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Biomedical subjects

K Morgan

Publications and source records attributed to K Morgan.

At least 73 records · Page 4Linked to original sources
PubMed2000

The association between heel ultrasound and hormone replacement therapy is modulated by a two-locus vitamin D and estrogen receptor genotype.

Evidence supports the role of estrogen deprivation in the process of bone remodeling and increased risk of fracture in postmenopausal women but little is known about the genetic basis of individual differences in response to therapy. In a cross-sectional study, 425 ambulatory postmenopausal French-Canadian women from Quebec (age range, 42-85 years old) were genotyped for a common Bsm I polymorphism at the vitamin D receptor (VDR) gene as well as a Pvu II polymorphism in the estrogen receptor (ESR1) gene. Heel ultrasound was determined by right calcaneal quantitative ultrasound (QUS) and results were expressed as an age-and-weight-adjusted stiffness index (heel SI z score). Our aim was to investigate the interaction between hormone-replacement therapy (HRT) and receptor genotypes in an effect on heel SI. Notably, a two-locus genotype (VDR-bb/ESR-PP) present in 9.5% of women was responsible for over 30% of the total HRT-related heel SI difference in the whole sample. Women bearing this combined VDR/ESR1 genotype who received HRT for more than 5 years had a 21% (1.25 SD) greater heel SI (p = 0.002) than those bearing the same genotype but who received HRT for <5 years. This may translate into a 2- to 3-fold difference in the risk of fracture. Although follow-up studies are needed, our findings suggest that QUS of the heel in postmenopausal women taking HRT is affected by variation in VDR and ESR1 loci, jointly.

Adult↗
PubMed2000

A polymorphism in the tumor necrosis factor-alpha gene promoter region may predispose to a poor prognosis in COPD.

STUDY OBJECTIVES: To determine whether the adenine (A)-guanine (G) substitution polymorphism at position - 308 on the tumor necrosis factor-alpha gene confers susceptibility to COPD or to the development of a more severe form of disease. DESIGN: A cross-sectional study was undertaken to compare the frequency of the A allele in a group of 106 patients with COPD with that in a control population (n = 99). Patients were followed up prospectively for a period of 2 years. PARTICIPANTS AND SETTING: Participants included 106 COPD patients recruited from a respiratory outpatient clinic and 99 control subjects recruited from patients admitted for cardiac catheterization. MEASUREMENTS AND RESULTS: DNA was extracted from venous blood, and each subject was genotyped for the polymorphism by polymerase chain reaction amplification and restriction digestion using Nco1. There was no increased frequency of the A allele in patients compared to control subjects. AA homozygous patients had less reversible airflow obstruction (p<0.05) and a significantly greater mortality (both all-cause and respiratory deaths) on follow-up (p<0.001), despite a shorter cigarette smoking history. CONCLUSIONS: This study suggests that homozygosity for this A allele predisposes to more severe airflow obstruction and a worse prognosis in COPD.

Aged↗
PubMed2000

Hepatitis A in south-eastern Sydney 1997-1999: continuing concerns for gay men and an outbreak among illicit drug users.

The incidence of hepatitis A virus (HAV) in south-eastern Sydney is one of the highest in Australia with large outbreaks previously associated with male-to-male sexual contact. We report HAV notification trends over the period 1 June 1997 to 31 May 1999 for this location. In the first twelve-month period, 233 cases were notified (crude rate 30.5/100,000 per year) with a peak incidence of 110/100,000 in males aged 20-39 years. Over 60% of male cases reported male-to-male sexual contact. The notification rate (crude rate 15.5/100,000) and proportion of males (61%) was considerably lower in the following twelve month period with 118 cases notified. Less than a third of males reported male-to-male sexual contact. An outbreak (n = 45) of HAV among illicit drug users and their contacts was detected in December 1998. The transmission of HAV remains endemic in south-eastern Sydney. Vaccination among high-risk groups remains an important preventive strategy.

