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Biomedical subjects

M G Brown

Publications and source records attributed to M G Brown.

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

DNA cross-linker-induced G2/M arrest in group C Fanconi anemia lymphoblasts reflects normal checkpoint function.

Cells from individuals with Fanconi anemia (FA) arrest excessively in the G2/M cell cycle compartment after exposure to low doses of DNA cross-linking agents. The relationship of this abnormality to the fundamental genetic defect in such cells is unknown, but many investigators have speculated that the various FA genes directly regulate cell cycle checkpoints. We tested the hypothesis that the protein encoded by the FA group C complementing gene (FAC) functions to control a cell cycle checkpoint and that cells from group C patients (FA[C]) have abnormalities of cell cycle regulation directly related to the genetic mutation. We found that retroviral transduction of FA(C) lymphoblasts with wild-type FAC cDNA resulted in normalization of the cell cycle response to low-dose mitomycin C (MMC). However, when DNA damage was quantified in terms of cytogenetic damage or cellular cytotoxicity, we found similar degrees of G2/M arrest in response to equitoxic amounts of MMC in FA(C) cells as well as in normal lymphoblasts. Similar results were obtained using isogenic pairs of uncorrected, FAC- or mock-corrected (neo only) FA(C) cell lines. To test the function of other checkpoints we examined the effects of hydroxyurea (HU) and ionizing radiation on cell cycle kinetics of FA(C) and normal lymphoblasts as well as with isogenic pairs of uncorrected, FAC-corrected, or mock-corrected FA(C) cell lines. In all cases the cell cycle response of FA(C) and normal lymphoblasts to these two agents were identical. Based on these studies we conclude that the aberrant G2/M arrest that typifies the response of FA(C) cells to low doses of cross-linking agents does not represent an abnormal cell cycle response but instead represents a normal cellular response to the excessive DNA damage that results in FA(C) cells following exposure to low doses of cross-linking agents.

Caffeine↗
PubMed1998

Hospital-based psychiatric service utilization and morbidity in multiple sclerosis.

BACKGROUND: Despite the common association of psychiatric morbidity and multiple sclerosis (MS), population-based prevalence estimates of these disorders are limited. Such estimates are of particular importance to those conducting trials of interventions for the treatment of MS. This study examined the prevalence of bipolar disorder, depression, and attempted suicide among hospital service utilizers in Nova Scotia and compared these measures for the MS and non-MS population. METHODS: Data regarding diagnosis and utilization were extracted from two linked databases which included all hospital separation records for Nova Scotia over a 3 year period (1992/93-1994/95). RESULTS: The prevalence of bipolar disorder in hospitalized MS patients was 1.97% and depression was 4.27%. These rates were significantly higher than the 0.92% and 2.04%, respectively, for the non-MS hospital utilizers. These diagnoses also accounted for more than half of the primary diagnostic codes for psychiatric service separations by MS patients. The proportion of total hospital utilization which was accounted for by psychiatric services did not differ between MS and non-MS utilizers. While suicide attempts were rare, the estimated frequency of suicide attempts in the total MS population was more than three times that of the general population. CONCLUSIONS: Bipolar disorder and depression were twice as prevalent in hospitalized MS patients as in the general population of hospital utilizers while the estimated frequency of suicide attempts was at least three times greater. These results illustrate that psychiatric morbidity and service utilization are important considerations in the care of MS patients.

Bipolar Disorder↗
PubMed1998

Educating future physicians for Ontario.

