weight (HMW) adiponectin to total adiponectin were significantly higher compared with controls. During weight recovery, leptin levels and homeostasis model assessment-insulin resistance increased significantly, whereas adiponectin and HMW adiponectin/total adiponectin ratio decreased significantly, to levels similar to controls. An initial increase in adiponectin levels was observed after 1 month of refeeding. There was no correlation between adiponectin and either T4 or cortisol levels. Conclusions: Our study demonstrates hyperadiponectinemia, increased adiponectin HMW isoform, and increased insulin sensitivity in adolescent AN female patients and reversal of these findings with weight rehabilitation. We hypothesize that increased adiponectin levels may have a protective role in maintaining energy homeostasis during extreme malnourishment.

Contains fulltext : 52708.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To examine plasma homocysteine, vitamin B(12), and folate levels in females with restricting and bingeing/purging eating disorders (EDs). METHOD: Adolescent and adult female patients were compared to appropriate control groups with regard to plasma homocysteine levels. RESULTS: The plasma homocysteine level of the adult ED patients was higher than that of controls for all age groups examined. In adolescents, no significant difference was found comparing ED patients younger than 16 years of age to control data, whereas in the 16-20 year age group, the plasma homocysteine level was significantly higher among the ED group, regardless of the type of ED. Vitamin B(12) and folate levels were within normal limits in all ED groups. CONCLUSION: Elevated plasma homocysteine levels were found in adult and older adolescent female ED patients (but not in younger adolescents) compared to controls. This finding is not related to deficiencies in vitamin B(12) or folate.

Each person expresses a potentially unique subset of ∼ 400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the "olfactory fingerprint." Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P < 10(-10)), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10(-4)), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10(-6)). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information.

BACKGROUND: Several studies have shown that women with unexplained recurrent miscarriage (RM) have increased numbers and activity of peripheral blood NK cells and that elevated levels of these cells predict subsequent miscarriages in women with RM. Because catecholamines rapidly mobilize NK cells into the circulation, such increases may not reflect a steady state of overactive immunity but may result from a transient increase in the number of NK cells because of the stress associated with blood withdrawal. METHODS: Blood was drawn from 22 controls and 38 RM patients immediately after vein cannulation, and again 20 min later. The percentage of NK cells within lymphocytes, their concentration per microlitre of blood and their activity were assessed. RESULTS: All three indices of NK cells did not change in the controls across the two samples. However, women with RM had elevated levels in all three NK indices in the first blood sample, but these levels declined to values similar to those seen in the controls. This decline was mainly observed in primary aborters whose NK activity was highest in the first blood withdrawal. Accordingly, there was a high correlation between the magnitude of the decline and the initial NK cell indices in women with RM. The change in activity highly correlated with the change in the concentration of NK cells. CONCLUSION: The increased NK number and activity previously observed in RM patients may result from a transient stress response at the time of blood withdrawal. Patients with primary RM may be characterized by exaggerated acute stress responses in other circumstances.

Pemphigus vulgaris (PV) is a human leukocute antigen (HLA) class II-associated autoimmune disease of the skin of unknown etiology. We recently described the association of pemphigus vulgaris with two clusters of microsatellite loci within the major histocompatibility complex region. One cluster includes the microsatellite marker TAP1CA, located in proximity to the transporter associated with antigen processing (TAP) genes. These genes are essential for class I antigen processing machinery and could be an additional set of genes involved in susceptibility to PV. The aim of this study was to investigate a possible association between TAP gene polymorphisms and PV. For this purpose we examined 37 unrelated Jewish Israeli patients with PV and compared them with 37 healthy Israeli Jewish HLA-matched controls. Significant differences were detected in TAP2 amino acid residues (p = 0.001). Two PV TAP2 risk alleles were identified (TAP2*C and TAP2*D), the frequency of which was estimated to be 37.8% in the patients and 5.3 % in the controls. This association was found to be independent of HLA-DR. It is therefore likely that TAP2 genes are involved in susceptibility to development of PV.