Adolescent↗
PubMed2000

Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the steroid hormone receptor super family involved in the control of cellular lipid utilization. This makes PPARalpha a candidate gene for type 2 diabetes and dyslipidemia. The aim of this study was to investigate whether genetic variation in the human PPARalpha gene can influence the risk of type 2 diabetes and dyslipidemia among French Canadians. We therefore first determined the genomic structure of human PPARalpha, and then designed intronic primers to sequence the coding region and the exon-intron boundaries of the gene in 12 patients with type 2 diabetes and in 2 nondiabetic subjects. Sequence analysis revealed the presence of a L162V missense mutation in exon 5 of one diabetic patient. Leucine 162 is contained within the DNA binding domain of the human PPARalpha gene, and is conserved among humans, mice, rats, and guinea pigs. We subsequently screened a sample of 121 patients newly diagnosed with type 2 diabetes and their age and sex-matched nondiabetic controls, recruited from the Saguenay-Lac-St-Jean region of Northeastern Quebec, for the presence of the L162V mutation by a PCR-RFLP based method. There was no difference in L162 homozygote or V162 carrier frequencies between diabetics and nondiabetics. However, whether diabetic or not, carriers of the V162 allele had higher plasma apolipoprotein B levels compared to noncarriers (P 5 0.05). To further this association, we screened another sample of 193 nondiabetic subjects recruited in the greater Quebec City area. Carriers of the V162 allele compared with homozygotes of the L162 allele had significantly higher concentrations of plasma total and LDL-apolipoprotein B as well as LDL cholesterol (P </= 0.02). These results suggest an association between the PPARalpha V162 allele and the atherogenic/hyperapolipoprotein B dyslipidemia.

Animals↗
PubMed2000

Changing times in rehab staffing.

Historically, a low supply of physical and occupational therapists existed in the home care marketplace. Home care agencies have had to contract with private practices and accept therapists who could only provide two or three visits a week to keep up with the demand. However, cutbacks have occurred at the acute, sub-acute, and rehabilitation levels of inpatient care. Now, many therapists who would not have considered home care employment in the past are asking for interviews. For once, many home care agencies have the opportunity to carefully select the therapists they hire.

Home Care Services↗
PubMed1999

Analysis of 14 CAG repeat-containing genes in schizophrenia.

Recently, it has been suggested that trinucleotide repeat-containing genes may be involved in the etiology of schizophrenia. This study was aimed at investigating putative associations between allelic variants or expansions of CAG repeat-containing genes (CAGrCG) and schizophrenia or its variability with respect to responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14 expressed sequences were compared among three groups of subjects: neuroleptic-responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic patients, and a control group (C; n = 122). No CAG expansions, in the range of those observed in neurodegenerative diseases, were identified in these 14 expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48, Bonferroni corrected P = 0.047). Comparisons among the different groups indicated that neuroleptic responders have shorter alleles compared to controls (Mann-Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from controls. These preliminary results suggest that the hGT1 gene, or a gene in its vicinity, may be involved in the etiology of schizophrenia or in modifying the disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.

Adolescent↗
PubMed1999

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): high-resolution physical and transcript map of the candidate region in chromosome region 13q11.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is a neurodegenerative disease frequent in northeastern Québec. In a previous study, we localized the disease gene to chromosome region 13q11 by identifying excess sharing of a marker allele in patients followed by linkage analysis and haplotyping. To create a detailed physical map of this region, we screened CEPH mega-YACs with 41 chromosome 13 sequence-tagged-sites (STSs) known to map to 13q11-q12. The YAC contig, composed of 27 clones, extends on the genetic map from D13S175 to D13S221, an estimated distance of at least 19.3 cM. A high-resolution BAC and PAC map that includes the ARSACS critical region flanked by D13S1275 and D13S292 was constructed. These YAC and BAC/PAC maps allowed the accurate placement of 29 genes and ESTs previously mapped to the proximal region of chromosome 13q. We confirmed the position of two candidate genes within the critical region and mapped the other 27 genes and ESTs to nearby intervals. Six BAC/PAC clones form a contig between D13S232 and D13S787 for sequencing within the ARSACS critical region.

Bacteriophage P1↗
PubMed1999

Unusual cluster of mild invasive serogroup C meningococcal infection in a university college.

The objective of this study was to describe the epidemiology and public health response to an apparent cluster of Neisseria meningitidis serogroup C infection in university students in a residential college. A conventional epidemiological approach was taken, supported by routine and novel diagnostic techniques. Over the two days of 21-22 August 1997, three cases of suspected meningococcal infection were notified from a residential college complex at a university campus in the Sydney metropolitan area. Neisseria meningitidis was grown from throat swabs of all three cases, and was isolated from the blood of one case only. All three isolates were typed as C:2a:P1.5,2. Seroconversion was demonstrated by a novel method in the three cases. Rifampicin was given to all identified contacts. Forty-seven days after the index case, a 19 year old female living in the same complex was diagnosed with bacterial meningitis, and identified contacts given rifampicin. When this isolate was found to be group C, it was decided to vaccinate residents of the college complex. Genotyping and serotyping (C:2a:P1.5) later revealed the fourth isolate to be distinct from isolates from Cases 1-3. In conclusion the authors note that Australia's increasing capacity to type meningococcal strains is essential to understanding the epidemiology of this disease. Furthermore, typing information is of critical importance when decisions are made regarding mass vaccination. As early antibiotic treatment may inhibit isolation of the organism, development of novel approaches to diagnosis and typing should be supported.

