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PubMed2001

Analysis of TCR Vbeta repertoire and cytokine gene expression in patients with idiopathic dilated cardiomyopathy.

Although the etiopathogenesis of idiopathic dilated cardiomyopathy (IDC) is still unclear, it is widely accepted that a complex interplay between viral infections and immune mechanisms is the basis of disease genesis. Previously, we showed that heart-infiltrating T cells of patients suffering from acute, fulminant Coxsackie virus B3+-IDC shared a preferential usage of three variable gene segments of the T cell receptor beta chain-(TCR-Vbeta) encoding families Vbeta3, 7 and 13.1. This indicated the possible presence of a superantigen-driven immune response. Here, we further investigated the IDC immunological scenario by analysing different phenotypes of heart-infiltrating cells: TCR repertoires, cytokine expression and presence of enterovirus-specific antigens. IDC patients who underwent heart transplantation at different times after the onset of heart failure were studied. A cardiac infiltrate of CD4+ and CD8+ T cells was present together with activated macrophages. Furthermore, the same Vbeta gene families, previously found to be skewed in hearts from fulminant cases of CVB3+-IDC, together with two additional Vbeta gene families, Vbeta1 and 5B, were increased. IL-1beta, IL-2, IL-6 and IFN-gamma were expressed in the myocardium while others, like IL-4 were not. In conclusion, an orchestrated complex of immune mechanisms seems to be the basis of IDC etiopathogenesis.

Antigens, Viral↗

PubMed1993

The fear of fear concept: stability, retest artefact and predictive power.

Three related issues concerning the theory, measurement and clinical utility of the fear of fear construct as operationalized by the Agoraphobic Cognitions and Bodily Sensations Questionnaires (Chambless, Caputo, Bright & Gallagher, Journal of Consulting and Clinical Psychology, 52, 1090-1097, 1984) were addressed: stability of ranked scores, stability of means (retest effect) and predictive ability. In addition to measures assessing moods and enduring personality traits, the relevant fear of fear scales (and introducing a companion frequency measure to the BSQ-intensity scale) were administered to somewhat over 60 clients with "panic disorder with agoraphobia" or "agoraphobia without a history of panic attacks" on two occasions, 3 months apart, with no intervention having taken place between first and second testing. As predicted, ranked fear of fear scores were highly stable. In addition, Howarth's mu index values pointed to the description of the fear of fear constructs in terms of traits. Specific fear of fear scales showed evidence of a retest effect. The short-term course of agoraphobic avoidance behaviour in untreated cases was predictable from specific fear of fear variables, even after controlling for their shared variance with pre-test measures of either state anxiety-panic or trait neuroticism. Implications of the findings are discussed.

Adult↗

PubMedDate not supplied

The expression of results of lipid determinations in arterial tissues: mass per unit weight vs mass per unit area.

The interrelations among four methods of expressing the results of lipid determinations in the intima of the abdominal aorta were examined using rank order and product moment correlation methods. The rank order correlations among the four methods were all uniformly high (0.90 or better), indicating that the method of expressing results of lipid analyses is not important when ranking by amount of lipid is the object. The product moment correlations showed a pattern of strong association when the methods paired are expressions of either "content" (mg lipid per 1/2 abdominal aorta vs mg lipid per unit area of aorta, r = 0.980) or "concentration" (mg lipid per dry weight of tissue vs mg lipid per dry defatted weight of tissue, r = 0.980). Correlations of paired methods that express "content" and "concentration" were lower and share only about 50% of common variability. This result can be interpreted as evidence that it is worthwhile to consider reporting chemical findings in reference to units of intimal (or artery) area as well as to unit of weight. If both methods are used some of the problems in interpreting chemical findings in the arterial wall may be clarified.

Adolescent↗

PubMed1986

Variability in humoral responses to DNP-KLH of rainbow trout (Salmo gairdneri). Comparison of antibody kinetics and immunoglobulins spectrotypes between normal trouts and trouts obtained by gynogenesis or self-fertilization.

The anti-DNP antibody responses were compared between conventional trouts produced in fishfarm and trouts experimentally obtained by self-fertilization of hermaphrodites or by gynogenesis. The variability of anti-DNP antibody titres was equivalent between normal and gynogenetic fish, but significantly reduced for fish obtained by self-fertilization. Isoelectrofocusing analysis of individually-isolated anti-DNP antibodies indicate low molecular heterogeneity but large variability between conventional trouts. Almost complete sharing of individual spectrotypes was observed between self-fertilized fish and large similarities between gynogenetics animals. These results suggest that the intensity of antibody synthesis in trout is under a complex genetic control, even in inbred animals expressing large similarities in their antibody repertoires.

