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Biomedical subjects

A MacGregor

Publications and source records attributed to A MacGregor.

At least 19 recordsLinked to original sources
PubMed2006

Genetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study.

OBJECTIVE: Genetic influences on rates of osteoarthritis (OA) progression are unknown. Our aim was to estimate the heritability of progression of radiographic knee OA using a longitudinal twin study. METHODS: Unselected monozygotic (MZ) and dizygotic (DZ) twin pairs from the TwinsUK registry were utilized. Anteroposterior radiographs were performed on both knees at baseline and follow-up using the same protocol. Radiographic features of knee OA including osteophyte and joint space narrowing (JSN) were assessed on a four-point scale using a standard atlas. Progression of knee osteophyte and JSN was defined as the difference in the corresponding score between follow-up and baseline > or =1. Liability threshold modelling using logistic regression was utilized for heritability estimation. RESULTS: A total of 114 MZ pairs and 195 DZ pairs were studied. The average follow-up time was 7.2 years. Medial progression of osteophyte and JSN was more common than lateral progression. Prevalence of progression was generally higher in the MZs than the DZs. Similarly, concordances and tetrachoric correlations for both osteophyte and JSN were higher in the MZs than the DZs although only significant for overall and medial JSN and osteophyte. The heritability estimates were 69% [95% confidence interval (CI) 42-97%] and 80% (95% CI 50-100%) for medial osteophyte and JSN, respectively. The estimates were reduced by 7-15% after adjustment for age, body mass index (BMI), and the severity of osteophyte/JSN at baseline. CONCLUSION: Our data documented a substantial genetic influence on the progression of knee OA--as seen in the medial compartment, providing a solid basis to search for genes involved in this highly relevant clinical trait.

Aged↗
PubMed2004

Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are at increased risk of myocardial infarction and stroke. We sought to determine how much of this risk was dependent on recognized cardiovascular risk factors. METHODS: Initially a software package 'Cardio-Risk-Manager', which utilizes Framingham data, was used to calculate a 10-yr risk of coronary heart disease (CHD) and stroke for 202 patients with SLE (Group 1) in comparison with hypothetical age- and sex-matched comparators. Subsequently 47 patients who had been followed since 1991 (Group 2) were studied to compare their predicted risks in 1991 with the actual number of cardiovascular events that occurred during the subsequent decade. RESULTS: Patients in Group 1 had a higher predicted 10-yr risk of stroke (P<0.0001), but not of CHD, than their comparators. However, following age stratification, traditional risk factors predicted a higher risk of CHD (P<0.0001) and of stroke (P<0.0001) in patients under 40 with SLE compared with age-matched comparators. The predicted 10-yr risks of CHD and stroke for patients aged 40 and above were not significantly different from those of their comparators. Predicted risks, however, were lower than the true 10-yr event rate for CHD and stroke in patients in Group 2. In this group, during the 10 yr of follow-up four patients (8.5%) suffered a CHD event and five patients (10.6%) had a stroke, significantly more than were predicted by the presence of conventional risk factors (P<0.001 for CHD and P<0.001 for stroke, respectively). CONCLUSIONS: Conventional risk factors predicted an increased risk of stroke and CHD in younger patients. They do not, however, fully explain the high risk of cardiovascular disease in patients with SLE. Although it is important to address the management of orthodox risk factors for cardiovascular disease in patients with SLE, other causes must be sought to explain the increased incidence of CHD and stroke, especially in those aged over 40.

Adult↗
PubMed2002

Clinical and functional results of open operative repair for Achilles tendon rupture in a non-specialist surgical unit.

We followed up 25 patients (average age 47.9 years, range 22 to 77) after open repair of their Achilles tendon rupture. All had been operated on by a single general surgeon using an end-to-end reabsorbable suture, and immobilised in a plaster of Paris cast for six weeks. All patients had been discharged from follow up by 18 weeks from the operation. At an average of 3.4 years (range six months to 9.25 years), 18 had "excellent", six (24%) "good" and one (4%) "satisfactory" results. All but one patient were able to walk on tiptoes, and 20 of the 22 patients examined directly walked without a limp. Ultrasonography showed the injured tendons to be on average 2.3 times thicker in the antero-posterior diameter and 1.7 times thicker in the transverse diameter. In the hands of a single non-specialist but fully trained general surgeon, this management regimen produced full return to pre-operative activities in the majority of patients, and a low rate of local complications. The macroscopic and ultrasonographic appearance of the operated tendon remained abnormal, but this was not associated with any overt clinical disturbance

Achilles Tendon↗
PubMed2001

Testing the fetal origins hypothesis in twins: the Birmingham twin study.

