Biomedical subjects
Publications and source records attributed to M G Brown.
We describe three cases that presented with symptoms suggestive of appendicitis but were found at operation to have an inflamed solitary caecal diverticulum. All were treated successfully with diverticulectomy or inversion of the diverticulum. We wish to highlight this diagnosis and its surgical management so that informed decisions can be made if this is first encountered in the operating theatre.
OBJECTIVES: To evaluate the practical application and psychometric properties of three health utility measures in a sample of MS patients with a broad range of neurological disability as measured by the Extended Disability Status Scale (EDSS). METHODS: Patients randomly selected from two MS clinic registries were assessed using standard clinical methods and completed three generic measures of health utility (EQ-5D, HUI Mark III, SF-6D). The proportion of missing data, test/retest reliability, and construct validity of each health utility measure were examined. RESULTS: The assessments were completed by 187 patients. Less than 10% of data were missing for the subscales of the SF-6D (< 3.2%), HUI Mark III (<1.6%), and EQ-5D (< or =7.5%). Severely disabled patients were more likely to omit physical function questions for the SF-6D (20%), and EQ-5D (43%). Retest reliability for the SF-6D (ICC = 0.83), EQ-5D (ICC = 0.81), and HUI Mark III (ICC = 0.87) were adequate for population surveys. Correlations between assessment of clinical function and each health utility measure were strongest for the HUI Mark III (HUI Mark III EDSS rho = -0.77, HUI Mark III ambulation index rho = -0.76, HUI Mark III timed 25 foot walk rho = -0.73, HUI Mark III nine hole peg test rho = -0.65). CONCLUSIONS: The health utility measures were generally feasible and reliable but the HUI Mark III demonstrated highest concordance with the EDSS across the full range of neurological disability. Of the three measures studied, the HUI Mark III may be the most appropriate for cost effectiveness evaluations of MS therapies.
Ray stability is investigated in environments consisting of a range-independent background sound-speed profile on which a range-dependent perturbation is superimposed. Theoretical arguments suggest and numerical results confirm that ray stability is strongly influenced by the background sound speed profile. Ray instability is shown to increase with increasing magnitude of alpha(I)=(I/omega)d omega/dI, where 2pi/omega(I) is the range of a ray double loop and I is the ray action variable. This behavior is illustrated using internal-wave-induced scattering in deep ocean environments and rough surface scattering in upward refracting environments.
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The effect of exciting each of the three classes of intermolecular vibrations on the hydrogen bond lifetime (tau(H)) of the isolated water trimer is investigated by far-infrared laser spectroscopy. Single excitation of a librational vibration decreases tau(H) by 3 orders of magnitude to tau(H) = 1-6 ps, comparable to the time scale of a number of important bulk water dynamical relaxation processes. In contrast, excitation of translational or torsional vibrations has no significant effect (tau(H) = 1-2 ns). Although such a dependence of tau(H) on intermolecular motions has also been proposed for liquid water via computer simulations, these are the first experiments that provide a detailed molecular picture of the respective motions without extensive interpretation.
Vibrational studies that selectively probe molecular structure at CCl4/H2O and hydrocarbon/H2O interfaces show that the hydrogen bonding between adjacent water molecules at these interfaces is weak, in contrast to generally accepted models of water next to fluid hydrophobic surfaces that suggest strong hydrogen bonding. However, interactions between these water molecules and the organic phase result in substantial orientation of these weakly hydrogen-bonded water molecules in the interfacial region. The results have important implications for understanding water adjacent to hydrophobic surfaces and the penetration of water into hydrophobic phases.
Natural killer (NK) cells are lymphocytes that can be distinguished from T and B cells through their involvement in innate immunity and their lack of rearranged antigen receptors. Although NK cells and their receptors were initially characterized in terms of tumor killing in vitro, we have determined that the NK cell activation receptor, Ly-49H, is critically involved in resistance to murine cytomegalovirus in vivo. Ly-49H requires an immunoreceptor tyrosine-based activation motif (ITAM)-containing transmembrane molecule for expression and signal transduction. Thus, NK cells use receptors functionally resembling ITAM-coupled T and B cell antigen receptors to provide vital innate host defense.
Allelic variability for mouse Chromosome 6 Nkc loci was assessed in 22 common laboratory strains of mice using selected natural killer gene complex (Nkc)-linked sequence tagged site markers. Most Nkc markers distinguished three or more alleles for a particular locus in the assessed mouse strains. Nkc locus alleles were highly conserved among genealogically related inbred strains, whereas far less similarity was observed among unrelated strains. Concurrent strain-to-strain comparisons for all Nkc-linked loci revealed common and uncommon Nkc haplotypes, including some that were likely recombinant. Nkc allele and haplotype assignments in inbred mouse strains and correlation with phenotypic traits should facilitate positional gene cloning strategies for unknown Nkc-linked trait modification loci.