In 1987, Ontario's physicians conducted a strike, ultimately not successful, over the issue of "extra billing." The fact that the Ontario public did not support this action reflected a major gap between the profession's view of itself and the public's view of the profession. In 1990, the province's five medical schools launched a collaborative project to determine more specifically what the people of Ontario expect of their physicians, and how the programs that prepare future physicians should be changed in response. The authors report on the first five years of that ongoing project. Consumer groups were asked to state their views concerning the current roles of physicians, future trends that would affect these roles, changes in roles they wished to see, and suggestions for changes in medical education. Methods used included focus groups, key informant interviews, an extensive literature review, and surveys, including a survey of health professionals. Concurrently, inter-university working groups prepared tools and strategies for strengthening faculty development, assessing student performance, and preparing future leadership for Ontario's medical education system. Eight specific physician roles were identified: medical expert, communicator, collaborator, health advocate, learner, manager ("gatekeeper"), scholar, and "physician as person." Educational strategies to help medical students learn to assume these eight roles were then incorporated into the curricula of the five participating medical schools. The authors conclude that the project shows that it is feasible to learn specifically what society expects of its physicians, to integrate this knowledge into the process of medical education reform, and to implement major curriculum changes through a collaborative, multi-institutional consortium within a single geopolitical jurisdiction.

Consumer Behavior↗
PubMed1997

A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6.

We have constructed a physical map of a > 2-Mb region on mouse chromosome 6 that contains the natural killer gene complex (NKC). The map comprises a contig of 14 overlapping yeast artificial chromosomes onto which we positioned 25 NKC markers. NKC genetically linked genes encode > 17 proteins that directly control innate NK cell-mediated tumor lysis and disease resistance. Herein we show that Nkrp1 genes are clustered in a region flanked by A2m and Cd69 genes and that most Ly49 genes are clustered in a distal region -1 Mb distant. Importantly, syntenic intervals of mouse chromosome 6 and human chromosome 12p that include the NKC are conserved. NKC species conservation suggests that the human NKC may contain orthologues for the mouse viral disease resistance genes, Cmv1 and Rmp1. The high-resolution NKC map will facilitate investigation of NKC gene regulation and identification of phenotypically defined gene products that confer NK cell defense against viral pathogens.

Animals↗
PubMed1997

The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6.

Natural killer (NK) cells play important roles in controlling tumor cells and against a range of infectious organisms. Recent studies of mouse NK cell surface receptors, which may be involved in the specificity of NK cells, have shown that many of these molecules are encoded by the Ly49 and Ly55 (Nkrp1) multigene families that map to distal mouse chromosome 6. Also mapping to this NK cell gene complex (NKC) is the resistance locus, Cmv1, which is involved in genetically determined resistance to murine cytomegalovirus (MCMV). The aim of this study was to localize Cmv1 more precisely in relation to other NKC loci by generating a high-resolution genetic map of the region. We have analyzed 1250 backcross mice comprising panels of 700 (BALB/c x C57BL/6J)F1 x BALB/c and 550 (A/J x C57BL/6J)F1 x A/J progeny. A total of 25 polymorphic genes or microsatellite markers were analyzed over a region of 10 map units from D6Mit134 to D6Mit59. The Cmv1 phenotypes of mice recombinant in this interval were tested by infection with MCMV. The results obtained indicate that the functionally important NKC region is a tightly linked cluster of loci spanning at least 0.4 map units. Furthermore, Cmv1 maps distal to, but very closely linked to, the Ly49 multigene family (< 0.2 map units), suggesting that MCMV resistance may be conferred by MHC class I-specific NK cell receptors.

Animals↗
PubMed1997

The natural killer gene complex: a genetic basis for understanding natural killer cell function and innate immunity.

The natural killer gene complex encodes proteins, some of which are structurally unrelated, that impact on NK-cell function. Detailed analyses have indicated that these molecules are involved in NK-cell recognition, activation, and inhibition. The importance of this genomic region is highlighted by studies indicating that NKC-associated genes significantly influence NK cell-mediated innate host defense against life-threatening pathogens and that the NKC is conserved among diverse species. Thus, further elucidation of the NKC and its gene products will provide a genetic basis for understanding innate immunity and NK-cell activity at the molecular level.

Animals↗
PubMed1996

Far-infrared VRT spectroscopy of two water trimer isotopomers: vibrationally averaged structures and rearrangement dynamics.

