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Biomedical subjects

P J Morrison

Publications and source records attributed to P J Morrison.

At least 91 records · Page 5Linked to original sources
PubMed1993

Age at onset in Huntington's disease and methylation at D4S95.

Age at onset in Huntington's disease (HD) is variable and is influenced by parental sex, paternal age, and genetic background. Several recent models have tried to explain this variable expressivity by invoking parental imprinting and related aspects of epigenetic inheritance. Some of these mechanisms may result in variable DNA methylation at or near the HD gene. We show here that methylation at D4S95, a locus tightly linked to the HD gene, is highly variable. A comparison between patients with early onset HD, late onset HD, and normal controls showed no significant correlation between methylation and age at onset. However, we found a significant association of the age of the patient with demethylation at D4S95. Older persons tend to have lower levels of methylation at this locus. This observation is of interest with regard to studies that show an effect of paternal age, or more generally of 'ageing genes', on age at onset in HD.

Adolescent↗
PubMed1993

Huntington disease in County Donegal: epidemiological trends over four decades.

The prevalence rate of Huntington disease in County Donegal between 1961 and 1991 showed a decrease from 4.4 to 1.6 per 100,000 population. Emigration and reduction in family size probably account for the progressive decline in prevalence. Over the same time period in the rest of Europe, prevalence has declined only gradually, or has remained static.

Adult↗
PubMed1992

Cardiovascular abnormalities in the oculo-auriculo-vertebral spectrum (Goldenhar syndrome).

We describe the phenotypic characteristics of 25 individuals with oculo-auriculo-vertebral spectrum (OAVS) and its variants, seen in Northern Ireland between 1969-1989, with special reference to cardiovascular defects. We report the type and prevalence of cardiovascular findings and also estimate the minimum prevalence rate of OAVS to be 1 in 45,000.

Abnormalities, Multiple↗
PubMed1992

Interstitial deletion 8p21.3----p23.1 in a 6-year-old girl.

We present a 6-year-old mentally retarded girl. Chromosome analysis showed an interstitial deletion of chromosome 8; 46,XX,del(8) (pter----p23.1::p21.3----qter). The proposita had normal activities of glutathione synthetase reductase (GSR) and factor VII. Parental chromosomes were normal.

Child↗
PubMed1992

Pharmacokinetics of temafloxacin in humans after multiple oral doses.

The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects.

Administration, Oral↗
PubMed1991

Pharmacokinetics of temafloxacin in humans after single oral doses.

Temafloxacin (A-63004) is a new quinolone antibacterial agent with a broad spectrum of activity against gram-positive and gram-negative aerobes and anaerobes. The pharmacokinetics and metabolism of temafloxacin were determined in healthy volunteers after administration of single oral doses of 100, 200, 400, 600, 800, and 1,000 mg. The corresponding peak concentrations in plasma (mean +/- standard deviation) were 0.98 +/- 0.26, 1.61 +/- 0.57, 2.43 +/- 0.56, 3.87 +/- 0.64, 4.54 +/- 1.03, and 6.67 +/- 0.74 micrograms/ml. The times that elapsed to attain peak levels ranged from 1.25 to 3.5 h. Statistical analyses of parameters related to the extent of absorption and the linearity of the dispositional pharmacokinetics detected no dose-related trends. Study-wide, total clearance (223 ml/min) and renal clearance (125 ml/min) showed low intersubject variability, with coefficients of variation near 20%. The terminal-phase rate constant of 0.090 +/- 0.008 h-1 corresponds to a half-life of 7.7 h. Temafloxacin was excreted mainly in the urine, with 57 +/- 11% of the dose appearing in the urine unchanged. Conjugated temafloxacin, oxidative metabolites, and conjugates thereof were minor components in urine, collectively accounting for 5 to 8% of the dose. Since intravenously dosed dogs eliminated 50% of the dose by nonrenal processes, urinary recoveries approaching two-thirds of the dose in humans were consistent with high, if not quantitative, absorption. Reported adverse events were generally mild, were randomly distributed between temafloxacin- and placebo-treated subjects, and were not dose related.