BACKGROUND: Colorectal cancer (CRC) is the second most common invasive cancer in Canada. Estimates of the costs of care allow estimation of the cost effectiveness of screening for premalignant and early disease. OBJECTIVE: To estimate, from administrative data, the hospital costs incurred by a population-based cohort of CRC cases over three years from diagnosis. DESIGN: All Nova Scotia residents with CRC who were diagnosed in 1990 were identified from the Nova Scotia Cancer Registry. These cases were linked to the administrative files of the Nova Scotia Department of Health, which contain information on diagnosis, procedures and length of stay for all admissions and day surgery visits to Nova Scotia hospitals. MEASUREMENTS: The lengths of stay and hospital-specific per diem rates were used as the measures of resource use. The costs were analyzed in terms of the extent of spread at diagnosis; the time period after diagnosis; the time period before death; and, for typical cases, the age and presence of comorbidity identified during the initial surgical admission. RESULTS: The estimated three-year hospital cost for the complete cohort of 593 cases was $9.8 million. This cost was significantly less for cases with local spread, highest in the six months around, and after diagnosis and in the final six months of life, and highest in the typical cases (patients who were older and had significant comorbid conditions). CONCLUSIONS: Hospital-specific per diem rates and lengths of stay are an approximate measure of hospital resource use.
OBJECTIVE: To estimate the cost-effectiveness (CE) of interferon beta-1b (IFN beta-1b) in slowing disability progression in persons with relapsing-remitting multiple sclerosis (RRMS). METHODS: Treatment program costs and health outcomes are modeled for cohorts of 1,000 females and 1,000 males followed 40 years from onset. Fifteen scenarios model MS natural history progression, treatment efficacy, direct treatment costs, and MS healthcare costs. A single randomized placebo-controlled trial of IFN beta-1b found reduced disease activity by MRI, reduced frequency and severity of exacerbations, and a tendency toward slower disability progression. Disability years avoided are modeled as the primary health outcome analyzed. A ministry of health (MOH) perspective is adopted, using Nova Scotia population-based data. Annual IFN beta-1b direct treatment costs (Can $16,685) are high relative to both MOH healthcare costs per person with MS (Can $2,000) and estimated MOH costs avoided. RESULTS: Given "reference case" assumptions for women with RRMS, treatment reduces lifetime disability years by 10%. Cost per disability year avoided before discounting is Can $189,230 (US $124,892), and Can $274,842 (US $181,395) after discounting at 5%. Estimates for alternative scenarios vary greatly, leaving main findings unchanged. CONCLUSIONS: Using the Expanded Disability Status Scale, cost per disability year avoided due to interferon beta-1b treatment in RRMS is quite high. Comparable CE estimates, using MS-specific or generic health-related quality-of-life outcome measures, are even higher. Further research is required to better measure treatment effects, modification of MS natural history, and net societal costs of IFN beta-1b in RRMS.
Between January 1995 and August 1998, a study was conducted to elucidate the epidemiology of hepatitis A virus (HAV) in Jamaica. Participants were recruited from six sites across the island. The potential risk factors for transmission which were studied included age of the individual, gender, residence (urban v. rural area), sanitary facilities (flush toilet v. pit) and source of domestic water (indoor plumbing v. other). There were 128 male subjects and 211 female, aged 3-90 years. The mean ages of the males and females were 24.9 and 25.6 years, respectively. The seroprevalence of HAV in the study population, estimated by ELISA, was 59.9%. Logistic regression indicated that age (P < 0.001) and source of domestic water (P = 0.006) were the major contributors to exposure to HAV. The rate of exposure to the virus was seen to increase with age. By the age of 10 years, 30% of children had been exposed, and almost 100% of the oldest subjects were seropositive. Rates of exposure to HAV were higher among households which had external sources of water, including standpipes, rivers and tanks, than those with indoor plumbing. Although the seroprevalence of HAV in Jamaica is similar to that seen in developing countries, the age-related pattern of exposure mirrors the pattern seen in developed countries.
In 1990, a collaborative project was launched to determine what the people of Ontario expect of their physicians and how the programs that prepare future physicians should be changed in response. The project, called Educating Future Physicians for Ontario (EFPO), brought together the five Ontario medical schools, the Council of Ontario Faculties of Medicine (COFM); a nonprofit, charitable organization, Associated Medical Services (AMS); and the Ontario Ministry of Health. The first phase ran for five years and was described in the November 1998 issue of Academic Medicine. After an external review, the project was continued for a second phase (EFPO II) for four more years until December 1998; that second phase is the topic of this article. EFPO II (1) focused more on residents' education; (2) emphasized four of the EFPO I-created physician roles in project activities; (3) maintained the province-wide, inter-institutional medical education framework of phase I, but fostered greater involvement of the seven sites (five medical schools and two regional health centers) in project activities; (4) stressed five project components (e.g., needs assessment and community partnerships) and worked for collaboration among components at all sites; (5) enhanced the original EFPO I Fellowship Program by adding residents and community fellows to the existing fellowships and by initiating leadership development activities, all of which bode well for the future leadership of medical education in Ontario. Students and residents played a vital role in EPFO II. Most of EFPO II's objectives were met, but the overall view of external reviewers was that the project was less successful than EFPO I. For example, the impact on clinical education, especially residency education, was less than anticipated. On the other hand, the project helped encourage the wide adoption of the eight physician roles that originated in EFPO I and advanced faculty development and assessment activities based on these roles. A third phase of EFPO concerning continuing medical education was planned, but support was not available. However, one of the funders will continue to support the successful fellowship and leadership program and the provincial education network for the next three years. Overall, the two phases of EFPO substantially modified medical education in Ontario to make it more responsive to evolving social needs.
