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D Sharon

Publications and source records attributed to D Sharon.

At least 19 recordsLinked to original sources
PubMed2001

Mouse-human orthology relationships in an olfactory receptor gene cluster.

The olfactory receptor (OR) subgenome harbors the largest known gene family in mammals, disposed in clusters on numerous chromosomes. One of the best characterized OR clusters, located at human chromosome 17p13.3, has previously been studied by us in human and in other primates, revealing a conserved set of 17 OR genes. Here, we report the identification of a syntenic OR cluster in the mouse and the partial DNA sequence of many of its OR genes. A probe for the mouse M5 gene, orthologous to one of the OR genes in the human cluster (OR17-25), was used to isolate six PAC clones, all mapping by in situ hybridization to mouse chromosome 11B3-11B5, a region of shared synteny with human chromosome 17p13.3. Thirteen mouse OR sequences amplified and sequenced from these PACs allowed us to construct a putative physical map of the OR gene cluster at the mouse Olfr1 locus. Several points of evidence, including a strong similarity in subfamily composition and at least four cases of gene orthology, suggest that the mouse Olfr1 and the human 17p13.3 clusters are orthologous. A detailed comparison of the OR sequences within the two clusters helps trace their independent evolutionary history in the two species. Two types of evolutionary scenarios are discerned: cases of "true orthologous genes" in which high sequence similarity suggests a shared conserved function, as opposed to instances in which orthologous genes may have undergone independent diversification in the realm of "free reign" repertoire expansion.

Animals↗
PubMed2001

[On bedside medical humanities].

This article presents a challenge which we call "the humane gap in medicine" and also raises some ideas on how to meet this challenge. This is the gap between the capacities of biomedicine as a bureaucratic and scientific establishment and the medical needs and expectations of its beneficiaries. It is argued that successful medicine relies on two pillars. The first is the corpus of biomedical knowledge, while the other is knowing the patients within their bio-psycho-social life-world. Both the second pillar and the bridging of the two pillars are dependent on the Humanities. The humanities in medicine also provide healthcare professionals with means of support against devastating encounters with suffering, disability or the relentless pressures of academic careers and overwhelming physical labor. The humanities serve as a shared platform for all healthcare providers, diminishing traditional, and sometimes obstructive, boundaries such as those that may exist between doctors and nurses. We provide a list of possible benefits that the Humanities may bring to clinical practice and medical education. We conclude with some suggestions on how the humanities may be incorporated into medical education and implemented at the bedside. We suggest that art students attend anatomical labs; courses in medical humanities be opened for the benefit of all students, within the faculty of medicine and beyond. We encourage students from every faculty to undertake academic activities which will combine voluntary work with the sick with participatory observation in the tradition of cultural anthropology.

Humanism↗
PubMed2000

Identification and characterization of coding single-nucleotide polymorphisms within a human olfactory receptor gene cluster.

Single-nucleotide polymorphisms (SNPs) were studied in 15 olfactory receptor (OR) coding regions, one control region and two noncoding sequences all residing within a 412 kb OR gene cluster on human chromosome 17p13.3, as well as in other G-protein coupled receptors (GPCRs). A total of 26 SNPs were identified in ORs, 21 of which are coding SNPs (cSNPs). The mean nucleotide diversity of OR coding regions was 0.078% (ranging from 0 to 0.16%), which is about twice higher than that of other GPCRs, and similar to the nucleotide diversity levels of noncoding regions along the human genome. The high polymorphism level in the OR coding regions might be due to a weak positive selection pressure acting on the OR genes. In two cases, OR genes have been found to share the same cSNP. This could be explained by recent gene conversion events, which might be a part of a concerted evolution mechanism acting on the OR superfamily. Using the genotype data of 85 unrelated individuals in 15 SNPs, we found linkage disequilibrium (LD) between pairs of SNPs located on the centromeric part of the cluster. On the other hand, no LD was found between SNPs located on the telomeric part of the cluster, suggesting the presence of several hot-spots for recombination within this cluster. Thus, different regions of this gene cluster may have been subject to different recombination rates.