Nineteen female adolescent inpatients diagnosed with anorexia nervosa, restricting type (AN-R) and 16 non-eating disordered (ED) controls were assessed for plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulphate (DHEA-S), and cortisol levels, and for eating-related and non-eating-related psychopathology. AN-R patients were assessed at admission, 1 month and 4 months following hospitalization. The non-ED controls were assessed once. No baseline between-group differences were found in plasma cortisol, DHEA, and DHEA-S levels, whereas the patient group had a significantly lower Cortisol/DHEA-S ratio and elevated scores on most psychopathological parameters. A significant increase was found in the body mass index of the AN-R patients at 4 months post-hospitalization, accompanied by a decrease in plasma cortisol levels and a trend towards decreased Cortisol/DHEA and Cortisol/DHEA-S ratios, whereas no change occurred in psychopathology. The difference in Cortisol/DHEA-S ratio between AN-R patients and non-ED controls, and the different patterns of change in cortisol vs. DHEA(-S) levels following weight restoration, may in part account for the feeding difficulties in AN, particularly during refeeding.

Pemphigus is a group of autoimmune blistering diseases of the skin and mucous membranes. The association of pemphigus with human leukocyte antigen (HLA) is widely accepted. It was described in many ethnic groups and in most countries of the world. Studies showed that the associated HLA haplotype in Jewish pemphigus vulgaris (PV) patients is HLA-B38, DRB1*0402, and DQB1*0302; or HLA-B35, DRB1*0402, and DQB1*0302. Similar associations with class II genes were found in Spanish non-Jewish PV patients. As Jews lived in Spain for hundreds of years and many converted to Christianity, the presence of the same HLA haplotype in the Jewish and Spanish PV suggests that they may share the same founder. Microsatellite markers which span the entire major histocompatibility complex (MHC) locus were used as genetic probes. They were utilized to dissect the MHC region in the search for possible common haplotypes, besides HLA, which may provide an answer to this question. It was found that in both cohorts, in addition to HLA class II genes, there are probably genes in the class I region which are associated with PV. Alleles belonging to the associated markers were used to construct haplotypes and to estimate genetic distances. The distance between the two PV cohorts is relatively short, but the distance between the Jewish patients and the Jewish controls is greater compared to the distance between Spanish patients and Spanish controls. In both PV populations, the same microsatellite haplotypes in addition to a common class II haplotype were found, suggesting that both patient populations originated from the same genetic stock and, therefore, share the same ancestral disease gene.

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.

Pemphigus vulgaris (PV) is the most severe autoimmune blistering disorder of the skin that is mediated by circulating autoantibodies against desmoglein 3 (Dsg3). It has been reported that in Jews the associated haplotype in PV is human leukocyte antigen (HLA) B38, DRB1*0402, DQB1*0302. Significant associations with HLA were observed also in non-Jews. Dsg3-specific T-cell responses were detected in PV patients but also in healthy individuals who were either carriers of the PV-associated DRB1*0402 allele or alleles that share similar or identical peptide binding motifs to DRB1*0402. This suggests that genes other than the classical major histocompatibility complex (MHC) genes are associated with the development of the autoimmune response. We used 16 microsatellite probes that span the entire MHC region to screen DNA samples from 38 PV patients and 76 healthy controls. Results demonstrated that some markers were associated with class II region including a TAP associated marker. However, four probes, D6S265, C_527, D6S510, and MOGC, which are all mapped to the region of HLA-A, were highly associated with PV. These results suggest that a gene, or genes in the class I region are important in the initiation of the autoimmune cascade. Activation/suppression of these genes might act as the trigger mechanism that starts the autoimmune destructive process.

Objective To compare peripheral natural-killer (NK) cell numbers and activity in women with primary recurrent miscarriage, secondary recurrent miscarriage and controls. Design Observational study. Setting Academic medical center. Patient(s) Thirty-eight women with primary recurrent miscarriage, 29 women with secondary recurrent miscarriage, and 25 control women. Intervention(s) None. Main outcome measure(s) [1] The proportion of NK cells in the total lymphocyte population, [2] the concentration of NK cells per microliter of blood, and [3] NK activity (NKA), using both standard and whole-blood assays. Result(s) Primary aborters had the highest proportion and concentration of NK cells and had the highest activity using the standard assay. Secondary aborters had an intermediate level of these NK cell indices, whereas the control patients had the lowest levels. Using the whole-blood NKA assay, the differences between primary and secondary aborters were most apparent: primary aborters had significantly higher NKA than did either secondary aborters or control women (72, 40, and 35 lytic units, respectively). Approximately 50% of the variability in NKA could be attributed to differences in concentrations of NK cell per microliter of blood. Conclusion(s) The higher NKA evident in primary recurrent miscarriage and the reported higher efficacy of immunotherapy in primary aborters support the involvement of NK cells in the etiology of primary recurrent miscarriage.