The Cmv1 locus controls NK cell-mediated resistance to infection with murine CMV. Our recent genetic analysis of backcross mice demonstrated that the NK gene complex (NKC)-linked Cmv1 locus should reside between the Ly49 and Prp gene clusters on distal mouse chromosome 6. We have aligned yeast artificial chromosome (YAC) inserts in a contig spanning the interval between the Ly49 and Prp gene clusters. This YAC contig includes 13 overlapping YAC inserts that span more than 2 megabases (Mb) in C57BL/6 (B6) mice. Since we have identified genomic clones that span the Ly49-Prp gene region, we hypothesize that at least one should contain the Cmv1 locus. To narrow the Cmv1 critical region, we developed novel NKC genetic markers and used these to genotype informative backcross and intra-NKC recombinant congenic mouse DNA samples. These data suggest that Cmv1 resides on a single YAC insert within an interval that corresponds to a physical distance of approximately 390 kb. This high resolution, integrated physical and genetic NKC map will facilitate identification of Cmv1 and other NKC-linked loci that regulate NK cell-mediated immunity.
A polarizable water pair potential was determined by fitting a potential form to microwave, terahertz, and mid-infrared (D2O)2 spectra through a rigorous calculation of the water dimer eigenstates. It accurately reproduces most ground state vibration-rotation-tunneling spectra and yields excellent second viral coefficients. The calculated dimer structure and dipole moment are very close to those determined from microwave spectroscopy and high-level ab initio calculations. The dimer binding energy and acceptor switching and donor-acceptor interchange tunneling barriers are in excellent agreement with recent ab initio theory, as are cyclic water trimer and tetramer structures and binding energies.
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The 1995 rubella outbreak in Jamaica indicated a need to survey the susceptibility rate in Jamaican antenatal women at risk. In this 1996 study, 389 women in the reproductive age group were investigated for rubella antibodies. In the public sector urban group (A), rubella susceptibility was 20.2%, while in a private sector urban clinic (B) practising routine rubella surveillance and recommending postpartum immunization in seronegatives, the susceptibility rate was 13.8%. The latter rate was significantly lower than that in the rural group (C) (35.9%; p < 0.001). The overall susceptibility rate was 21.3%. Rubella susceptibility has improved overall in women of childbearing age compared with levels in the prevaccine year of 1968. A significant thrust in rubella prevention will still be required before the next rubella epidemic in order to reduce the risk of congenital rubella syndrome.
We present clinical outcome, through several years of follow-up, of 4 mentally retarded patients, each with a small interstitial deletion in the long arm of chromosome 2, within a region on which clinical reports are infrequent. Our patient 1 was found to have del(2)(q22.3q23.3); patients 2 and 3, del(2)(q23.3q24.2); and patient 4, del(2) (q24.2q31). By comparison of our cases with each other and with those previously published with comparable interstitial deletion, we attempted to identify characteristic clinical findings. Short neck with excessive cervical skin was seen with monosomy of chromosome 2 bands q22.3-q23.3, while hypertrichosis and a peculiar high pitched cry were seen with monosomy of chromosome 2 bands q23.3-q24.2. As suggested by Moller et al. [1984: Hum Genet 68:77-86], a cleft between the first and second toes was seen with monosomy of chromosome 2 bands q24.2-q31. In addition, seizure disorder was present in patients 1 and 4 (with the more proximal and distal deletions, respectively).
Natural killer (NK) cells express C-type lectin-like receptors, encoded in the NK gene complex, that interact with major histocompatibility complex class I and either inhibit or activate functional activity. Human NK cells express heterodimers consisting of CD94 and NKG2 family molecules, whereas murine NK cells express homodimers belonging to the Ly-49 family. The corresponding orthologues for other species, however, have not been described. In this report, we used probes derived from the expressed sequence tag database to clone C57BL/6-derived cDNAs homologous to human NKG2-D and CD94. Among normal tissues, murine NKG2-D and CD94 transcripts are highly expressed only in activated NK cells, including both Ly-49A+ and Ly-49A- subpopulations. Additionally, mNKG2-D is expressed in murine NK cell clones KY-1 and KY-2, whereas mCD94 expression is observed only in KY-1 cells but not KY-2. Last, we have finely mapped the physical location of the Cd94 (centromeric) and Nkg2d (telomeric) genes between Cd69 and the Ly49 cluster in the NK complex. Thus, these data indicate the expanding complexity of the NK complex and the corresponding repertoire of C-type lectin-like receptors on murine NK cells.