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Biomedical subjects

J Nadeau

Publications and source records attributed to J Nadeau.

At least 19 recordsLinked to original sources
PubMed2006

Genomic pathways database and biological data management.

In this paper, we discuss the properties of biological data and challenges it poses for data management, and argue that, in order to meet the data management requirements for 'digital biology', careful integration of the existing technologies and the development of new data management techniques for biological data are needed. Based on this premise, we present PathCase: Case Pathways Database System. PathCase is an integrated set of software tools for modelling, storing, analysing, visualizing and querying biological pathways data at different levels of genetic, molecular, biochemical and organismal detail. The novel features of the system include: (i) genomic information integrated with other biological data and presented starting from pathways; (ii) design for biologists who are possibly unfamiliar with genomics, but whose research is essential for annotating gene and genome sequences with biological functions; (iii) database design, implementation and graphical tools which enable users to visualize pathways data in multiple abstraction levels and to pose exploratory queries; (iv) a wide range of different types of queries including, 'path' and 'neighbourhood queries' and graphical visualization of query outputs; and (v) an implementation that allows for web (XML)-based dissemination of query outputs (i.e. pathways data in BIOPAX format) to researchers in the community, giving them control on the use of pathways data.

Computational Biology↗
PubMed2003

Pathways database system: an integrated system for biological pathways.

MOTIVATION: During the next phase of the Human Genome Project, research will focus on functional studies of attributing functions to genes, their regulatory elements, and other DNA sequences. To facilitate the use of genomic information in such studies, a new modeling perspective is needed to examine and study genome sequences in the context of many kinds of biological information. Pathways are the logical format for modeling and presenting such information in a manner that is familiar to biological researchers. RESULTS: In this paper we present an integrated system, called Pathways Database System, with a set of software tools for modeling, storing, analyzing, visualizing, and querying biological pathways data at different levels of genetic, molecular, biochemical and organismal detail. The novel features of the system include: (a) genomic information integrated with other biological data and presented from a pathway, rather than from the DNA sequence, perspective; (b) design for biologists who are possibly unfamiliar with genomics, but whose research is essential for annotating gene and genome sequences with biological functions; (c) database design, implementation and graphical tools which enable users to visualize pathways data in multiple abstraction levels, and to pose predetermined queries; and (d) an implementation that allows for web(XML)-based dissemination of query outputs (i.e. pathways data) to researchers in the community, giving them control on the use of pathways data. AVAILABILITY: Available on request from the authors.

Database Management Systems↗
PubMed2001

The sequence of the human genome.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

Algorithms↗
PubMed2001

Shared bathing and drowning in infants and young children.

OBJECTIVE: A study was undertaken to look at possible risks of shared bathing in early childhood. METHODS: Autopsy databases were searched at the Women's and Children's Hospital and State Coroner's Office, Adelaide, Australia, from January 1963 to December 1999, the Victorian Institute of Forensic Medicine, Melbourne, Australia, from January 1991 to December 1999, and the Children's Hospital-San Diego, San Diego, USA, from January 1990 to December 1999, for all cases registered as drowning in children aged 2 years and under who were in a bath with another child around the time of death. RESULTS: A total of 17 cases were found. The age range of the victims was 8-22 months (average=11.8 months), with a male to female ratio of 10:7. The surviving children (who were all siblings) were significantly older, with an age range of 19-48 months (average=30.4 months), and a male to female ratio of 12:5. (The survivors were on average 18.5 months older than the victims, range=11-32 months). In every case the children had been left unsupervised for variable periods of time. CONCLUSIONS: These cases represented a significant component -- between 22 and 58% -- of bath drownings in the 2 years and under age group. It would appear that shared bathing for young children and infants may only acceptable if adult supervision is constant, and that a young sibling is not an appropriate person to look after an infant or toddler in the bath. While the risk of leaving an infant in a filled bath may be exacerbated if an older child is also present, further population-based studies are required to examine this hypothesis.

Age Distribution↗
PubMed2001

Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice.

The contribution of genetic and environmental factors to variations in bone quality are understood poorly. We tested whether bone brittleness varies with genetic background using the A/J and C57BL/6J inbred mouse strains. Whole bone four-point bending tests revealed a 70% decrease in postyield deflection of A/J femurs compared with C57BL/6J, indicating that A/J femurs failed in a significantly more brittle manner. Cyclic loading studies indicated that A/J femurs accumulated damage differently than C57BL/6J femurs, consistent with their increased brittleness. Differences in matrix composition also were observed between the two mouse strains. A/J femurs had a 4.5% increase in ash content and an 11.8% decrease in collagen content. Interestingly, a reciprocal relationship was observed between femoral geometry and material stiffness; this relationship may have contributed to the brittle phenotype of A/J femurs. A/J femurs are more slender than those of C57BL/6J femurs; however, their 47% smaller moment of inertia appeared to be compensated by an increased tissue stiffness at the expense of altered tissue damageability. Importantly, these differences in whole bone mechanical properties between A/J and C57BL/6J femurs could not have been predicted from bone mass or density measures alone. The results indicated that bone brittleness is a genetically influenced trait and that it is associated with genetically determined differences in whole bone architecture, bone matrix composition, and mechanisms of cyclical damage accumulation.