We report the measurement of far-infrared vibration-rotation tunnelling parallel bands of two partially deuterated water trimer isotopomers: (D2O)2DOH and (H2O)2DOH at 97.2607 cm-1 and approximately 86 cm-1, respectively. The hydrogen bond rearrangement dynamics of the two mixed trimers can be described by the simplified molecular symmetry G8, which accounts for both the flipping and bifurcation tunnelling motions previously established for (H2O)3 and (D2O)3. The observed donor tunnelling quartet, rather than triplet, splitting indicates that the two homogeneous monomers (D2O or H2O) in each mixed trimer experience slightly different environments. Vibrationally averaged structures of (H2O)3, (D2O)3, and (D2O)2DOH were examined in a Monte Carlo simulation of the out-of-plane flipping motions of the free atoms. The simulation addresses both the symmetric top behaviour and the negative zero-point inertial defect for (H2O)3 and (D2O)3, which were insufficiently counted in all previous structure models. The average ground state O--O separations, which are correlated to other angular coordinates, were determined to be 2.84 +/- 0.01 angstroms for all three species. The simulated difference in hydrogen bond nonlinearity also supports the inequivalency of the two homogeneous monomers. The structural simulation shows that the unique H in (D2O)2DOH is free, while a torsional analysis suggests the unique D in (H2O)2DOH is bound within the cyclic ring. Both bands can be assigned to the pseudorotational transitions which correlate to those found in the pure trimers.

Chemistry, Physical↗
PubMed1996

Quantifying hydrogen bond cooperativity in water: VRT spectroscopy of the water tetramer.

Measurement of the far-infrared vibration-rotation tunneling spectrum of the perdeuterated water tetramer is described. Precisely determined rotational constants and relative intensity measurements indicate a cyclic quasi-planar minimum energy structure, which is in agreement with recent ab initio calculations. The O-O separation deduced from the data indicates a rapid exponential convergence to the ordered bulk value with increasing cluster size. Observed quantum tunneling splittings are interpreted in terms of hydrogen bond rearrangements connecting two degenerate structures.

Deuterium Oxide↗
PubMed1995

Interstitial deletions of the short arm of chromosome 4 in patients with a similar combination of multiple minor anomalies and mental retardation.

Interstitial deletions of chromosome 4 have been described rarely and have had variable presentations. We describe the phenotypic characteristics associated with interstitial deletion of the p14-16 region of chromosome 4 in 7 patients with multiple minor anomalies in common, and with mental retardation. A review of published cases of interstitial deletions of the short arm of chromosome 4 is provided. These deletions present a distinct phenotype which is different from that of Wolf-Hirschhorn syndrome.

Abnormalities, Multiple↗
PubMed1995

Prenatal diagnosis of chromosome 15 abnormalities in the Prader-Willi/Angelman syndrome region by traditional and molecular cytogenetics.

With improvements in culturing and banding techniques, amniotic fluid studies now achieve a level of resolution at which the Prader-Willi syndrome (PWS) and Angelman syndrome (AS) region may be questioned. Chromosome 15 heteromorphisms, detected with Q- and R-banding and used in conjunction with PWS/AS region-specific probes, can confirm a chromosome deletion and establish origin to predict the clinical outcome. We report four de novo cases of an abnormal-appearing chromosome 15 in amniotic fluid samples referred for advanced maternal age or a history of a previous chromosomally abnormal child. The chromosomes were characterized using G-, Q-, and R-banding, as well as isotopic and fluorescent in situ hybridization of DNA probes specific for the proximal chromosome 15 long arm. In two cases, one chromosome 15 homolog showed a consistent deletion of the ONCOR PWS/AS region A and B. In the other two cases, one of which involved an inversion with one breakpoint in the PWS/AS region, all of the proximal chromosome 15 long arm DNA probes used in the in situ hybridization were present on both homologs. Clinical follow-up was not available on these samples, as in all cases the parents chose to terminate the pregnancies. These cases demonstrate the ability to prenatally diagnose chromosome 15 abnormalities associated with PWS/AS. In addition, they highlight the need for a better understanding of this region for accurate prenatal diagnosis.