AIMS/HYPOTHESIS: To test whether the link between birthsize and raised blood pressure or glucose tolerance is due to genetic or intrauterine factors, we studied whether differences in birthweight between pairs of monozygous and dizygous twins are associated with adult differences in blood pressure and glucose tolerance. METHODS: A sample of 58 monozygous and 140 dizygous twins were identified from a register of births in Birmingham, United Kingdom, between 1950 and 1954. The twins had their blood pressure measured and underwent an oral glucose tolerance test. RESULTS: There were no statistically significant associations between birthweight, length or ponderal index, and either blood pressure or glucose tolerance in the twins. Although there were substantial within-pair differences in birthweight between monozygous and dizygous twin pairs, these differences did not correlate with the adult outcomes. Monozygous correlations, however, for both blood pressure and glucose tolerance were statistically significantly higher than dizygous correlations and a quantitative genetic model suggested statistically significant heritability for these traits. In contrast correlations of birthsize were similar in monozygous and dizygous pairs suggesting only a small genetic component in determining fetal size. CONCLUSION/INTERPRETATION: Our results show that birthsize in twins does not predict adult blood pressure or glucose tolerance. We also suggest that shared genetic determinants for fetal growth and adult outcomes are not likely to be prevalent or powerful.

Adult↗
PubMed2000

Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein.

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5'-region of the ETS-related gene, TEL (ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 or PEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruiting N-CoR to AML1 target genes and thus imposing an altered pattern of their expression.

Core Binding Factor Alpha 2 Subunit↗
PubMed2000

Patterns of maxillofacial injuries as a function of automobile restraint use.

OBJECTIVE: To determine the pattern and severity of maxillofacial injuries sustained in a motor vehicle accident (MVA) resulting from automobile restraint use. DESIGN: Retrospective database review of patients injured in a MVA who were admitted to the level I trauma center at the University of Louisville Hospital in Louisville, Kentucky. METHODS: Demographic data, drug and alcohol impairment screening, and comorbidity data were obtained from database searches of trauma records. Forty-four patients had an airbag deployed, 34 patients wore seat belts, and 94 patients were unrestrained. All maxillofacial Abbreviated Injury Scale (AIS) ratings were compared among the three groups. RESULTS: Twenty-two of the 44 patients (50%) in the airbag group sustained only facial injuries. Fifteen of them had lacerations; four others had only facial abrasions. Three of the airbag patients had moderate facial injuries (AIS = 2); none required operative management. The airbag group had a mean AIS rating of 1.13, the seat belt group a mean AIS of 1.29, and the unrestrained group a mean AIS of 1.46. Patients using either seat belts (mean age, 40.5 y) or airbags (mean age, 44.9 y) were older than the unrestrained group (mean age, 39.6 y). Drug and/or alcohol impairment was significantly greater in the unrestrained group (mean, 38%) compared with the seat belt group (mean, 26%) and the airbag group (mean 11%.). CONCLUSIONS: Use of airbags is associated with less severe maxillofacial injuries compared with either a seat belt alone or no restraint. There is an inherent risk of minor maxillofacial injuries with airbag usage, but the severity of injury is distinctly reduced.

Accidents, Traffic↗
PubMed2000

Migraine associated with menstruation.

Many women report increased frequency of migraine in association with menstruation. The term 'menstrual' migraine is often used despite lack of an agreed definition. The International Headache Society has classified most headaches but not 'menstrual' migraine. A proposed definition is based on the finding that the prevalence of migraine increases on day 1 +/- 2 of the menstrual cycle. Attacks occurring at this time of the cycle are typically without aura. Effective acute therapy is the mainstay of management for menstrual and non-menstrual attacks although there is some evidence that attacks linked to menstruation are less responsive to treatment compared with migraine at other times of the cycle. If several attacks occur throughout the cycle, standard prophylactic agents should be used. Women with exclusive 'menstrual' migraine may benefit from perimenstrual prophylaxis but this should only be instigated once the association between migraine and menstruation has been confirmed with prospective records kept for a minimum of three cycles. NSAIDs are the treatment of choice in reducing migraine associated with menorrhagia and/or dysmenorrhoea, otherwise perimenstrual oestrogen supplements using percutaneous or transdermal oestrogens are recommended. Combined oral contraceptives are useful for women requiring contraception although there is a tendency for attacks to occur during the pill-free interval. If these are contraindicated, depot progestogen is an alternative as it also inhibits ovulation and can improve migraine, provided amenorrhoea is achieved. Oral progestogen-only contraception has little place in the management of 'menstrual' migraine as it does not inhibit ovulation and is often associated with a disrupted menstrual cycle. Some women consulting with menstrual migraine are menopausal and may be considering hormone replacement therapy. Studies suggest that non-oral routes of delivery of oestrogen, which provide stable levels, are more likely to improve migraine than oral oestrogens, which produce variable day-to-day levels. Too low a dose of oestrogen is ineffective at controlling symptoms but too high a dose, particularly if coupled with surges of endogenous oestrogen, can trigger migraine aura. Once the route and dose has been optimised, continuous oestrogens can control migraine as well as menopausal symptoms. Additional progestogen, necessary for unhysterectomised women, can exacerbate migraine. To minimise this, progesterone derivatives or non-oral routes of delivery are recommended, with continuous regimens used where possible.

Female↗
PubMed1999

Estrogen replacement and migraine aura.