Animals↗
PubMed2001

Teaching subjects with type 2 diabetes how to incorporate sugar choices into their daily meal plan promotes dietary compliance and does not deteriorate metabolic profile.

OBJECTIVE: To determine whether teaching free-living subjects with type 2 diabetes how to incorporate added sugars or sweets into their daily meal plan results in a greater consumption of calories (fat or sugar) and deteriorates their glycemic or lipid profiles but improves their perceived quality of life. RESEARCH DESIGN AND METHODS: In an 8-month randomized controlled trial, 48 free-living subjects with type 2 diabetes were taught either a conventional (C) meal plan (no concentrated sweets) or one permitting as much as 10% of total energy as added sugars or sweets (S). Mean individual nutrient intake was determined using the average of six 24-h telephone recalls per 4 months. Metabolic control and quality of life were evaluated every 2 months. Quality of life was assessed using the Medical Outcome Survey and the Diabetes Quality of Life questionnaire. RESULTS: The S group did not consume more calories (fat or sugar) and in fact ate significantly less carbohydrate (-15 vs. 10 g) and less starch (-7 vs. 8 g) and had a tendency to eat fewer calories (-77 vs. 81 kcal) than the C group. Weight remained stable, and there was no evidence that consuming more sugar worsened metabolic profile or improved their perceived quality of life. CONCLUSIONS: Giving individuals with type 2 diabetes the freedom to include sugar in their daily meal plan had no negative impact on dietary habits or metabolic control. Health professionals can be reassured and encouraged to teach the new "sugar guidelines," because doing so may result in a more conscientious carbohydrate consumption.

Adult↗
PubMed2000

Oriented asymmetric divisions that generate the stomatal spacing pattern in arabidopsis are disrupted by the too many mouths mutation.

Wild-type stomata are spaced by intervening cells, a pattern disrupted in the Arabidopsis mutant too many mouths (tmm). To determine the mechanism of wild-type spacing and how tmm results in pattern violations, we analyzed the behavior of cells through time by using sequential dental resin impressions. Meristemoids are stomatal precursors produced by asymmetric division. We show that wild-type patterning largely results when divisions next to a preexisting stoma or precursor are oriented so that the new meristemoid is placed away. Because this placement is independent of cell lineage, these divisions may be oriented by cell-cell signaling. tmm randomizes this orientation and releases a prohibition on asymmetric division in cells at specific locations, resulting in stomatal clusters. TMM is thus necessary for two position-dependent events in leaves: the orientation of asymmetric divisions that pattern stomata, and the control of which cells will enter the stomatal pathway. In addition, our findings argue against most previous hypotheses of wild-type stomatal patterning.

Arabidopsis↗
PubMed1999

Clinical experience over 48 years with pheochromocytoma.

OBJECTIVE: To analyze the presentation, localization, surgical management, pathology, and long-term outcome of a large series of patients with pheochromocytomas. SUMMARY BACKGROUND DATA: There are several areas of controversy pertaining to pheochromocytomas. Although many studies report a higher rate of malignancy for extraadrenal pheochromocytomas than for adrenal pheochromocytomas, the number of patients with the former tumor are small and statistical analysis is lacking. There has also been recent debate as to whether microscopic features of the tumor may be predictive of future behavior. METHODS: From 1950 to 1998, the authors observed 108 pheochromocytomas in 104 patients. The outcome of these patients has been followed prospectively. The medical records of these patients were reviewed for data on the presentation, localization, surgical management, pathology, and outcome. Patient survival was analyzed using Kaplan-Meier survival distributions. RESULTS: This study included 66 female patients and 38 male patients. The average age at surgery was 42.3 years. Sporadic cases accounted for 84% of the patients; the other 16% had multiple endocrine neoplasia type 2, von Recklinghausen's disease, von Hippel-Lindau disease, or Carney's syndrome. Of 64 adrenal tumors, 55 were initially considered benign, 6 had microscopic malignant features, and 3 had malignant disease. Mean patient follow-up was 12.6 years. To date, in five additional patients (none with microscopic disease) malignant disease developed (13% overall rate of malignancy). Recurrence occurred as late as 15 years after resection. Of 26 extraadrenal pheochromocytomas, 14 were initially considered benign, 8 had microscopic malignant features, and 4 had malignant disease. Thus, 46% of patients had either malignant disease or tumors with malignant features. Mean patient follow-up was 11.5 years. In one patient with benign disease and in one patient with malignant features, malignant disease developed (23% overall rate of malignancy). The difference in the rate of malignancy was not statistically significant between adrenal and extraadrenal pheochromocytomas. Patients with adrenal and extraadrenal pheochromocytomas also had similar rates of survival (p = NS). CONCLUSIONS: The data suggest that patients with extraadrenal pheochromocytomas have the same risk of malignancy and the same overall survival as patients with adrenal pheochromocytomas. Lifelong follow-up of these patients is mandatory.

