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Biomedical subjects

D Shore

Publications and source records attributed to D Shore.

At least 37 records · Page 2Linked to original sources
PubMed1998

Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium.

Schizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment.

Adolescent↗
PubMed1998

NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees.

The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.

Adolescent↗
PubMed1998

Cellular senescence: lessons from yeast for human aging?

Recent results point to an important role for the nucleolus in the senescence of yeast cells. A further report suggests that the formation and preferential accumulation in mother cells of extrachromosomal rDNA circles is a cause of aging in yeast; this may be an ancient and conserved mechanism of senescence.

Aging↗
PubMed1997

A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae Rap1 protein binds with high affinity to sites within the poly(C(1-3)A) tracts at telomeres, where it plays a role in both telomere length regulation and the initiation of telomeric silencing. Rap1p initiates silencing at telomeres by interacting through its carboxy-terminal domain with Sir3p and Sir4p, both of which are required for repression. This same domain of Rap1p also negatively regulates telomere elongation, through an unknown mechanism. We have identified a new Rap1-interacting factor (Rif2p) that plays a role in telomere length regulation. Rif2p has considerable functional similarities with a Rap1p-interacting factor (Rif1p) identified previously. Mutations in RIF1 or RIF2 (unlike mutations in the silencing genes SIR3 and SIR4) result in moderate telomere elongation and improved telomeric silencing. However, deletion of both RIF1 and RIF2 in the same cell results in a dramatic increase in telomere length, similar to that seen with a carboxy-terminal truncation of Rap1p. In addition, overexpression of either RIF1 or RIF2 decreases telomere length, and co-overexpression of these proteins can reverse the telomere elongation effect of overexpression of the Rap1p carboxyl terminus. Finally, we show that Rif1p and Rif2p can interact with each other in vivo. These results suggest that telomere length regulation is mediated by a protein complex consisting of Rif1p and Rif2p, each of which has distinct regulatory functions. One role of Rap1p in telomere length regulation is to recruit these proteins to the telomeres.

Bacterial Proteins↗
PubMed1997

A protein-counting mechanism for telomere length regulation in yeast.

In the yeast Saccharomyces cerevisiae, telomere elongation is negatively regulated by the telomere repeat-binding protein Rap1p, such that a narrow length distribution of telomere repeat tracts is observed. This length regulation was shown to function independently of the orientation of the telomere repeats. The number of repeats at an individual telomere was reduced when hybrid proteins containing the Rap1p carboxyl terminus were targeted there by a heterologous DNA-binding domain. The extent of this telomere tract shortening was proportional to the number of targeted molecules, consistent with a feedback mechanism of telomere length regulation that can discriminate the precise number of Rap1p molecules bound to the chromosome end.

Binding Sites↗
PubMed1997

Genetic recombination: sex-change operations in yeast.

The 'directionality' of mating-type switching in building yeast is determined by mechanisms that regulate genetic recombination along the whole left arm of chromosome III. In MATa cells, a cis-acting 'recombinational enhancer' activates this entire region, while in MATalpha cells the enhancer is turned off by the alpha2 repressor.

Chromosomes, Fungal↗
PubMed1997

Rap1p and telomere length regulation in yeast.

Telomere length in the yeast Saccharomyces cerevisiae is under stringent genetic control such that a narrow length distribution of TG1-3 repeats is observed. Previous studies have shown that Rap1p, which binds to the double-stranded telomeric repeats, plays a role in regulating repeat length: point mutations in the Rap1p C-terminus often result in a higher average telomere length and deletion of this region causes extreme telomere elongation. We have investigated further the role of Rap1p in this process. Our results suggest that telomere length is regulated by a negative feedback mechanism that can sense the number of Rap1p molecules bound at the chromosome end. This length regulatory mechanism requires two other proteins, Rif1p and Rif2p, that interact with each other and with the Rap1p C-terminus. Although the same C-terminal domain of Rap1p is also involved in the initiation of telomere position effect (telomeric transcriptional silencing), this Rap1p function appears to be separate from, and indeed antagonistic to, its role in telomere length regulation.

Carrier Proteins↗
PubMed1997

Coagulation factor abnormalities after the Fontan procedure and its modifications.