Animals↗

PubMed1994

Effect of HLA incompatibility in marrow transplantation from unrelated and HLA-mismatched related donors.

Transplants from related donors who share one HLA haplotype and are variably matched with the recipient for HLA-A, B, or DRB1 loci on the unshared haplotype are associated with increased risks of graft failure and graft-versus-host disease (GVHD) that correlate with the degree of HLA mismatch. Survival, however, is not necessarily inferior if recipient incompatibility is limited to one HLA locus. Available methods for post-transplant immunosuppression have not allowed similar success with transplants incompatible for two or three HLA loci. GVHD incidence and severity can be decreased by depletion of donor T cells from the marrow inoculum. However, the potential benefit is offset by increased graft failure and leukemia relapse with no improvement in survival. Since fewer than 30% of the patients in North America or Europe have an HLA-matched sibling and less than 5% have a one HLA-locus mismatched relative, most candidates for an allogeneic marrow transplant are in need of an unrelated donor. As of October 1993, the National Marrow Donor Program (NMDP) has accrued more than 1 million volunteers typed for HLA-A and B, including 200,000 typed for HLA-DR, and has provided donors for more than 2000 transplants. The probability of finding an HLA-A, B, DR match at the initial search has increased from 10-15% in 1987, to 50-55% in 1992. An additional 12% of patients will find a match when available HLA-A and B matched donors are typed for DR, and 20% of patients have a one HLA-locus incompatible unrelated donor. Through an international network of regional registries a search for an unrelated donor can now be conducted among 1.7 million volunteers worldwide. Unrelated donor transplants have allowed long-term disease-free survival of patients with a variety of hematological disorders. When compared to HLA-matched sibling transplants, unrelated donor transplants are associated with an increase in the incidence of graft failure and GVHD. Such an increase may be due to undetected HLA disparities or to non-HLA-linked histocompatibility genes. At our center patients with CML in chronic phase, the most common indication for unrelated donor transplantation, have a 50-55% probability of survival 2-6 years after an unrelated donor transplant, whereas patients with aplastic or refractory anemia have a 25-35% probability of survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow Transplantation↗

PubMed2005

Congenital macrothrombocytopenias.

Congenital macrothrombocytopenias comprise a heterogeneous group of rare disorders, characterized by abnormal giant platelets, thrombocytopenia and bleeding tendency with variable severity. Many of these disorders share common clinical and laboratory features, making accurate diagnosis difficult and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura. Recent progress in the elucidation of underlying defects and further developments of specific diagnostic techniques for several congenital macrothrombocytopenias have renewed our approach to the classification and the diagnosis of the disease. This review summarizes the current knowledge on the clinical and laboratory features of common congenital macrothrombocytopenias and discusses how that knowledge aids in making a proper diagnosis.

Blood Platelets↗

PubMed2005

HLA B44 is associated with decreased severity of autoimmune lymphoproliferative syndrome in patients with CD95 defects (ALPS type Ia).

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis characterized by non-malignant lymphadenopathy and splenomegaly, expansion of T cells without either CD4 or CD8 surface markers, and increased incidence of autoimmune diseases and lymphoma. Most patients with ALPS have dominant, heterozygous mutations in tumor necrosis factor receptor superfamily member 6 (TNFRSF6), which encodes CD95, also known as Fas, a mediator of apoptosis. Penetrance and range of disease manifestations in ALPS are highly variable, even among family members who share the same dominant TNFRSF6 mutation. To evaluate HLA as a candidate modifier locus, we typed HLA A, B (including subtypes), and DQB alleles in 356 individuals from 63 unrelated families with defined TNFRSF6 mutations associated with ALPS. We also developed a quantitative severity score and performed statistical analysis. Among the healthier, mutation-bearing individuals, transmission of HLA B44 was significantly overrepresented (nominal P<0.0074) as compared to transmission in patients with severe clinical features of ALPS. The B44 allele may exert a protective role in ALPS.

Alleles↗

PubMed2006

Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: identification and structural characterization of two novel TAT mutations.