Adolescent↗
PubMed1999

Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity.

Adequate bile flow, maintained in part by the efficient enterohepatic recirculation of bile acids, is critical for normal liver function. One important component of this process is the uptake of bile acids from the portal circulation into hepatocytes by the bile acid uptake transporter sodium taurocholate cotransporting polypeptide (NTCP). Thus, the expression and functional activity of this transporter may affect the rate of bile acid removal from the portal circulation. Accordingly, we assessed NTCP mRNA expression from human livers using a sensitive RNase protection assay. In addition, the ability of various bile acids and drugs to inhibit NTCP activity was determined using a recombinant vaccinia expression system. A 40-fold interindividual variability was found in NTCP mRNA levels determined in eight liver samples of disease-free donors. Expressed NTCP exhibited high-affinity, sodium-dependent uptake of taurocholate, and as expected, this was markedly inhibited by bile acids and organic anions. A number of drugs, including peptidomimetic renin inhibitors, propranolol, cyclosporin, and progesterone, were found to be potent inhibitors, whereas antiarrhythmic agents, including bupivicaine, lidocaine, and quinidine, were found to enhance NTCP activity. Accordingly, these results indicate that large interindividual variability exists in NTCP mRNA level and that a number of drugs currently in clinical use have the potential to interact with and alter NTCP activity, thereby affecting hepatic bile acid uptake.

Bile Acids and Salts↗
PubMed1997

Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus.

Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is due to autoimmune destruction of pancreatic beta-cells. Genetic susceptibility to IDDM is encoded by several loci, one of which (IDDM2) maps to a variable number of tandem repeats (VNTR) minisatellite, upstream of the insulin gene (INS). The short class I VNTR alleles (26-63 repeats) predispose to IDDM, while class III alleles (140-210 repeats) have a dominant protective effect. We have reported that, in human adult and fetal pancreas in vivo, class III alleles are associated with marginally lower INS mRNA levels than class I, suggesting transcriptional effects of the VNTR. These may be related to type 1 diabetes pathogenesis, as insulin is the only known beta-cell specific IDDM autoantigen. In search of a more plausible mechanism for the dominant effect of class III alleles, we analysed expression of insulin in human fetal thymus, a critical site for tolerance induction to self proteins. Insulin was detected in all thymus tissues examined and class III VNTR alleles were associated with 2- to 3-fold higher INS mRNA levels than class I. We therefore propose higher levels of thymic INS expression, facilitating immune tolerance induction, as a mechanism for the dominant protective effect of class III alleles.

Abortion, Therapeutic↗
PubMed1996

Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor.

Mice that have been made deficient for the cystic fibrosis transmembrane conductance regulator (Cftr) usually die of intestinal obstruction. We have created Cftr-deficient mice and demonstrate prolonged survival among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity is genetically determined. A genome scan showed that the major modifier locus maps near the centromere of mouse chromosome 7. Electrophysiological studies on mice with prolonged survival show that the partial rectification of Cl- and Na+ ion transport abnormalities can be explained in part by up-regulation of a calcium-activated Cl- conductance. Identification of modifier genes in our Cftr(m1HSC)/Cftr(m1HSC) mice should provide important insight into the heterogeneous disease presentation observed among CF patients.

Animals↗
PubMed1996

Differential effects of angiotensin converting enzyme inhibitors on the vasodepressor and prostacyclin responses to bradykinin.