Benign familial leukopenia (BFL) has been reported in several ethnic groups, including Ethiopians of Jewish origin. To date, there are no reported cases of patients with BFL developing granulocytopenia following administration of neuroleptics. We report a case of a young Ethiopian Jew suffering from schizophrenia, who exhibited premorbid benign reduced white blood cells (WBC) count and developed leukopenia and neutropenia following exposure to typical (zuclopentixol, perphenazine, haloperidol) antipsychotics and the atypical antipsychotic risperidone. The diagnosis of BFL was established and tissue typing of the patient was determined. To the best of our knowledge, this is the first report of leukopenia with neutropenia in an ethnically susceptible (due to BFL) schizophrenia patient following exposure to typical and atypical antipsychotics. HLA typing of this patient was distinct from that reported in patients susceptible to clozapine-induced agranulocytosis. Further extensive investigations including HLA typing in a larger cohort of schizophrenic patients is needed in order to define the association between HLA haplotypes and neuroleptic-induced hematological reactions and to identify the potentially vulnerable individuals.

Background A monochorionic-diamniotic placenta (MCDAP) is rare in dizygotic (DZ) twinning. All reported cases have been documented in pregnancies achieved by the induction of ovulation alone or during the IVF cycle. Methods and Results We report a spontaneous pregnancy in a 39-year-old patient with evidence of MCDAP in DZ twins, discordant for trisomy 21. The first and second-trimester sonographic scans indicated male twins with MCDAP. Amniocentesis, performed because of advanced maternal age, revealed a normal karyotype in one fetus, and trisomy 21 in the other. Molecular studies, performed in order to confirm the zygosity and chorionicity, demonstrated that the fetuses were DZ. In order to identity the affected twin, a detailed sonographic examination was repeated, but no abnormal findings associated with Down syndrome were demonstrated in any of the fetuses. Therefore, umbilical cord blood samples were obtained from both fetuses. Chromosomal analysis revealed in both fetuses two cell lines: a normal cell line of 46,XY and a 47,XY,+ 21 cell line, in 65 and 80% of the cells, respectively. This result was independently confirmed by both FISH and G-banding. DNA extracted from both cord blood samples demonstrated an admixture of two distinct genotypes in each sample. Conclusions We propose that this case represents a monochorionic-dizygotic twin pregnancy with blood chimerism. The most plausible mechanism underlying this phenomenon is placental fusion early in pregnancy, resulting in an architecturally single placenta originating from two distinct zygotes. The newly formed blood vessels created anastomoses between the DZ twins and allowed reciprocal blood chimerism between the normal and the trisomic twin. Copyright © 2006 John Wiley & Sons, Ltd.

Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, and a high incidence of myelodysplasia and acute myeloid leukemia. Stem cell transplantation is the only curative treatment. In the absence of matched- sibling donor, an alternative mismatched family or matched unrelated donor can be used, but the results are inferior to the matched-sibling transplant and carry a high risk of morbidity and mortality. Preimplantation genetic diagnosis (PGD) has been increasingly used in recent years for mutation analysis for many genetic disorders and results in the birth of healthy children, saving the need for the termination of pregnancy of an affected embryo. The use of PGD for combined analysis of mutation and HLA-matching was reported for the first time in 2001. This enables the birth of an unaffected child who can serve as a donor for an affected sibling in need for stem cell transplantation. We report successful cord blood transplantation for a Fanconi anemia patient from his HLA-matched sibling, born after PGD that included mutation analysis for Fanconi anemia and HLA typing. PGD can provide an unaffected donor for a sibling affected by genetic disease in the absence of a compatible related donor.

Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder in the fetus or neonate caused by maternal alloantibodies directed against fetal platelet (PLT) antigens inherited from the father. The immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs), usually DRB3*0101 leading to an immune response.In this study our aims were to find whether other allele variants of the β subunit of the HLA-DR family specifically focused on the HLA residues that bind Position 33 of the HPA-1 integrin contribute to FNAIT development and affect response to treatment and whether coexistence of both anti-HPA-1a and anti-HLA class I specific against the father's antigens leads to a more severe thrombocytopenia in the newborn. We examine the genotype of 23 mothers to newborns with FNAIT compared to a control group.Our results suggested that, when HPA-1 incompatibility with the husband is found, the presence of two HLA alleles (DRB3*01:01 and DRB4*01:01) in the mother increases the risk and severity of FNAIT and reduces the success of a preventive immunoglobulin G treatment. We provide a structural model for the molecular basis of the rational effects of the different HLA alleles. In addition, we found that the presence of both anti-HPA-1 and anti-HLAs did not aggravate FNAIT in comparison to mothers harboring only anti-HPA-1.Overall, we suggest that a specific genotyping of the mother in relation to HLA-DRB as well as HPA-1 can serve as an antenatal diagnostic tool, particularly in siblings of women who gave birth to neonates with FNAIT.

Prostate cancer is the most common non-dermatologic malignancy in men in the Western world. Recently, a frequent chromosomal aberration fusing androgen regulated TMPRSS2 promoter and the ERG gene (TMPRSS2/ERG) was discovered in prostate cancer. Several studies demonstrated cooperation between TMPRSS2/ERG and other defective pathways in cancer progression. However, the unveiling of more specific pathways in which TMPRSS2/ERG takes part, requires further investigation. Using immortalized prostate epithelial cells we were able to show that TMPRSS2/ERG over-expressing cells undergo an Epithelial to Mesenchymal Transition (EMT), manifested by acquisition of mesenchymal morphology and markers as well as migration and invasion capabilities. These findings were corroborated in vivo, where the control cells gave rise to discrete nodules while the TMPRSS2/ERG-expressing cells formed malignant tumors, which expressed EMT markers. To further investigate the general transcription scheme induced by TMPRSS2/ERG, cells were subjected to a microarray analysis that revealed a distinct EMT expression program, including up-regulation of the EMT facilitators, ZEB1 and ZEB2, and down-regulation of the epithelial marker CDH1(E-Cadherin). A chromatin immunoprecipitation assay revealed direct binding of TMPRSS2/ERG to the promoter of ZEB1 but not ZEB2. However, TMPRSS2/ERG was able to bind the promoters of the ZEB2 modulators, IL1R2 and SPINT1. This set of experiments further illuminates the mechanism by which the TMPRSS2/ERG fusion affects prostate cancer progression and might assist in targeting TMPRSS2/ERG and its downstream targets in future drug design efforts.

The circular dichroism spectrum of barnase has been analyzed by examining the spectra of a series of mutants in which every single aromatic residue has been replaced. The spectrum of wild-type barnase is quite atypical for a protein of the alpha + beta class, with very low intensities and a minimum in the far-UV at 231 nm. The minimum at 231 nm is associated with the presence of Trp-94. Many other mutations involving aromatic residues have an effect on the spectral features in the far-UV. The major features in the near-UV spectra arise from essentially additive contributions of the three tryptophan residues Trp-35, Trp-71, and Trp-94. Tyrosine contributions are less prominent, with Tyr-78 and Tyr-97 contributing the most to the CD spectrum. The close charge-aromatic interaction between Trp-94 and His-18, which is important for the fluorescence properties of the protein, contributes little to the CD spectrum, as does the close aromatic-aromatic interaction between Tyr-13 and Tyr-17. However, the observed near-UV spectrum of wild-type barnase could not be simulated by the sum of the contributions of aromatic residues defined by difference spectra of protein variants carrying aromatic residues. Aromatic residues play an important role in determining the circular dichroism spectrum of proteins not only in the near-UV but also in the far-UV region.

Aromatic side-chains are found in the vicinity of histidine residues in many proteins and protein complexes. We have studied the interaction between a histidine residue (His18) and aromatic residues at position 94 in barnase. Three different techniques have been applied to show that Trp94 interacts more strongly with the protonated form of His18. The aromatic-histidine interaction stabilizes the protonated form of histidine by 0.8 to 1 kcal mol-1 relative to the unprotonated and, thereby, increases its pKa value. This was shown indirectly from the pH dependence of the stability of the wild-type protein and the mutant Trp94----Leu; and directly from the difference in pKa of His18 between wild-type barnase and the same mutant protein, and from double-mutant cycles that measure the total interaction energy of Trp94 with His18 at both low and high pH. When Trp94 is replaced by other aromatic amino acids, the strength of the interaction decreases in the series His-Trp greater than His-Tyr greater than His-Phe. The interaction is not masked by high salt concentrations. The raising of the pKa value of His18 by interaction with Trp94 is shown to be consistent with solution studies with model compounds. The histidine-aromatic interaction could have implications in binding and catalysis for modulation of the histidine pKa value.