Tyrosinemia type II or Richner-Hanhart Syndrome (RHS) is an autosomal recessive disorder characterized by keratitis, palmoplantar keratosis, mental retardation, and elevated blood tyrosine levels. The disease is due to a deficiency of hepatic cytosolic tyrosine aminotransferase (TATc), an enzyme involved in the tyrosine catabolic pathway. Because of the high rate of consanguinity this disorder seems to be relatively common among the Arab and Mediterranean populations. RHS is characterized by inter and intrafamilial phenotypic variability. A large spectrum of mutations within TATc gene has been shown to be responsible for RHS. In the present study, we report the clinical features and the molecular investigation of RHS in three unrelated consanguineous Tunisian families including 7 patients with confirmed biochemical diagnosis of tyrosinemia type II. Mutation analyses were performed and two novel missense mutations were identified (C151Y) and (L273P) within exon 5 and exon 8, respectively. The 3D-structural characterization of these mutations provides evidence of defective folding of the mutant proteins, and likely alteration of the enzymatic activity. Phenotype variability was observed even among individuals sharing the same pathogenic mutation.

Adult↗

PubMed2002

A novel chronic childhood sensory predominant neuropathy.

Chronic childhood neuropathies are predominantly hereditary in origin. Specific distinct clinical entities have been described, however, occasionally children with an unusual clinical phenotype are encountered in practice. We describe four children (3 males, 1 female) of Lebanese Moslem descent all sharing a common great-great-grandparent pairing with such a novel clinical spectrum. The three males were first cousins, each the product of a different parental consanguineous (i.e., parents second cousins) mating, whereas the female was a third cousin to each of the males whose parents were also second cousins. Each child presented early in life with developmental delay with associated hypotonia and areflexia. All had a sensorineural hearing loss documented and two of the patients were dysmorphic in facial appearance. Nerve conduction studies highlighted a sensory axonal neuropathy and sural nerve biopsy undertaken in two patients confirmed an axonal neuropathy. Detailed genetic and metabolic testing was negative. Followed into later childhood, each child continued to manifest motoric impairment, unsteadiness, areflexia, and cognitive disability. These children appear to provide evidence for a novel autosomal recessive inherited chronic predominantly sensory neuropathy that shares core clinical features with observed variability in associated symptoms.

Arabs↗

PubMed2005

High-nuclearity mixed-chelate ferric complexes from a new family of polynuclear precursors.

The syntheses, structures, and magnetochemical characterization of two novel mixed-chelate undeca- and dodecanuclear ferric complexes are reported. Preformed tri- and pentanuclear ferric complexes that possess tridentate Schiff base (L2- and (L'2-) and acetate ligands were reacted with 1,1,1-tris(hydroxymethyl)ethane (H3thme) to afford [Fe11O3(OH)(O2CMe)8(thme)2(L)6] (1) and [Fe12O4(O2CMe)8(thme)2(NH2(CH2)2O)2(L')6] (2), respectively, following structural agglomeration and rearrangement associated with ligand substitution. The incorporation of more than one type of ligand that can both chelate and bridge the Fe centers gives rise to the complicated molecular structures displayed by 1 and 2. As a result of the tripodal conformation of thme3-, the cores of both molecules incorporate several face-shared defect {Fe3O4}+ cuboidal subunits. Variable-temperature dc and ac magnetic susceptibility studies, together with low-temperature magnetization measurements, are consistent with S = 5/2 and S = 0 ground-state spins for 1 and 2, respectively, and suggest that excited states with higher spin values lie relatively close in energy to the ground state for both species. Low-temperature micro-SQUID measurements on oriented single crystals of 1 confirm the easy-axis type magnetic anisotropy suggested by conventional SQUID magnetometry. However magnetization hysteresis is not observed down to 0.04 K, which is ascribed to rapid quantum tunneling of the magnetization associated with transverse interactions.

Journal Article↗

PubMed2003

Subtypes of psychopathy: proposed differences between narcissistic, borderline, sadistic, and antisocial psychopaths.