Adolescent↗
PubMed1999

Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications.

BACKGROUND: Hippocampal volume reduction has been repeatedly demonstrated in schizophrenia. The relative contribution of genetic and environmental factors to this is unclear. METHODS: To address this question, we compared volumetric measurements of the left and right hippocampus, obtained using stereological methods from brain MRI scans, from two groups of patients with schizophrenia as well as healthy controls (n = 26). Patients (n = 27) in the first group, had no family history of schizophrenia and had experienced severe pregnancy and birth complications (PBCs). The second group comprised of patients (n = 21) without a history of severe PBCs from families multiply affected with schizophrenia. RESULTS: Reduction of the left hippocampal volume was associated with the diagnosis of schizophrenia but was present only in patients with a history of severe PBCs; in this group the smaller hippocampal volume, the earlier the onset of psychosis. CONCLUSIONS: Our findings suggest that environmental factors, in this case severe PBCs, make a significant contribution to hippocampal abnormalities in schizophrenia.

Adult↗
PubMed1999

Exclusion of linkage of Shwachman-Diamond syndrome to chromosome regions 6q and 12q implicated by a de novo translocation.

Shwachman-Diamond syndrome is a rare genetic disorder of unknown pathogenesis involving exocrine pancreatic insufficiency and hematological and skeletal abnormalities. There is broad clinical variability; the extent of heterogeneity is unknown but comparisons within a large cohort of patients show no striking differences between patients of families with single or multiple affected offspring. Segregation analysis of a cohort of 69 families has suggested an autosomal recessive mode of inheritance. A single constitutional de novo chromosome rearrangement was reported in a Japanese patient involving a balanced translocation, t(6;12)(q16.2;q21.2), thereby suggesting possible loci for a genetic defect. Evenly spaced microsatellite markers spanning 26-32 cM intervals from D6S1056 to D6S304 and D12S375 to D12S346 were analyzed for linkage in members of 13 Shwachman-Diamond syndrome families with two or three affected children. Two-point lod scores were calculated for each marker under assumptions of recessive inheritance and complete penetrance. Negative lod scores indicated exclusion of both chromosome regions. Further, affected sibs were discordant for inheritance of chromosomes in most families based on constructed haplotypes. The cytogenetic abnormality is not associated with most cases of Shwachman-Diamond syndrome.

Bone and Bones↗
PubMed1999

Validation of linkage by sampling based on environmental exposures.

After detecting linkage in one sample, most researchers will attempt to validate this finding in another sample. Three strategies for validating a primary linkage were compared, with a focus on methods that might be appropriate in the presence of gene x environment interaction. First, a validation sample was collected and analyzed using the same ascertainment procedure and methods as the primary sample. Second, a sample of families with particular exposure patterns were ascertained subsequent to a significant test for heterogeneity due to the exposure in the primary sample. A third strategy ascertained by exposure status when exposure-defined subgroup tests were significant in the primary sample. The second strategy reduced the number of false positive linkage signals identified through exposure subgroup identification (i.e., the third strategy), but in this GAW11 data that contained no qualitative gene x environment interactions, it had poor sensitivity. Power to detect heterogeneity depends on the differences in risk between exposed and unexposed.

Environment↗
PubMed1999

A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole-body hyperthermia.

PURPOSE: To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min. PATIENTS AND METHODS: Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 microg/m2) and six patients were treated at TNF dose level II (100 microg/m2). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH; L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m2 based on a previous phase I WBH/L-PAM trial. WBH was administered with an Aquatherm radiant heat device. RESULTS: Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I). CONCLUSION: We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach.

Adult↗
PubMed1999

The maternal DDK syndrome phenotype is determined by modifier genes that are not linked to Om.