A multifrequency phase fluorometric study is described for wild-type barnase and engineered mutant proteins in which tryptophan residues have been replaced by less fluorescent residues which do not interfere with the determination of the tryptophan emission spectra and lifetimes. The lifetimes of the three tryptophans in the wild-type protein have been resolved. Trp-35 has a single fluorescence lifetime, which varies in the different proteins between 4.3 and 4.8 ns and is pH-independent between pH 5.8 and 8.9. Trp-71 and Trp-94 behave as an energy-transfer couple with both forward and reverse energy transfer. The couple shows two fluorescence lifetimes: 2.42 (+/-0.2) and 0.74 (+/-0.1) ns at pH 8.9, and 0.89 (+/-0.05) and 0.65 (+/-0.05) ns at pH 5.8. In the mutant Trp-94----Phe the lifetime of Trp-71 is 4.73 (+/-0.008) ns at high pH and 4.70 (+/-0.004) ns at low pH. In the mutant Trp-71----Tyr, the lifetime of Trp-94 is 1.57 (+/-0.01) ns at high pH and 0.82 (+/-0.025) ns at low pH. From these lifetimes, one-way energy-transfer efficiencies can be calculated according to Porter [Porter, G.B. (1972) Theor. Chim. Acta 24, 265-270]. At pH 8.9, a 71% efficiency was found for forward transfer (from Trp-71 to Trp-94) and 36% for reverse transfer. At pH 5.8 the transfer efficiency was 86% for forward and 4% for reverse transfer (all +/-2%). These transfer efficiencies correspond fairly well with the ones calculated according to the theory of Förster [Förster, T. (1948) Ann. Phys. (Leipzig) 2, 55-75].(ABSTRACT TRUNCATED AT 250 WORDS)

We developed a method for selectively propagating disease-related autoreactive T-cell lines (auTCLs) based on their increased resistance to apoptosis. The generated auTCLs homogeneously co-express CD45RO and CD49a, adhere strongly to extracellular matrix proteins and express high interleukin-17 (IL-17) messenger RNA levels, resembling a T-cell subset proposed to transmigrate into tissues and induce systemic and local inflammation in rheumatoid arthritis. The combinations of T-cell oligoclones that comprise probable multiple sclerosis (pMS) disease-related lines use a unique portfolio of T-cell receptor beta-chain variable allele (BV genes) combinations forming 'disease-specific cluster patterns'. The auTCL derived from different patients and from different myelin epitopes display striking similarities in BV gene allele clusters and are derived primarily from a disease-prone hotspot residing in the BV gene locus between Vbeta6 and Vbeta9. Conversely, healthy subject TCLs use different BV gene allele sets, forming 'healthy responder usage formats'. These formats were absent from the pMS patient V-beta gene allele combinations evaluated in this study. Hierarchical clustering of the BV gene combinations, distinguish three pMS auTCL groups, implying existence of up to three disease-related immune response patterns. These subgroup patterns may reflect different disease subclasses or alternatively they may suggest immune reactivity to different aetiological agents. Analyses of clonal-clustering patterns may potentially aid in subclassification of MS or in characterizing aetiological agents of this disease.

Background NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands. Methodology/Principal Findings We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2Dhigh or NK30high donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies. Conclusions/Significance NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities.

Fluorescence spectra of wild-type barnase and mutants in which tryptophan and histidine residues have been substituted have been analyzed to give the individual contributions of the three tryptophan residues. The spectrum is dominated by the contribution of Trp-35. The fluorescence intensity varies with pH according to an ionization of a pKa of 7.75. This pKa is close to that previously determined by NMR titration of the C2-H resonances of His-18 as a function of pH (Sali et al., 1989). This histidine residue is close to Trp-94. The pH dependence of the spectrum is abolished when either His-18 or Trp-94 is mutated, and so appears to be caused by the His-18/Trp-94 interaction. The spectral response of this interaction can serve as a probe of the folding pathway and of electrostatic effects within the protein. Changes in the fluorescence spectra on substitution of Trp-94 and His-18 suggest that there is net energy transfer from Trp-71 to Trp-94.