Atascadero State Hospital (ASH) is a maximum-security forensic hospital that houses male patients with a wide range of psychiatric diagnoses. Psychopaths at this institution appear to be a heterogeneous group of individuals who, while sharing core personality characteristics, manifest substantial variability in their behavior. Identifying subtypes within this clinical classification can have implications for patient treatment and management, as well as for the safety of the staff who work with them and for the communities to which they will eventually return. Several means of identifying subtypes have been proposed in the literature, and potential subgroups have been identified. Clinical observations at ASH have suggested 4 possible subtypes of psychopathy: narcissistic, borderline, sadistic, and antisocial. Issues related to the conceptualization of psychopathy are addressed, recognizing that additional data are needed to understand the observed variations in cases of psychopathy.

Antisocial Personality Disorder↗

PubMed2026

Genetics of major depressive disorder in a homogeneous population with uniform phenotyping.

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. Liability-scale SNP-based heritability was 12.0% (SE = 1.4%) as estimated by LDSC (assuming a lifetime prevalence of 15%) and 26.6% (SE = 1.1%) when estimated by LDAK-REML on individual-level genotype data, indicating substantial common-variant signal in this clinically harmonized sample. The genetic correlation with the latest major depression GWAS from the Psychiatric Genomics Consortium (PGC-MD) was high (rG = 0.89, SE = 0.048). Polygenic scores (PGSs) based on BIONIC predicted depression in UK Biobank, and PGSs derived from PGC-MD predicted MDD in BIONIC, supporting transferability of depression polygenic signal across cohorts and phenotype definitions. Within-family PGS analyses in twins suggested that the observed prediction was not primarily driven by detectable family-level confounding, and twin concordance for MDD increased with polygenic burden. We identified one genome-wide significant locus, indexed by rs3818852 in PALMD, but this finding currently lacks independent replication and should be interpreted cautiously. Finally, genetic correlation and latent causal variable analyses identified multiple traits showing shared or directionally consistent genetic associations with MDD. Together, these findings underscore the value of clinically harmonized phenotyping in regional biobank collaborations for studying the genetic architecture of MDD.

Humans↗

PubMed2005

Immune function responds to selection for cuticular colour in Tenebrio molitor.

Cuticular colour in the mealworm beetle (Tenebrio molitor) is a quantitative trait, varying from tan to black. Population level variation in cuticular colour has been linked to pathogen resistance in this species and in several other insects: darker individuals are more resistant to pathogens. Given that cuticular colour has a heritable component, we have taken an experimental evolution approach: we selected 10 lines for black and 10 lines for tan adult cuticular phenotypes over at least six generations and measured the correlated responses to selection in a range of immune effector systems. Our results show that two immune parameters related to resistance (haemocyte density and pre-immune challenge activity of phenoloxidase (PO)) were significantly higher in selection lines of black beetles compared to tan lines. This may help to explain increased resistance to pathogens in darker individuals. Cuticular colour is dependent upon melanin production, which requires the enzyme PO that is present in its inactive form inside haemocytes. Thus, the observed correlated response to selection upon cuticular colour and immune variables probably results from these traits' shared dependence on melanin production.

Analysis of Variance↗

PubMed2003

The National Treatment Outcome Research Study (NTORS): 4-5 year follow-up results.

AIMS: The National Treatment Outcome Research Study (NTORS) is the first prospective national study of treatment outcome among drug misusers in the United Kingdom. NTORS investigates outcomes for drug misusers treated in existing services in residential and community settings. DESIGN, SETTING AND PARTICIPANTS: The study used a longitudinal, prospective cohort design. Data were collected by structured interviews at intake to treatment, 1 year, 2 years and at 4-5 years. The sample comprised 418 patients from 54 agencies and four treatment modalities. MEASUREMENTS: Measures were taken of illicit drug use, injecting and sharing injecting equipment, alcohol use, psychological health and crime. FINDINGS: Rates of abstinence from illicit drugs increased after treatment among patients from both residential and community (methadone) programmes. Reductions were found for frequency of use of heroin, non-prescribed methadone, benzodiazepines, injecting and sharing of injecting equipment. For most variables, reductions were evident at 1 year with outcomes remaining at about the 1 year level or with further reductions. Crack cocaine and alcohol outcomes at 4-5 years were not significantly different from intake. CONCLUSIONS: Substantial reductions across a range of problem behaviours were found 4-5 years after patients were admitted to national treatment programmes delivered under day-to-day conditions. The less satisfactory outcomes for heavy drinking and use of crack cocaine suggest the need for services to be modified to tackle these problems more effectively. Despite differences between the United Kingdom and the United States in patient populations and in treatment programmes, there are many similarities between the two countries in outcomes from large-scale, multi-site studies.

