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Biomedical subjects

U Liberman

Publications and source records attributed to U Liberman.

At least 19 recordsLinked to original sources
PubMed2000

XDH gene mutation is the underlying cause of classical xanthinuria: a second report.

BACKGROUND: Classical xanthinuria is a rare autosomal recessive disorder characterized by excessive excretion of xanthine in urine. Type I disease results from the isolated deficiency of xanthine dehydrogenase (XDH), and type II results from dual deficiency of XDH and aldehyde oxidase. The XDH gene has been cloned and localized to chromosome 2p22-23. The aim of this study was to characterize the molecular basis of classical xanthinuria in an Iranian-Jewish family. METHODS: The apparently unrelated parents originated from a community in which consanguineous marriages are common. Subtyping xanthinuria was attempted by homozygosity mapping using microsatellite markers D2S352, D2S367, and D2S2374 in the vicinity of the XDH gene. Mutation detection was accomplished by PCR-SSCP screening of all 36 exons and exon-intron junctions of the XDH gene, followed by direct sequencing and confirmation of sequence alteration by restriction analysis. RESULTS: The index case was homozygous for all three microsatellite markers analyzed. The expected frequency of this genotype in a control population was 0. 0002. These results suggested that xanthinuria in the patient is linked to the XDH gene. Consequently, a 1658insC mutation in exon 16 of the XDH gene was identified. The 1658insC mutation was not detected in 65 control DNA samples. CONCLUSION: A molecular approach to the diagnosis of classical xanthinuria type I in a female patient with profound hypouricemia is described. Linkage of xanthinuria to the XDH locus was demonstrated by homozygosity mapping, and a 1658insC mutation, predicting a truncated inactive XDH protein, was identified. These results reinforce the notion that mutations in the XDH gene are the underlying cause of classical xanthinuria type I.

Amino Acid Sequence↗
PubMed1998

Discrete chiasma formation models and their associated high order interference.

We introduce some special chiasma formation processes. First a family of discrete chiasma formation processes is introduced and we determine the nature of higher order interference associated with those processes. Secondly we consider a two-stage chiasma formation process, where the associated recombination frequency between two markers depends not only on their map distance but also on their location along the chromosomes. We characterise under this process, in some cases, the nature of interference between two segments.

Chromosome Mapping↗
PubMed1997

Quality of life as outcome in the treatment of osteoporosis: the development of a questionnaire for quality of life by the European Foundation for Osteoporosis.

The morbidity of osteoporosis is caused by fractures. Vertebral fractures lead to pain and disability and a decrease in quality of life. A Working Party of the European Foundation for Osteoporosis has developed a specific questionnaire for patients with established vertebral osteoporosis. This questionnaire is intended for use in clinical trials. The questionnaire consists of questions and visual analogue scales in the following domains: pain, activities of daily living, jobs around the house, mobility, leisure and social activities, general health perception and mood. The questionnaire has been translated from English into French, German, Italian, Hebrew, Swedish and Dutch. The questionnaire is currently being validated in a multicentre study involving patients with stable osteoporosis and control subjects. Preliminary results indicate that the reproducibility is sufficient and that the questionnaire is able to discriminate between patients with vertebral osteoporosis and control subjects.

Activities of Daily Living↗
PubMed1996

On the modification of recombination with sex-dependent fitnesses and linkage.

According to the Reduction Principle, when a recombination-reducing allele is introduced near an equilibrium that depends on recombination, that allele will increase in frequency. If the allele increases the recombination rate, it will be expelled from the population. There are known cases where this principle fails. In this respect, an interesting question is what kind of two-sex viability regimes support a general Reduction Principle. In this paper, we construct a model of viabilities, due to two autosomal linked genes, which differ between the sexes, such that recombination is different in the sexes. A complete analysis is provided for the case where recombination is absent in one sex. It is proved that the Reduction Principle is still valid for recombination in the other sex.

Alleles↗
PubMed1996

Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis.