Hyperphenylalaninemia (HPA) is a group of diseases characterized by a persistent elevation of phenylalanine levels in tissues and biological fluids. The most frequent form is phenylalanine hydroxylase deficiency, causing phenylketonuria (PKU). Among 159 Israeli patients (Jews, Muslim and Christian Arabs and Druze) with HPA, in whom at least one of the mutations was characterized, a total of 43 different mutations were detected, including seven novel ones. PKU was very rare among Ashkenazi Jews and relatively frequent among Jews from Yemen, the Caucasian Mountains, Bukhara and Tunisia. The mutations responsible for the high frequency were: exon3del (Yemenite Jews), L48S (Tunisian Jews) and E178G, P281L and L48S (Jews from the Caucasian Mountains and Bukhara). Among the non-Jewish Israeli citizens, the disease was relatively frequent in the Negev and in the Nazareth vicinity, and in many localities a unique mutation was detected, often in a single family. While marked genetic heterogeneity was observed in the Arab and Jewish populations, only one mutation A300S, was frequent in all of the communities. Several of the other frequent mutations were shared by the non-Ashkenazi Jews and Arabs; none were mutual to Ashkenazi Jews and Arabs.

Background: The neurosteroids allopregnanolone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulphate (DHEA-S) may have a role in the pathophysiology and control of feeding behaviors. This influence is related to neurosteroid modulation of neurotransmitters that affect feeding, the influence that stress might have on their activity, and the changes found in eating disorders (ED) patients in the activity of the hypothalamic–pituitary–adrenal cortex (HPA) axis, which regulates neurosteroid secretion. The aim of this review is to summarize the findings of studies assessing neurosteroids in EDs. Method: The review is based on an updated comprehensive systematic literature search of the Cochrane, PUBMED, PSYCHLIT, PSYCHINFO, and ERIC databases. Results: We found 12 studies assessing neurosteroids in EDs, most of them in anorexia nervosa (AN), and a few in bulimia nervosa and binge eating disorder. Significant inconstancies were found among these studies. Whereas cortisol was usually elevated in underweight AN patients, DHEA and DHEA-S were decreased in some studies, not different from controls in other, and elevated in still other studies. Similar discrepancies in DHEA and DHEA-S were found weight-restored AN patients, whereas cortisol levels usually decreased. Conclusions: Despite these inconsistencies, several conclusions can be drawn with respect to the role of neurosteroids in EDs, particularly AN. The studies showing elevated levels of DHEA and DHEA-S in underweight AN patients relate this derangement to HPA hyperactivity, associated with malnutrition. The studies Pediatric Psychosomatic Department, The Safra Children’s Hospital, The Chaim Sheba Medical Center, Tel Hashomer Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tiqva Tissue-Typing Laboratory and Bone Marrow Registry, The Safra Children’s Hospital, The Chaim Sheba Medical Center, Tel Hashomer Geha Mental Health Center, Rabin Medical Center, Beilinson Campus, Petah Tiqva All affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel M.S. Ritsner and A. Weizman (eds.), Neuroactive Steroids in Brain Function, 493 Behavior and Neuropsychiatric Disorders © Springer 2008 494 D. Stein et al. showing reduced DHEA and DHEA-S but normal or high cortisol levels in malnourished AN patients, suggest that this dissociation represents a regression to prepubertal HPA system functioning. The reduction in cortisol but persistence of elevated DHEA and DHEA-S in weight restored AN patients may account for the feeding problems these patients encounter; this because cortisol increases food intake whereas DHEA and DHEA-S decrease it.

HLA-G belongs to the non-classical HLA class-I family of genes presently designated as class-Ib genes. There are four membrane-bound (HLA-G1 to -G4) and three soluble forms (HLA-G5 to -G7) generated by alternative splicing of the primary transcript. HLA-G in the soluble form is found in the plasma, amniotic fluid, and cord blood of healthy individuals. Quantitative determination suggested that HLA-G levels are genetically controlled. While quantifying soluble HLA-G by ELISA, we observed that when plasma and serum levels were measured for the same individual, HLA-G plasma values were almost invariably higher than those from serum. Our results suggest that HLA-G is trapped and/or consumed during clot formation. The amount trapped within the clot is variable and inconsistent. To obtain values which reflect the true biological levels, it is therefore recommended that HLA-G should be determined in the plasma. If serum levels are determined, they should be compared with matched control sera. It should always be borne in mind that conclusions concerning sera levels might be erroneous, because the true plasma level of the protein can be significantly higher.