Adult↗
PubMed1995

Laparoscopic 'physiological' antireflux procedure: preliminary results of a prospective symptomatic and objective study.

The 'physiological' antireflux procedure has been shown to be as effective as Nissen fundoplication in reflux control, but with a significant reduction in the incidence of mechanical complications. This technique was attempted laparoscopically in 26 patients in a prospective study involving independent symptomatic, manometric and pH assessment performed before operation and at a mean of 5.5 months after operation. The procedure was successfully completed laparoscopically in 23 (88 per cent) patients. Mean hospital stay was 3.8 days and mean time to return to work 1.8 weeks. There was neither mortality nor reoperation; 91 per cent of patients obtained symptomatic relief (82 per cent Visick grade 1). There was no gas-bloat or inability to belch or vomit. All 14 patients who underwent objective testing had a normal oesophageal pH profile, the mean percentage total time that pH < 4 falling from 11.0 to 1.1 (P < 0.001). Lower oesophageal sphincter characteristics, including relaxation, were similar to control values. These preliminary results suggest symptomatic and objective results comparable to those following open surgery, but with the benefits of a shorter hospital stay and time off work. In addition to a lower incidence of mechanical complications, the relative ease of performance of this procedure confers an additional advantage over Nissen fundoplication when performed laparoscopically.

Adolescent↗
PubMed1995

Cost-effectiveness: the case of home health care physician services in New Brunswick, Canada.

Home health care programs have direct and indirect effects within a health care system. A complete cost-benefit evaluation would include all such effects. A study of New Brunswick's Extra-Mural Hospital (EMH) home health care program used population-based administrative data on physician services utilization to examine whether home care services act indirectly as substitutes for physician services. Evidence suggests that the introduction and expansion of New Brunswick's EMH home health care program had unanticipated substitution effects, which reduced health system costs by reducing the rate of growth of per-capita utilization of physician services.

Age Distribution↗
PubMed1995

Prescribing patterns of antilipemic drugs and prevalence of hypercholesterolemia in the Nova Scotia population more than 65 years old.

OBJECTIVE: To examine the prevalence of antilipemic drug use, demographic characteristics of patients using these drugs, and the prevalence of hypercholesterolemia in the Nova Scotia population over 65 years of age. DESIGN: Information was collected on the prescribing of antilipemic drugs using Nova Scotia Medical Services Insurance Pharmacare program data from October 1991 through March 1992. Pharmacare data were compared with prevalence data on increased low-density lipoprotein (LDL) cholesterol concentrations obtained from the Nova Scotia Heart Health Survey (NSHHS). SETTING: Pharmacare is a centrally administered drug insurance system maintained in computerized claims files since 1974. It provides prescription drugs to all residents of Nova Scotia who are at least 65 years old and who are insured under the provincial Medicare program. PARTICIPANTS: In the 1991-1992 fiscal year, 47,000 men and 65,700 women were eligible for Pharmacare. The NSHHS was administered to a probability sample of 2,108 individuals, representative of the 1986 population aged 18-74 years. MAIN OUTCOME MEASURES: Prescriptions for antilipemic agents. RESULTS: The NSHHS data indicated that 3.7% of women and 2.3% of men at least 65 years old and 4.8% of women and 2.8% of men 65-74 years old received a prescription for antilipemic drugs.

Aged↗
PubMed1994

Phenotypic correction of Fanconi anemia in human hematopoietic cells with a recombinant adeno-associated virus vector.