OBJECTIVE: Recently we reported the prevalence of thromboembolism in patients who underwent the Fontan procedure and its modifications. Although hemodynamic factors may well contribute to thromboembolism, recent evidence suggests that coagulation factor abnormalities may also play a role. We therefore set out to investigate the coagulation status in a group of patients who had undergone the Fontan procedure. METHODS: The study population consists of 20 children who had undergone the Fontan procedure and its modifications. They were examined for coagulation factor abnormalities. Concentrations of serum albumin, total protein, and liver enzymes were also measured. The median age at the time of the operation was 6.2 years (17 months to 8 years) with a male/female ratio of 2.3:1. The median time from the Fontan repair was 4.9 years (18 to 76 months). RESULTS: Protein C (p < 0.001), protein S (p < 0.02), and factor VII (p < 0.001) were significantly lower than the normal range. The changes in serum albumin and total protein and factors II, IX, and X were not significant. CONCLUSIONS: It is possible that deficiency in protein C, protein S, and factor VII partly account for the prevalence of thromboembolism after Fontan-type repairs. The risk of long-term anticoagulation should be weighed against the best palliative procedure for these patients. We suggest that reduced protein C, protein S, and factor VII levels in this group of patients should be regarded as risk factors and that such patients should be treated with anticoagulants.

Child↗
PubMed1997

Anatomical criteria for the diagnosis of sinus venosus defects.

BACKGROUND: The diagnosis of sinus venosus defects remains a matter of debate. It is crucial to provide solid anatomical criteria, by identifying the very nature of the atrial septum relative to sinus venosus defects, to diagnose and differentiate them from other interatrial communications. OBJECTIVE: This study was designed to reestablish the anatomical criteria for the diagnosis of sinus venosus defects. METHODS: Five specimens with sinus venosus defects from the cardiopathological museum were examined. Study of the abnormal hearts was supplemented by examining the extent and structure of the atrial septum in 10 normal hearts. The echocardiograms and surgical notes were reviewed from 18 patients seen between July 1991 and August 1996 at the Royal Brompton Hospital in London diagnosed preoperatively to have a sinus venosus defect. RESULTS: The nature of the oval fossa and its muscular borders were identified in the normal hearts. In all three autopsied specimens of the superior variety of sinus venosus defect, the mouth of the superior caval vein was overriding the intact muscular anterosuperior border of the oval fossa. Two specimens thought initially to have the inferior variety of sinus venosus defect were re-classified as having defects within the oval fossa as it was the deficient oval fossa itself, rather than its intact muscular border, that was overridden by the mouth of the inferior caval vein. Sixteen patients had been diagnosed echocardiographically as exhibiting the superior variant of the defect. Retrospective review showed overriding of the superior caval vein across the upper rim of the oval fossa in 12 patients. These findings were confirmed by surgery in 11 patients with the 12th awaiting operation. Overriding of the fossa by the caval vein was not found in the other four patients. Surgery in all of these showed the defect to be within the oval fossa. In two patients diagnosed echocardiographically as having inferior defects, the surgical findings confirmed a biatrial connection of the inferior caval vein in one patient, the findings in the second were equivocal. CONCLUSIONS: The key anatomical criterion for the diagnosis of sinus venosus defects is overriding of the mouth of the superior or inferior caval vein across the intact muscular border of the oval fossa. The interatrial communication is then formed within the mouth of the overriding vein, and is outside the confines of the oval fossa.

Adolescent↗
PubMed1997

Left ventricular parallel conductance during cardiac cycle in children with congenital heart disease.

This study examines the accuracy of the conductance catheter technique and, in particular, parallel conductance [expressed as offset volume (Vc)] changes during the cardiac cycle in the human left ventricle. Two groups of patients were assessed: group 1, with an open atrial septal defect, and group 2, with an interventricular communication. In a subgroup, pre- and postoperative data were compared to assess the possible impact of shunting or anatomic considerations on our measurements. Vc is normally obtained by a saline-dilution technique previously described by Baan et al. [Vc(Baan); J. Baan, E. T. Van der velde, H. G. Debruin, G. J. Smeenk, J. Koops, A. D. Van Dijk, D. Temmerman, P. J. Senden, and B. Buis. Circulation 70: 812-823, 1984]. This does not take into account potential changes during the cardiac cycle. Four cardiac cycles were taken from the hypertonic saline washin and were divided into six equal isochrones between the maximum and minimum first derivatives of left ventricular pressure (dP/dtmax and dP/dtmin, respectively). The apparent ventricular volume was regressed against stroke volume for the corresponding cardiac cycle. The volume at the gamma-intercept corresponds to the Vc at each time interval [Vc(t)]. In group 1, there was a variation in Vc(t) during systole, but the temporal changes were quite small, on the order of 4.28% (SD = 5.18%) of total corrected end-diastolic volume (mean maximal variation of 2.60 ml). Furthermore, the value of Vc obtained at dP/dtmax was not significantly different from that obtained at dP/dtmin. For group 2 as a whole, mean Vc(Baan) did not change significantly with ventricular septal defect closure (preoperative, 8.85 +/- 11.1 ml; postoperative, 9.82 +/- 11.84 ml). Group 2 children also exhibited a systolic cyclical variation in Vc(t) similar to group 1. Finally, Vc(t) as a percentage of end-diastolic volume was no different when group 1 and group 2 were compared. We conclude that in the left ventricle, even in the presence of a left-to-right shunt, there is a small but insignificant difference in parallel conductance during ventricular ejection. The magnitude of this cyclical change does not preclude ventricular volume measurement in congenital heart disease by the conductance catheter technique.