Efficient antitumor immune response requires the coordinated function of integrated immune components, but is finally exerted by the differentiated effector tumor-infiltrating lymphocytes (TIL). TIL cells comprise, therefore, an exciting platform for adoptive cell transfer (ACT) in cancer. In this study, we show that the inhibitory carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) protein is found on virtually all human TIL cells following preparation protocols of ACT treatment for melanoma. We further demonstrate that the CEACAM1 homophilic interactions inhibit the TIL effector functions, such as specific killing and IFN-γ release. These results suggest that CEACAM1 may impair in vivo the antitumor response of the differentiated TIL. Importantly, CEACAM1 is commonly expressed by melanoma and its presence is associated with poor prognosis. Remarkably, the prolonged coincubation of reactive TIL cells with their melanoma targets results in increased functional CEACAM1 expression by the surviving tumor cells. This mechanism might be used by melanoma cells in vivo to evade ongoing destruction by tumor-reactive lymphocytes. Finally, CEACAM1-mediated inhibition may hinder in many cases the efficacy of TIL ACT treatment of melanoma. We show that the intensity of CEACAM1 expression on TIL cells constantly increases during ex vivo expansion. The implications of CEACAM1-mediated inhibition of TIL cells on the optimization of current ACT protocols and on the development of future immunotherapeutic modalities are discussed.

Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin of unknown etiology. While various environmental factors have been implicated as triggering agents, HLA association is probably the most important predisposing factor. The aim of this review is to highlight the association of HLA with pemphigus vulgaris. In addition, we present recent results showing a possible association with the nonclassical HLA-G antigen.

Pemphigus is a group of life-threatening autoimmune blistering diseases of the skin and mucous membranes. The etiology and pathogenesis of this destructive autoimmune process remains unknown, but significant association with human leukocyte antigen (HLA) factors have been described in pemphigus vulgaris (PV) patient cohorts worldwide. We have recently analyzed DNA samples obtained from pemphigus patients and matched controls with a set of microsatellite markers, and found that markers mapped to HLA class I region are significantly associated with the disease. In order to narrow the region that is associated with the disease single nucleotide polymorphism (SNP) technology was used. In this study, a set of 26 SNP markers, which span a chromosomal region of about 600,000 bp, were used to screen DNA samples of the patients and their matched controls. Of the 26 SNPs, four markers were found informative, all mapped to HLA-G. Typing patients and controls for HLA-G polymorphism revealed significant differences in the exon 8 deletion/insertion variant. The latter is probably associated with the efficiency of transcription of this gene. Taken together, the results suggest that HLA-G is associated with PV in Jewish patients.

Pemphigus vulgaris (PV) is the most severe autoimmune blistering disorder of the skin that is mediated by circulating autoantibodies against desmoglein 3 (Dsg3). It has been reported that in Jews the associated haplotype in PV is human leukocyte antigen (HLA) B38, DRB1*0402, DQB1*0302. Significant associations with HLA were observed also in non-Jews. Dsg3-specific T-cell responses were detected in PV patients but also in healthy individuals who were either carriers of the PV-associated DRB1*0402 allele or alleles that share similar or identical peptide binding motifs to DRB1*0402. This suggests that genes other than the classical major histocompatibility complex (MHC) genes are associated with the development of the autoimmune response. We used 16 microsatellite probes that span the entire MHC region to screen DNA samples from 38 PV patients and 76 healthy controls. Results demonstrated that some markers were associated with class II region including a TAP associated marker. However, four probes, D6S265, C_527, D6S510, and MOGC, which are all mapped to the region of HLA-A, were highly associated with PV. These results suggest that a gene, or genes in the class I region are important in the initiation of the autoimmune cascade. Activation/suppression of these genes might act as the trigger mechanism that starts the autoimmune destructive process.