Alleles↗
PubMed2000

The olfactory receptor gene superfamily: data mining, classification, and nomenclature.

The vertebrate olfactory receptor (OR) subgenome harbors the largest known gene family, which has been expanded by the need to provide recognition capacity for millions of potential odorants. We implemented an automated procedure to identify all OR coding regions from published sequences. This led us to the identification of 831 OR coding regions (including pseudogenes) from 24 vertebrate species. The resulting dataset was subjected to neighbor-joining phylogenetic analysis and classified into 32 distinct families, 14 of which include only genes from tetrapodan species (Class II ORs). We also report here the first identification of OR sequences from a marsupial (koala) and a monotreme (platypus). Analysis of these OR sequences suggests that the ancestral mammal had a small OR repertoire, which expanded independently in all three mammalian subclasses. Classification of "fish-like" (Class I) ORs indicates that some of these ancient ORs were maintained and even expanded in mammals. A nomenclature system for the OR gene superfamily is proposed, based on a divergence evolutionary model. The nomenclature consists of the root symbol 'OR', followed by a family numeral, subfamily letter(s), and a numeral representing the individual gene within the subfamily. For example, OR3A1 is an OR gene of family 3, subfamily A, and OR7E12P is an OR pseudogene of family 7, subfamily E. The symbol is to be preceded by a species indicator. We have assigned the proposed nomenclature symbols for all 330 human OR genes in the database. A WWW tool for automated name assignment is provided.

Animals↗
PubMed2000

Dichotomy of single-nucleotide polymorphism haplotypes in olfactory receptor genes and pseudogenes.

Substantial efforts are focused on identifying single-nucleotide polymorphisms (SNPs) throughout the human genome, particularly in coding regions (cSNPs), for both linkage disequilibrium and association studies. Less attention, however, has been directed to the clarification of evolutionary processes that are responsible for the variability in nucleotide diversity among different regions of the genome. We report here the population sequence diversity of genomic segments within a 450-kb cluster of olfactory receptor (OR) genes on human chromosome 17. We found a dichotomy in the pattern of nucleotide diversity between OR pseudogenes and introns on the one hand and the closely interspersed intact genes on the other. We suggest that weak positive selection is responsible for the observed patterns of genetic variation. This is inferred from a lower ratio of polymorphism to divergence in genes compared with pseudogenes or introns, high non-synonymous substitution rates in OR genes, and a small but significant overall reduction in variability in the entire OR gene cluster compared with other genomic regions. The dichotomy among functionally different segments within a short genomic distance requires high recombination rates within this OR cluster. Our work demonstrates the impact of weak positive selection on human nucleotide diversity, and has implications for the evolution of the olfactory repertoire.

Alleles↗
PubMed2000

X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function.

PURPOSE: To assess the frequency of RPGR and RP2 mutations in a set of 85 patients with X-linked retinitis pigmentosa (XLRP) and to compare the visual function of patients with mutations in RPGR versus RP2. METHODS: Eighty-five unrelated patients with XLRP were ascertained, mainly from North America. The single-strand conformation polymorphism (SSCP) and a direct sequencing technique were used to screen their DNA for mutations in the coding region and splice sites of RPGR and RP2. The Snellen visual acuities, visual field areas, and 0.5-Hz and 30-Hz electroretinograms (ERGs) were measured in male patients. The visual function parameters were compared using multiple regression analysis. RESULTS: A wide spectrum of mutations was found in both genes, including missense, nonsense, splice-site, and frameshift mutations. Twenty putative pathogenic mutations in RPGR, 15 of which were novel, were found in 22 patients (26%), whereas 6 mutations in RP2, 4 of which were novel, were found in 6 patients (7%). A high fraction of the mutations in both genes affected amino acid residues within or adjacent to presumed functional domains. Comparison of visual function between comparably aged patients with mutations in RPGR versus RP2 showed that, on average, patients with RPGR mutations have lower ERG amplitudes and smaller visual field areas. CONCLUSIONS: Mutations in RPGR and RP2 genes together account for approximately 33% of cases of XLRP in North America. Patients with RPGR mutations have less overall retinal function on average than those with RP2 mutations, on the basis of measurements of visual field areas and full-field ERG amplitudes.