To determine the effects of long-term daily oral alendronate sodium (ALN) on bone mass in postmenopausal women with osteoporosis, 19 centers enrolled 516 postmenopausal women aged 45-80 years with spine bone mineral density (BMD) at least 2.5 SD below the mean for young premenopausal women in a 3-year, double-blind, placebo-controlled study. Subjects were randomly allocated to one of four treatment groups: placebo; alendronate, 5 or 10 mg/day for 3 years; or alendronate, 20 mg/day for 2 years followed by 5 mg/day for the 3rd year. All patients received 500 mg/day of supplemental calcium to ensure adequate calcium intake. BMD was measured by dual-energy X-ray absorptiometry at several skeletal sites. Nonsignificant mean decreases in BMD of the spine, femoral neck, and trochanter of 0.6, 0.7, and 0.4%, respectively, occurred in the placebo group at 3 years. Relative to placebo-treated patients, spine BMD increased by 5.4%, 7.4%, and 8.4% in the 5, 10, and 20/5 mg ALN groups, respectively. Increases at the femoral neck were 3.5%, 5.5%, and 4.3%, and those at the trochanter were 5.1%, 7.2%, and 7.2%, respectively. Thus, efficacy of 10 and 20/5 mg ALN was similar, whereas the 5 mg dose was less effective. BMD continued to increase over the entire 3-year study duration in the ALN-treated groups and, compared with the other dosage groups, 10 mg ALN produced the largest gains in BMD during the 3rd year. Changes in biochemical markers of bone turnover and mineral homeostasis confirmed the effect of ALN to decrease bone turnover to a new steady-state level. The safety and tolerability of ALN were comparable with those of placebo. In summary, 10 mg daily oral ALN given for 3 years significantly and progressively increases bone mass and is a generally well-tolerated treatment for osteoporosis in postmenopausal women.

Administration, Oral↗
PubMed1996

The development of a European questionnaire for quality of life in patients with vertebral osteoporosis.

The complaints of vertebral osteoporosis usually result from wedge or crush fractures and biconcave deformities. These are caused by a decrease of bone mass and deterioration of bone structure leading to loss of strength. Treatment of osteoporosis should result in an increase of bone mass, and the incidence of new vertebral fractures should diminish. However, new vertebral fractures are not always accompanied by pain, and disability does not well correlate with the number of vertebral fractures. Patients with osteoporosis often have other problems e.g. with taking a shower, preparing meals, gardening, walking stairs, visiting friends and attending social activities. In addition, pain and disability may influence mood and lead to depression. The assessment of quality of life should be a primary endpoint in clinical trials in patients with osteoporosis and in individual patients care. Recently, the European Foundation for Osteoporosis (EFFO) has decided a develop a questionnaire for patients with vertebral osteoporosis, i.e. patients with vertebral deformities. The questionnaire is meant for use in clinical trials. A questionnaire was made including 48 questions and 6 visual analogue scales. The questions concern the following domains: pain, activities of daily living, jobs around the house, moving, leisure and social activities, general health perception and mood. The questionnaire ("Qualeffo") has now entered the validation phase. The first study in 8 centres concerns the within-subject reproducibility, the internal coherence, and the specificity by comparing osteoporotic patients with a control group not suffering from osteoporosis or backpain.

Humans↗
PubMed1995

Mutations in the SLC3A1 transporter gene in cystinuria.

Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. Guided by the identification of the SLC3A1 amino acid-transport gene on chromosome 2, we recently established genetic linkage of cystinuria to chromosome 2p in 17 families, without evidence for locus heterogeneity. Other authors have independently identified missense mutations in SLC3A1 in cystinuria patients. In this report we describe four additional cystinuria-associated mutations in this gene: a frameshift, a deletion, a transversion inducing a critical amino acid change, and a nonsense mutation. The latter stop codon was found in all of eight Ashkenazi Jewish carrier chromosomes examined. This report brings the number of disease-associated mutations in this gene to 10. We also assess the frequency of these mutations in our 17 cystinuria families.

Americas↗
PubMed1994

Theoretical recombination processes incorporating interference effects.

With the acquisition of genetic, physical, and sequence maps, linkage relationships among genes (markers) may be more accurately approached in terms of global models for the distribution of recombination events that take into account interference. There are two principal analytical methods used for ascertaining linkage relationships. The first method, the Haldane-Kosambi differential equation approach, has the limitation that all of its calculations rest on consideration of only three gene markers, where recombination depends only on the physical distance between markers. In this formulation the resulting map function is in general not feasible for use with multiple markers. The second method starts with a model of the crossover process from which recombination values are determined. The best studied global recombination processes are based on sequential (renewal) crossover formation processes, the count-location crossover structure, and crossovers evolving by a cascade mechanism. This paper, containing both review and new results, concentrates on two aspects of recombination structures: (i) classifications and characterizations of multimarker crossover distributions; and (ii) analysis of regular and higher order crossover interference forms. In eucaryotic species, the general impression is that positive interference prevails, while in procaryotic and viral organisms, there may be circumstances of negative interference. We would propose in estimating the crossover formation process a binomial count distribution or any other count distribution satisfying property (a) of Theorem 9.1 and a location distribution fitted by the data. It is also reasonable to try one or more obligate crossover points superimposed on independent Poisson processes determining other crossover points. This latter model also generates a situation of positive interference (Theorem 3.1).