4-Quinolones↗
PubMed1991

Gene probe analysis in an informative family with multiple endocrine neoplasia syndrome type 2A (MEN 2A). Improvement in carrier risk estimation.

Gene probe analysis of the MEN 2A locus on chromosome 10 has been undertaken using the markers TB10.163, RBP 3 and TB14.34 in a large kindred with familial medullary thyroid carcinomas, with or without phaeochromocytomas or primary hyperparathyroidism. A maximum LOD score of 2.97 gave strong evidence of close linkage with zero recombination. For 12 members of the family so far not known to be affected by any form of the disease the estimated risk of carrying the gene has been considerably decreased in all but one, whose risk has been greatly increased.

Adolescent↗
PubMed1989

Linkage disequilibrium and CF allele segregation analysis in cystic fibrosis families in Northern Ireland.

Linkage disequilibrium and cystic fibrosis (CF) allele segregation were analysed in 46 CF families in Northern Ireland. The smaller (+) allele of the KM19/PstI polymorphism and the larger (-) allele of the XV-2c/TaqI polymorphism showed marked linkage disequilibrium with CF. This information can be used to alter the risk of an individual being a carrier of CF away from the expected population risk of 1 in 20. The high-risk genotypes K+K+ or X-X- have a risk of 1 in 10 and the low-risk genotypes K-K- or X+X+ have a risk of 1 in 50. A study of the segregation of CF alleles in the 46 families, using KM19 and Xv-2c, showed preferential inheritance of the paternal (79%), as opposed to the maternal (21%), CF allele by the heterozygous carriers. A mechanism that might explain this observation is discussed.

Alleles↗
PubMed1989

MEN 2A: update on the Northern Ireland and Australian family.

The Northern Ireland/Australian family with multiple endocrine neoplasia type 2A (MEN 2A) originally described in 1987 is presented with a revised and enlarged pedigree. Four members of the first generation studied have died. A seventh member of the second generation studied has developed medullary thyroid carcinoma and has progressed to surgery. None of the third generation members studied has shown any conclusive abnormality in metabolic screening tests. Each member of the third and fourth generations has had genetic counseling and (if appropriate) DNA analysis with gene probes close to the MEN 2A gene locus on chromosome 10. All members of this highly penetrant family have remained asymptomatic for their disease.

Adult↗
PubMed1988

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses.

The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 micrograms/ml for the 100- to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 +/- 28.8 min. The elimination half-life and plasma clearance averaged 7.7 +/- 0.52 h and 259 +/- 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 micrograms/ml following the 100- and 800-mg doses, respectively. Concentrations above 20 micrograms/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 micrograms/ml during the 12- to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion. Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.

4-Quinolones↗
PubMed1987

ORG 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man.

ORG 10172 is a heparinoid with mean molecular weight 6500 daltons. Intravenous bolus injections of ORG 10172 were compared with placebo and heparin injections in 91 separate studies in 83 healthy male subjects. 6400 units ORG 10172 produced a mean maximum change of 14.7 s in kaolin cephalin time (c.f. greater than 120 s for 5000 units heparin). Changes in prothrombin time were minimal (1.6 s for 6400 units ORG 10172 and 4.5 s after 5000 units heparin). A dose-related increase in bleeding time occurred after ORG 10172 and at high doses (greater than 3200 units) some secondary bleeding, which was never serious, occurred at between 1 and 4 h after incision. A dose-dependent reduction in ex vivo platelet adhesiveness was found at 10 min after ORG 10172 injection. ORG 10172 promoted a much smaller release of lipoprotein lipase as compared with heparin. The effect of ORG 10172 on plasma factor Xa activity (one measure of its action) was described by a biexponential decay with a mean distribution half-life of 2.34 (s.e. mean 0.16) h and mean disposition half-life of 17.6 (s.e. mean 1.1) h. It thus has a much longer duration of effect than heparin. There was a linear relationship of plasma anti-Xa response to increasing dose although there was some variability only partly explained by differences in body weight or surface area. ORG 10172 administration by bolus intravenous injection was well tolerated and there was no evidence of adverse effects on clinical chemistry or haematology tests.

Adolescent↗