Angiotensin converting enzyme (ACE) inhibitors block degradation of bradykinin and bradykinin stimulates prostacyclin production. ACE inhibitors are reported to increase prostaglandins. Therefore, we set out to determine 1) the contribution of prostacyclin to the bradykinin-mediated vasodepressor effects of ACE inhibitors, 2) whether ACE inhibitors alter the effect of bradykinin on prostacyclin, and 3) whether the effects of ACE inhibitors on bradykinin and prostaglandins are class effects or dependent on ACE inhibitor structure. To address these questions, we compared the effects of captopril, quinapril and placebo on blood pressure, urinary excretion of 2,3-dinor-6-keto-PGF1 alpha, and the vasodepressor response to i.v. bradykinin in 21 salt-replete normal-to-high renin hypertensive patients. Captopril and quinapril doses were titrated to lower pressure similarly. Captopril, but not quinapril, increased excretion of prostacyclin metabolite (217 +/- 50 vs. 135 +/- 21 pg/mg Cr base line, P < .05). Both ACE inhibitors dramatically, equally potentiated the vasodepressor response to bradykinin; the bradykinin dose required to decrease mean arterial pressure 15 mm Hg or increase pulse 20 bpm was 50-fold lower in ACEI-treated than in placebo-treated subjects (10 +/- 0 and 12.1 +/- 2.1 ng/kg/min in captopril and quinapril groups vs. 567 +/- 109 ng/kg/min in the placebo group; P < .005). ACE inhibition significantly attenuated the prostacyclin response to bradykinin at any given level of hypotensive response. Indomethacin abolished the prostacyclin response to bradykinin but did not alter the vasodepressor response. These data demonstrate that ACE inhibitors potentiate bradykinin-mediated vasodepression through a prostaglandin-independent mechanism. They suggest that although ACE inhibitors increase prostaglandins by increasing bradykinin, ACE inhibitors may attenuate prostaglandin production through a second bradykinin-independent mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Analysis of the Pax-3 gene in the mouse mutant splotch.

In a linkage analysis of Pax-3 and splotch no recombinations were found in 117 backcross mice. Molecular analysis of Pax-3 in three alleles of splotch shows a number of significant alterations to the Pax-3 gene. In Sp/Sp embryos, cDNA PCR analysis reveals a shortened transcript in which exon 4 of Pax-3 is deleted due to mutation of the splice acceptor site of intron 3. In the Sp4H allele, the Pax-3 gene is deleted and in Spd embryos, Pax-3 expression is significantly lower than that in normal littermate embryos. The linkage analysis, shortened Pax-3 transcript in Sp, and deletion of Pax-3 in Sp4H described here, together with the previous report of an intragenic deletion in Pax-3 in Sp2H mice and the deletion of Pax-3 in Spr mice, provide strong evidence for the allelic identity of Pax-3 and Sp.

Alleles↗
PubMed1993

Caffeine attenuates the renal vascular response to angiotensin II infusion.

Non-modulation has been proposed as an intermediate phenotype in human essential hypertension. The trait is characterized by blunted aldosterone and renal plasma flow responses to short-term angiotensin II (Ang II) infusion. Elevated tissue Ang II levels or decreased tissue adenosine levels could account for this decreased sensitivity to Ang II. In support of the latter possibility, endogenous adenosine has been shown to contribute to the renal vasoconstrictive response to Ang II in animals. We therefore tested the hypothesis that endogenous adenosine contributes to modulation of renal plasma flow in sodium-replete humans. We examined the effect of long-term administration of the adenosine receptor antagonist caffeine on baseline renal plasma flow and on the renal plasma flow response to short-term Ang II infusion in six salt-replete normotensive subjects in a single-blind, placebo-controlled study. para-Aminohippurate clearance was used to assess renal plasma flow. Ang II was infused in graded doses (0.3 to 3 ng/kg per minute) in the presence and absence of caffeine (250 mg PO TID for 7 days). Blood pressure, plasma renin activity, Ang II, electrolytes, and para-aminohippurate clearance were measured before and after each dose of Ang II. Caffeine did not alter either baseline blood pressure or the blood pressure response to Ang II but did increase baseline plasma renin activity from 0.72 +/- 0.09 to 1.42 +/- 0.26 ng angiotensin I/mL per hour (P = .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

Ethanol and circadian rhythms in the Syrian hamster: effects on entrained phase, reentrainment rate, and period.

Wheel-running rhythms were examined in male hamsters with access to 28% ethanol in lieu of water. One group was recorded in a light-dark (LD) cycle that was phase advanced by 8 h on three occasions separated by 23-27 days. On two of the three occasions, hamsters were subjected to a 2- to 3-h cage change procedure designed to stimulate wheel running, which accelerates the rate of reentrainment to 8-h advances. Ethanol and control hamsters showed no group differences in rhythm amplitude, entrained phase, or reentrainment rate. Both groups showed faster reentrainment in the cage change condition. A second group of hamsters recorded in constant dim showed a small but significant lengthening of the free-running period of their wheel-running rhythm when provided with a 28% ethanol solution. Wheel running decreased during ethanol access in this group. Voluntary ethanol consumption evidently can slow the circadian pacemaker regulating activity rhythms in hamsters but has no measurable effect on photic entrainment or pacemaker response to LD shifts or nonphotic manipulations (stimulated activity). Period lengthening may be secondary to decreased activity, but other period-activity correlations obtained did not reveal a strong association between these two variables.

Alcohol Drinking↗