Adolescent↗
PubMed2000

Patients' violence towards the staff in psychiatric institutions--a professional and ethical dilemma.

To address the violence phenomenon in psychiatric institutions towards the staff, to find the causes of these phenomena and to examine effective methods that will help to prevent the occurrence and/or confront it. To break the "conspiracy of silence" around the subject matter and to raise the awareness of all personnel in order to formulate a policy of responses to violent incidents and to learn procedures for the management of these complex situations.

Hospitals, Psychiatric↗
PubMed1999

Primate evolution of an olfactory receptor cluster: diversification by gene conversion and recent emergence of pseudogenes.

The olfactory receptor (OR) subgenome harbors the largest known gene family in mammals, disposed in clusters on numerous chromosomes. We have carried out a comparative evolutionary analysis of the best characterized genomic OR gene cluster, on human chromosome 17p13. Fifteen orthologs from chimpanzee (localized to chromosome 19p15), as well as key OR counterparts from other primates, have been identified and sequenced. Comparison among orthologs and paralogs revealed a multiplicity of gene conversion events, which occurred exclusively within OR subfamilies. These appear to lead to segment shuffling in the odorant binding site, an evolutionary process reminiscent of somatic combinatorial diversification in the immune system. We also demonstrate that the functional mammalian OR repertoire has undergone a rapid decline in the past 10 million years: while for the common ancestor of all great apes an intact OR cluster is inferred, in present-day humans and great apes the cluster includes nearly 40% pseudogenes.

Animals↗
PubMed1998

Genome dynamics, evolution, and protein modeling in the olfactory receptor gene superfamily.

The human olfactory subgenome represents several hundred olfactory receptor (OR) genes in a dozen or more clusters on several chromosomes. One OR gene cluster on human chromosome 17 has been characterized by us in detail. Based on a large-scale DNA sequence analysis, we have identified events of gene duplication and fusion as well as the generation of pseudogenes. The latter instances of 'gene death' could underlie the widespread phenomenon of human specific anosmias. Sixteen OR coding regions were found on this cluster, and six of them are pseudogenes. One of these pseudogenes, OR17-23, was found to be an intact open reading frame in an old world monkey. This may be a reflection of an OR repertoire diminution in man. A homology model of the OR protein was constructed by utilizing the rich information available on approximately 200 OR sequences. The putative odorant complementarity determining regions (CDR) was found to consist of 20 hypervariable residues facing an interior caving defined by transmembrane helices 3, 4 and 5. Such a model could be useful in analyzing additional OR gene sequences in the human genome in terms of odorant binding.

Base Sequence↗
PubMed1998

Encouraging initial response of restless legs syndrome to pramipexole.

Restless legs syndrome (RLS) is a common condition that results in uncomfortable sensations and an urge to move the limbs. Two centers tested a new dopamine agonist, pramipexole, in 23 patients with RLS in a time-limited, open-label, clinical trial. After 4 weeks or more, 19 patients reported significant improvement as assessed by the short International Restless Legs Syndrome Study Group questionnaire (p < 0.0001). These encouraging preliminary results justify larger, controlled trials for pramipexole in patients with RLS.

Adult↗
PubMed1997

Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes.

Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K+ channel, GIRK, is activated by the beta gamma subunits of G proteins and is widely expressed in the brain. We investigated whether an interaction between mGluRs and GIRK is possible, using Xenopus oocytes expressing mGluRs and a cardiac/brain subunit of GIRK, GIRK1, with or without another brain subunit, GIRK2. mGluRs known to inhibit adenylyl cyclase (types 2, 3, 4, 6, and 7) activated the GIRK channel. The strongest response was observed with mGluR2; it was inhibited by pertussis toxin (PTX). This is consistent with the activation of GIRK by Gi/Go-coupled receptors. In contrast, mGluR1a and mGluR5 receptors known to activate phospholipase C, presumably via G proteins of the Gq class, inhibited the channel's activity. The inhibition was preceded by an initial weak activation, which was more prominent at higher levels of mGluR1a expression. The inhibition of GIRK activity by mGluR1a was suppressed by a broad-specificity protein kinase inhibitor, staurosporine, and by a specific protein kinase C (PKC) inhibitor, bis-indolylmaleimide, but not by PTX, Ca(2-)chelation, or calphostin C. Thus, mGluR1a inhibits the GIRK channel primarily via a pathway involving activation of a PTX-insensitive G protein and, eventually, of a subtype of PKC, possibly PKC-mu. In contrast, the initial activation of GIRK1 caused by mGluR1a was suppressed by PTX but not by the protein kinase inhibitors. Thus, this activation probably results from a promiscuous coupling of mGluR1a to a Gi/Go protein. The observed modulations may be involved in the mGluRs effects on neuronal excitability in the brain. Inhibition of GIRK by phospholipase C-activating mGluRs bears upon the problem of specificity of G protein (GIRK interaction) helping to explain why receptors coupled to Gq are inefficient in activating GIRK.

Adenylate Cyclase Toxin↗
PubMed1990

An efficacy study of single- versus double-seizure induction with ECT in major depression.

Twenty-nine patients with major depression, with and without psychosis, were randomly assigned to bilateral conventional electroconvulsive therapy (ECT) or modified multiple monitored ECT (MMECT) limited to two seizure inductions in a session. From pretreatment to after the fourth treatment session, modified MMECT was associated with more rapid amelioration of depressive symptoms on the basis of blindly rated Hamilton Rating Scale for Depression scores. No medical complications occurred. Sixty-two percent of patients in the modified MMECT group had posttreatment confusion, whereas 15% of patients treated with conventional ECT were confused. Modified MMECT appears to confer some clinical advantage over conventional ECT in the treatment of major depression while carrying an increased risk of treatment-related reversible confusion.

Clinical Protocols↗
PubMed1986

Cost analysis of antibiotics in the management of perforated or gangrenous appendicitis.

Costs associated with treating patients for gangrenous or perforated appendicitis were compared. Patients received single agent therapy with cefoperazone or cefamandole or combination antibiotics consisting of clindamycin and serum level-adjusted gentamicin. Forty-eight patients received cefamandole, 47 received cefoperazone, and 52 received combination clindamycin and gentamicin. Costs to the pharmacy for drugs were greater for the combination therapy; however, the higher failure rate associated with the cephalosporins created greater expenses for the single agent therapy than for combination therapy.

Adolescent↗
PubMed1986

Pattern-reversal visual evoked potentials in hepatic cirrhosis.

Whole-field pattern-reversal VEPs (VEP) were examined in fifteen patients screened for hepatic cirrhosis. Twelve age- and sex-matched normal individuals and twenty-four psychotic patients on maintenance neuroleptic medication served as controls. There were no differences in latency or amplitude of the major positive component VEP (P100) to binocularly or monocularly presented reversing patterns between hepatic and control groups. Pre-exposure to flicker (the "photostress test") caused no abnormalities of VEP. Only in one patient with hepatic cirrhosis did monocular stimulation in the photostress condition cause a marked delay of P100. It is possible that this was an idiosyncratic response and that visual abnormalities detectable with the VEP technique can be attributed to other factors such as poor attention or accompanying disorders of the visual system.

Electroencephalography↗