Allele distributions of 10 short tandem repeat (STR) polymorphic DNA loci used in forensic and paternity testing were determined for a cohort comprising 163 individuals representing a mixed Jewish Caucasian population. Typing was carried out by the commercial AmpF lSTR SGM Plus kit. The polymorphism and the utility of three of these markers for forensic studies in Israel were established for the first time. Results were compared with data for U.S. Caucasians and African Americans. The probability of identity of two persons of different ethnic origins for identification purposes is discussed. A lemma is presented to show that the chance of erroneous identification of an innocent person who belongs to a population that had not committed a crime will, in most cases, be smaller than for those who belong to a population that had truly committed the crime.

Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by impaired peroxisomal betaoxidation of very-long-chain fatty acids (VLCFAs). This is probably due to reduced activation of the VLCFAs and results in demyelination of the nervous system and adrenocortical insufficiency. The ALD gene is localized on Xq28, has 10 exons and encodes a protein of 745 amino acids with significant homology to the membrane peroxisomal protein PMP70. Characterizing the disease causing mutations is of importance in prenatal diagnosis because 12-20% of women who are obligatory carriers show false-negative results when tested for VLCFA in plasma. We have analyzed DNA from blood samples of 7 Jewish (5 Sephardi and 2 Ashkenazi) and 3 Arab Israeli families suffering from ALD. Five missense-type mutations were identified: R104H, Y174C, L229P, R401Q, and G512C. A single mutation, R464X, was nonsense, and two, Y171 frameshift and E471 frameshift, were frameshift. Interestingly, a single mutation was identified in three families of Moroccan Jewish descent, probably due to a founder effect.

The aim of this study was to evaluate the screening policies of cystic fibrosis (CF) in the Jewish population. The prevalence of mutations that account for CF in Israel have been defined in the past by determining the frequency of CF mutations in affected individuals. This study is a population-based study and is, therefore, different from previous patient-based studies. We found that the CF mutations D1152H, W1089X, and 405 + IG-->A were present in some ethnic groups in which no CF patients carrying these mutations were reported. These facts necessitate a reevaluation of the screening policy regarding the ethnic groups in Israel. We studied 9,430 healthy Jewish Israeli individuals of 36 countries of origin. The prevalence of CF mutations was 1:19, 1:19, 1:28, and 1:42 for the Ashkenazi, Sephardi, North African, and Eastern Jews, respectively. CF mutations were identified in 374 (4.0%) individuals. These included 173 (46.3%) carriers of the W1282X mutation; 110 (29.4%) found to carry delF508; 23 (6.1%) who carried G542X; 22 (5.9%) who carried 3849 + 10Kb (C-->T; 20 (5.3%) who carried D1152H; 10 (2.7%) who carried N1303K; 11 (2.9%) who carried 405 + IG-->A; 4 (1.1%) who carried W1089X; and one (0.3%) who carried S549R. No carriers were detected for the 1717-1G-->A, G85E, and T360K mutations, which were tested for in 7,383, 1,558, and 41 individuals, respectively.

Anti-paternal antibodies directed towards paternal leukocytes have been used to predict the prognosis for the subsequent pregnancy in women with consecutive recurrent miscarriages (CRM) and also to determine if the patient has become immune after paternal leukocyte immunization. The predictive value is controversial, as these antibodies are not essential for pregnancy to develop, and only occur in a minority of parous women. This study tried to determine the predictive value of these antibodies when assessed separately for women with five or more abortions and compared to women with three or four abortions. The patients were assessed separately so that the higher live birth rate in the latter group would not obscure meaningful results in the former group with a poor prognosis. Antibody production, whether spontaneous, or induced by immunization, raised the live birth rate in primary and tertiary aborters with three, four, five or more abortions. Anti-paternal antibodies increased the proportion of live births from 18.5 to 53. 7% (P/= 0.01) and from 44.4 to 67.5% (P/= 0.001) in primary aborters with/= 5 CRM and 3-4 CRM respectively. Both immunization with paternal leukocytes per se and the ability to express anti-paternal antibodies were associated with an increased proportion of live births in the next pregnancy. Multivariate analysis showed that that the odds ratio for a live birth was approximately four times greater in women who were immunized and produced anti-paternal antibodies than in control patients. The lack of anti-paternal antibodies at initial testing could serve as a marker for the benefit of immunization with paternal leukocytes; the subsequent presence as a prognostic marker for the subsequent pregnancy.