Fanconi anemia (FA) is a recessive inherited disease characterized by defective DNA repair. FA cells are hypersensitive to DNA cross-linking agents that cause chromosomal instability and cell death. FA is manifested clinically by progressive pancytopenia, variable physical anomalies, and predisposition to malignancy. Four complementation groups have been identified, termed A, B, C, and D. The gene for the FA complementation group C, FACC, has been cloned. Expression of the FACC cDNA corrects the phenotypic defect of FA(C) cells, resulting in normalized cell growth in the presence of DNA cross-linking agents such as mitomycin C (MMC). Gene transfer of the FACC gene should provide a survival advantage to transduced hematopoietic cells, suggesting that FA might be an ideal candidate for gene therapy. We demonstrated efficient transduction, expression, and phenotypic correction in lymphoblastoid cell lines derived from FA (C) patients using a recombinant adeno-associated virus (rAAV) vector containing the FACC gene. Molecular characterization of the transduced FACC gene showed an intact unrearranged proviral genome with expression sufficient to normalize cell growth, cell cycle kinetics and chromosomal breakage in the presence of MMC. These observations were extended by testing rAAV transduction in hematopoietic progenitor cells. Peripheral blood CD34+ cells isolated from a FA (C) patient and transduced with rAAV/FACC virus yielded 5-10-fold more progenitor colonies than mock-infected cells, consistent with genetic "rescue" of corrected cells. This is the first demonstration of rAAV gene correction in primary human hematopoietic progenitor cells and has important implications for gene therapy of hematopoietic disorders, specifically FA.

Base Sequence↗
PubMed1993

MHC-linked LMP gene products specifically alter peptidase activities of the proteasome.

Proteasomes are highly conserved macromolecular structures which function as endopeptidases. They are found in the cytoplasm and nucleus of eukaryotic tissues and consist of at least 14 non-identical subunits with molecular masses ranging from approximately 20 to 32K. Proteasomes are essential in the selective degradation of ubiquitinated and certain non-ubiquitinated proteins, acting as the proteolytic core of an energy-dependent 26S (1,500K) proteolytic complex. Two proteasome subunits, LMP2 and LMP7 (refs 4-7), are encoded within the major histocompatibility complex (MHC), implicating proteasomes in antigen processing. Here we determine the function of these two MHC-linked subunits by comparing the proteolytic activities of purified proteasomes containing (LMP+) or lacking (LMP-) these components. We find that proteasomes of both types have endopeptidase activity against substrates bearing hydrophobic, basic or acidic residues immediately preceding the cleavage site (the P1 position) and at sites following asparagine, glycine and proline residues. The activity of LMP+ proteasomes is much higher than that of LMP- proteasomes against substrates with hydrophobic, basic or asparagine residues at P1, whereas their activities are comparable when acidic and glycine residues are present at P1. The MHC-linked LMP2 and LMP7 subunits therefore function to amplify specific endopeptidase activities of the proteasome.

Amino Acid Sequence↗
PubMed1993

MHC-linked low-molecular mass polypeptide subunits define distinct subsets of proteasomes. Implications for divergent function among distinct proteasome subsets.

Proteasomes are 650-kDa, multisubunit endopeptidases that might be involved in the MHC class I Ag processing pathway. We demonstrate the existence of multiple structurally distinct subsets of proteasomes. Distinct forms of proteasomes share a hypothetical core to which unique subunits are added. One of these subsets, LMP2+ proteasome, contains the product of the MHC-linked Lmp-2 gene, and can be distinguished serologically and structurally from other proteasome subsets. The expression of LMP2+ and LMP2- proteasomes is variable among cell lines of different tissue types, and their relative abundance and subunit composition are regulated by IFN-gamma. LMP2+ proteasomes comprise 0 to 74% of total cellular proteasomes. Both LMP2+ and LMP2- proteasomes are proteolytically active. We suggest proteasome function might be regulated by subunit composition, and some, or all proteasome subsets, might participate in the production or delivery of peptides to MHC class I molecules. Both LMP2+ and LMP2- subsets can be further subdivided on the basis of the presence or absence of other unique subunits. Implications of the existence of structurally distinct forms of proteasomes in different tissue types is discussed.

Amino Acid Sequence↗