Animals↗
PubMed1994

Localization of a gene causing cystinuria to chromosome 2p.

Cystinuria is an autosomal recessive disorder of amino acid transport. It is a common hereditary cause of kidney stones worldwide, and is associated with significant morbidity. In 17 affected families, we found linkage between cystinuria and three chromosome 2p markers. Maximal two-point lod scores between cystinuria and D2S119, D2S391 and D2S288 were 8.23 (theta = 0.07), 3.73 (theta = 0.15) and 3.03 (theta = 0.12), respectively. Analysis of recombinants and multipoint linkage data indicated that the most likely order is cen-D2S391-D2S119-cystinuria-D2S177-tel. We also observed high rates of homozygosity for markers in this chromosomal region among 11 affected offspring of consanguineous marriages. Based on its map position and function, the recently cloned SLC3A1 amino acid transporter gene is a primary candidate gene for this disease.

Amino Acid Transport Systems, Basic↗
PubMed1991

On the relation between the instability of ESS in discrete dynamics and segregation distortion.

There is a simple correspondence between discrete dynamical systems associated with evolutionary game dynamics and general locus multiallele selection models with non-Mendelian segregation. When interpreted properly the payoff matrix has two components, a fitness matrix component and a segregation matrix component. The presence of segregation distortion which corresponds to a non-symmetric payoff matrix, is a source of instability. With non-symmetric payoff an ESS does not usually correspond to a stable equilibrium. It is always externally stable but does not necessarily have an internally stable equilibrium.

Alleles↗
PubMed1991

Multilocus autosomal sex determination.

The two basic one locus sex determination models, diploid individual sex determination and parental sex determination, are generalized to the multilocus framework. As in the single locus case, it is established that there are two classes of polymorphic equilibria, equilibria with even sex ratio and equilibria with equal allele frequencies in the two sexes. The condition for external stability of this second class equilibria to invasion by a "new" mutant allele is that a "new" appropriately averaged sex ratio near the equilibrium be moved closer to the even sex ratio. However, stable polymorphisms with noneven sex ratio are not those that have a sex ratio as close as possible to 1/2, in contrast to the single locus case.

Animals↗
PubMed1990

Global convergence properties in multilocus viability selection models: the additive model and the Hardy-Weinberg law.

A natural coordinate system is introduced for the analysis of the global stability of the Hardy-Weinberg (HW) polymorphism under the general multilocus additive viability model. A global convergence criterion is developed and used to prove that the HW polymorphism is globally stable when each of the loci is diallelic, provided the loci are overdominant and the multilocus recombination is positive. As a corollary the multilocus Hardy-Weinberg law for neutral selection is derived.

Genetics, Population↗
PubMed1990

Two-locus autosomal sex determination: on the evolutionary genetic stability of the even sex ratio.

In two-locus models of sex determination, there are two kinds of interior (polymorphic) equilibria. One class has the even sex ratio, and the other has equal allele frequencies in the two sexes. Equilibria of the second class may exhibit linkage disequilibrium. The condition for external stability of these second-class equilibria to invasion by a new allele is that the appropriately averaged sex ratio near the equilibrium be moved closer to the even sex ratio than the average among the resident genotypes. However, invasion by a new chromosome depends on the recombination fraction in a way that appears to preclude general results about the evolutionary genetic stability of the even sex ratio in this situation.

Alleles↗
PubMed1986

Modifiers of mutation rate: a general reduction principle.

A deterministic two-locus population genetic model with random mating is studied. The first locus, with two alleles, is subject to mutation and arbitrary viability selection. The second locus, with an arbitrary number of alleles, controls the mutation at the first locus. A class of viability-analogous Hardy-Weinberg equilibria is analyzed in which the selected gene and the modifier locus are in linkage equilibrium. It is shown that at these equilibria a reduction principle for the success of new mutation-modifying alleles is valid. A new allele at the modifier locus succeeds if its marginal average mutation rate is less than the mean mutation rate of the resident modifier allele evaluated at the equilibrium. Internal stability properties of these equilibria are also described.

Alleles↗