Alcoholism↗

PubMed2000

Distinguishing full siblings from half-siblings in limited pedigrees.

BACKGROUND: Full siblings were compared with half-siblings to observe how well the two relationships could be distinguished by informative tests. STUDY AND DESIGN METHODS: Parentage analysis ascertained 25 pairs of full siblings and 25 pairs of half-siblings. The pairs were then examined for the sharing of alleles at three independent variable number of tandem repeat (VNTR) loci. A sibling index (SI) and a half-sibling index (HSI) were calculated for each pair, and an SI:HSI ratio was determined. RESULTS: The SI:HSI ratio favored full siblings in 18 of 25 full sibling pairs. The SI:HSI ratio exceeded 100 in 8 of those 25 pairs. Although the ratio favored half-siblings in 23 of 25 half-sibling pairs, as was expected with the use of only 3 loci, it exceeded 0.1 in all 25 pairs. CONCLUSION: Study of more than three highly informative loci is required to improve the identification of full siblings and might well permit the identification of half-siblings.

Alleles↗

PubMed2004

Collagen VI status and clinical severity in Ullrich congenital muscular dystrophy: phenotype analysis of 11 families linked to the COL6 loci.

Ullrich's congenital muscular dystrophy (UCMD) is an autosomal recessive myopathy characterised by neonatal muscle weakness, proximal joint contractures and distal hyperlaxity. Mutations in the COL6A1, COL6A2 (21 q22.3) and COL6A3 (2 q37) genes, encoding the alpha 1, alpha 2 and alpha 3 chains of collagen VI, respectively, have been recently identified as responsible for UCMD in a total of 9 families. We investigated in detail the clinical and morphological phenotype of 15 UCMD patients from 11 consanguineous families showing potential linkage either to 21 q22.3 (6 families) or to 2 q37 (5 families). Collagen VI deficiency was confirmed on muscle biopsies or skin fibroblasts in 8 families. Although all patients shared a common phenotype, a great variability in severity was observed. Collagen VI deficiency in muscle or cultured fibroblasts was complete in the severe cases and partial in the milder ones, which suggests a correlation between the degree of collagen VI deficiency and the clinical severity in UCMD. No significant phenotypical differences were found between the families linked to each of the 2 loci, which confirms UCMD as a unique entity with underlying genetic heterogeneity.

Adolescent↗

PubMed1988

Economic development, population and primacy.

"This paper investigates the relationship between economic development and primacy advanced by El-Shakhs, Mera and others, and finds no statistically significant link when obvious demographic influences are taken into account. Three variables (national population, the urban population share, and a Latin American dummy) explain 40% of the variation in primacy in a sample of 116 countries (including 82 developing countries). Economic factors do not appear to be important. Demography may be more influential than economics in attempts to explain primacy."

Demography↗

PubMed2001

Markovian domain fingerprinting: statistical segmentation of protein sequences.

MOTIVATION: Characterization of a protein family by its distinct sequence domains is crucial for functional annotation and correct classification of newly discovered proteins. Conventional Multiple Sequence Alignment (MSA) based methods find difficulties when faced with heterogeneous groups of proteins. However, even many families of proteins that do share a common domain contain instances of several other domains, without any common underlying linear ordering. Ignoring this modularity may lead to poor or even false classification results. An automated method that can analyze a group of proteins into the sequence domains it contains is therefore highly desirable. RESULTS: We apply a novel method to the problem of protein domain detection. The method takes as input an unaligned group of protein sequences. It segments them and clusters the segments into groups sharing the same underlying statistics. A Variable Memory Markov (VMM) model is built using a Prediction Suffix Tree (PST) data structure for each group of segments. Refinement is achieved by letting the PSTs compete over the segments, and a deterministic annealing framework infers the number of underlying PST models while avoiding many inferior solutions. We show that regions of similar statistics correlate well with protein sequence domains, by matching a unique signature to each domain. This is done in a fully automated manner, and does not require or attempt an MSA. Several representative cases are analyzed. We identify a protein fusion event, refine an HMM superfamily classification into the underlying families the HMM cannot separate, and detect all 12 instances of a short domain in a group of 396 sequences. CONTACT: jill@cs.huji.ac.il; tishby@cs.huji.ac.il.

Algorithms↗