The DDK syndrome is a polar, early embryonic lethal phenotype caused by incompatibility between a maternal factor of DDK origin and a paternal gene of non-DDK origin. Both maternal factor and paternal gene have been mapped to the Om locus on mouse Chromosome (Chr) 11. The paternal contribution to the syndrome has been shown to segregate as a single locus. Although the inheritance of the maternal contribution has not been characterized in depth, it as been assumed to segregate as a single locus. We have now characterized the segregation of the DDK fertility phenotype in over 240 females. Our results demonstrate that females require at least one DDK allele at Om to manifest the syndrome. However, the DDK syndrome inter-strain cross-fertility phenotype of heterozygous females is highly variable and spans the gamut from completely infertile to completely fertile. Our results indicate that this phenotypic variability has a genetic basis and that the modifiers of the DDK syndrome segregate independently of Om.

Animals↗
PubMed1999

Differential risk factor profiles for indoor and outdoor falls in older people living at home in Nottingham, UK.

The objectives of this work were: to estimate the incidence of falls within an at-risk group of community-dwelling elderly people; to assess the risk factors associated with incident falls; to examine the effects of incident falls on survival. A random sample of 1042 community-dwelling older people in Nottingham (UK) were interviewed in 1985 and survivors re-interviewed at 4-year follow-up. The at-risk group was defined as survivors who had not fallen in the year prior to the baseline interview (n = 444). One-year fall recall was assessed using a questionnaire and included physical health, mobility, prescribed drugs and time spent walking. Body-weight and handgrip strength were measured. Eight-year post-fall mortality was recorded. In 1989 117 new fallers were identified. These people fell a total of 233 times in the year prior to re-interview (incidence rate: 524.8 per 1000 person-years at risk; 95% confidence intervals (CI): 473.3-576.3). People aged less than 75 were more likely to fall outdoors than people aged 75 and over (chi2 = 5.715, df = 1, p = 0.017). Risk factors associated with falling were: being less healthy (odds ratio (OR): 0.55; p = 0.052); having a walking speed in the range stroll/very slow/nonambulant compared with normal/brisk/fast (OR: 1.99; p<0.01); and number of prescribed drugs (OR: 1.30; p = 0.01). When analysed separately, indoor and outdoor falls presented differential risk profiles, with evidence that indoor falls were associated with frailty, while outdoor falls were associated with compromised health status in more active people. In 8-year post-fall monitoring, multiple (3+) fallers and indoor fallers showed a significant excess mortality. The differences in risk factors for, and prognoses following, indoor and outdoor falls, emphasise the complex interactions between intrinsic and extrinsic factors associated with falling among older people.

Accidental Falls↗
PubMed1999

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.

Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).

ATP Binding Cassette Transporter 1↗
PubMed1999

Evaluation of polymorphisms in the presenilin-1 gene and the butyrylcholinesterase gene as risk factors in sporadic Alzheimer's disease.

The E4 allele of the apolipoprotein E gene (APOE) is a major risk factor for late-onset Alzheimer's disease (LOAD) but is neither necessary nor sufficient to cause the disease. In this study, we investigated polymorphisms in the presenilin-1 (PS-1), and butyrylcholinesterase (BChE) genes, which have been implicated as risk factors for LOAD. Our data-set comprised 177 AD and 118 control patients, all of whom had been histopathologically confirmed following autopsy. We have tested homozygosity for the PS-1 allele 1 and possession of the BChE-K variant in association with APOE epsilon4 as risk factors in LOAD. Our findings support an association between the PS-1 polymorphism and LOAD, finding homozygosity for allele 1 associated with an approximately two-fold increased risk. Our data also show that in subjects greater than 75 years of age possession of both BChE-K and APOE-epsilon4 alleles is associated with an increased risk of LOAD, whilst the risk associated with APOE-epsilon4 allele alone is not significant.

Aged↗
PubMed1999

A PC12 variant lacking regulated secretory organelles: aberrant protein targeting and evidence for a factor inhibiting neuroendocrine gene expression.

A variant of the PC12 pheochromocytoma cell line (termed A35C) has been isolated that lacks regulated secretory organelles and several constituent proteins. Northern and Southern blot analyses suggested a block at the transcriptional level. The proprotein-converting enzyme carboxypeptidase H was synthesised in the A35C cell line but was secreted by the constitutive pathway. Transient transfection of A35C cells with cDNAs encoding the regulated secretory proteins dopamine beta-hydroxylase and synaptotagmin I resulted in distinct patterns of mistargeting of these proteins. It is surprising that hybrid cells created by fusing normal PC12 cells with A35C cells exhibited the variant phenotype, suggesting that A35C cells express an inhibitory factor that represses neuroendocrine-specific gene expression.

Animals↗