Child↗
PubMed1997

Discrepancies in parent and teacher ratings of adaptive behavior of children with multiple disabilities.

Parent and teacher ratings of adaptive skills of 59 children with multiple disabilities (mean age 6 years) in a rehabilitation day treatment setting were compared. The Vineland Adaptive Behavior Scales Classroom and Survey Editions were administered to each child's teacher and mother or other primary caretaker, respectively. Correlational analyses indicated a robust relation between Vineland forms; however, mean score comparisons indicated that teachers systematically rated the children as more skilled in both the global and the specific domains of adaptive behavior than did caretakers. Sources of interrater disagreement and implications for assessment of children with multiple disabilities were discussed.

Activities of Daily Living↗
PubMed1997

Telomere length regulation: getting the measure of chromosome ends.

Telomeres, the protein-DNA complexes that comprise the ends of linear eukaryotic chromosomes, serve to protect the chromosome ends and allow their complete replication. Telomeres also appear to play an essential role in chromosome segregation. In most organisms telomeric DNA consists of a series of short repeats that are variable in length, but regulated at a fixed average value in the germline. The possible involvement of telomere repeat shortening in aging and carcinogenesis has recently attracted attention to the more basic question of how telomere length is sensed and regulated by the cell. Telomere length in the budding yeast Saccharomyces cerevisiae has been known for over a decade now to be under complex genetic control, and this organism has provided a useful model system to address basic mechanistic questions. This review focuses on recent studies in yeast which indicate that the double-strand telomere-repeat binding protein Rap1 may play an important role in a negative-feedback mechanism that senses and controls the length of the telomere repeats. Although the same carboxy-terminal domain of Rap1p is involved in both telomere length regulation and telomeric silencing (telomere position effect), it appears that these two functions are mediated by separate sets of Rap1p-interacting proteins. Results from other systems suggest that negative regulation of telomere elongation by a double-stranded telomere-repeat binding protein may be a highly conserved strategy for telomere length control.

Animals↗
PubMed1996

Silencing of genes at nontelomeric sites in yeast is controlled by sequestration of silencing factors at telomeres by Rap 1 protein.

Rap1p binds to silencer elements and telomeric repeats in yeast, where it appears to initiate silencing by recruiting Sir3p and Sir4p to the chromosome through interactions with its carboxy-terminal domain. Sir3p and Sir4p interact in vitro with histones H3 and H4 and are likely to be structural components of silent chromatin. We show that targeting of these Sir proteins to the chromosome is sufficient to initiate stable silencing either at a silent mating-type locus lacking a functional silencer element or at a telomere in a strain in which the Rap1p carboxy-terminal silencing domain has been deleted. Silencing by Sir protein targeting can also be initiated at a telomere-proximal site (ADH4), but is much weaker at an internal chromosomal locus (LYS2). Strikingly, deletion of the Rap1p silencing domain, which abolishes telomeric silencing, improves targeted silencing at LYS2 by both Sir3p and Sir4p, while weakening the silencing activity of these proteins at or near a telomere. This effect may result from the release of Sir proteins from the telomeres, thus increasing their effective concentration at other chromosomal sites. We suggest that telomeres and Rap1p serve a regulatory role in sequestering Sir proteins at telomeres, controlling silencing at other loci in trans and preventing indiscriminate gene silencing throughout the genome.

Chromosomes, Fungal↗