OBJECTIVE: To assess the association between estrogen replacement therapy and migraine aura. BACKGROUND: Estrogen replacement therapy is increasingly used by perimenopausal and postmenopausal women for management of menopausal symptoms and for long-term protection against osteoporosis and arterial disease. There are few reports about the effects of estrogen replacement therapy on migraine. METHOD: Case reports were collected from women developing migraine aura related to use of estrogen replacement therapy. RESULTS: Four patients who developed migraine aura associated with the use of estrogen replacement therapy are described. In all cases, reducing the dose of estrogen or changing the route of delivery was associated with loss of aura. CONCLUSION: These findings suggest that high levels of estrogen in women using replacement therapy can trigger migraine aura.

Adult↗
PubMed1999

Analysis of the region of the 5' end of the MLL gene involved in genomic duplication events.

Rearrangements of the MLL gene are associated with both myeloid and lymphoid acute leukaemia. The gene is commonly involved in reciprocal translocations leading to the creation of chimaeric genes encoding novel protein products. An alternative mechanism of MLL gene rearrangement is due to intragenic duplication, leading to partial duplication of the amino-terminal portion of the protein. This occurs in leukaemia, but it has recently been shown that partial duplications of the MLL gene are detectable in peripheral blood and bone marrow of healthy donors and in normal non-haemopoietic tissues. Sequence analysis of the 45 kb of the 5' end of the MLL locus encompassing the breakpoints of these genomic duplications has failed to show a definitive reason as to why this region is such a frequent target of rearrangement. Indeed, although the majority of the breakpoint joins are the result of apparent Alu-mediated homologous recombination, several joins do not involve Alu elements in the region, despite a high density of these repetitive elements in the sequence.

Base Sequence↗
PubMed1998

Isolation and characterization of a pufferfish MLL (mixed lineage leukemia)-like gene (fMll) reveals evolutionary conservation in vertebrate genes related to Drosophila trithorax.

The MLL gene is interrupted and fused to a number of partner genes as a result of chromosomal translocations in human leukemias. MLL is a very large protein with a unique domain structure and large regions of homology to Drosophila trx. To define the key structural and functional domains of the MLL protein in vertebrates, we have cloned the genomic region encoding an MLL-like gene in the compact model vertebrate genome of Fugu rubripes. While the similarity between the mouse and human MLL proteins is very high, a lower overall similarity is present between the Fugu and mammalian proteins. Several new highly conserved regions were identified in the portion of the protein included in the MLL leukemia-associated fusion proteins. The conserved nature of regions of similarity between vertebrate forms of MLL and the Drosophila TRX proteins, as well as other domains previously suggested to have a functional role in MLL (including the AT hooks and the DNA methyltransferase domain), was also observed. Therefore, strong evolutionary constraints limited sequence divergence within these domains. The information derived from this comparative analysis will form the basis for the functional study of the MLL protein, particularly as it relates to human leukemogenesis.

Amino Acid Sequence↗
PubMed1998

Exon scrambling of MLL transcripts occur commonly and mimic partial genomic duplication of the gene.

The MLL gene is frequently rearranged in acute human leukemia of both the myeloid and lymphoid lineages. Using a sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we identified several abnormally spliced transcripts in which MLL exons were joined in an order different from the genomic orientation (scrambled exons). Mis-splicing of MLL was present in both normal and malignant tissues. Although the majority of these scrambled transcripts were joined accurately at consensus splice sites, there were several examples in which the junctions of exons spliced in aberrant order were at non-consensus sites. A number of features differentiate mis-splicing of MLL from the previously described cases of scrambled exons and circular RNAs. Some scrambled transcripts appear to be present in the polyadenylated fraction of RNA. No correlation of exon scrambling with exon skipping was found, and there was no particular tendency for the exons involved to be near large introns. Our data show that splicing of MLL is extremely complex. The presence of scrambled transcripts in both normal and leukemic cells, indistinguishable from transcripts resulting from genomic MLL rearrangements, precludes the use of nested RT-PCR as a screening method for detection of tandem duplication of tandem duplication of MLL.

Acute Disease↗
PubMed1998

Chromatographic removal and heat inactivation of hepatitis A virus during manufacture of human albumin.

CSL Limited, an Australian biopharmaceutical company, has recently converted its method of manufacture for human albumin from a traditional Cohn-ethanol fractionation method to a method employing chromatographic techniques. Studies were undertaken to determine the efficiency of the chromatographic and pasteurization steps used in the manufacture of Albumex(R) (CSL's trade name for albumin) in removing and inactivating the potential viral contaminant, hepatitis A virus (HAV). The manufacturing process for Albumex(R) includes three chromatographic steps, two of which are ion-exchange steps (DEAE-Sepharose(R) Fast Flow and CM-Sepharose(R) Fast Flow) and the third is a gel-filtration step (Sephacryl(R) S200 HR). The final stage of the Albumex(R) process involves a bulk pasteurization step where product is held at 60 degrees C for 10 h. HAV partitioning experiments on the DEAE-Sepharose(R) FF and CM-Sepharose(R) FF ion-exchange and Sephacryl(R) S200 HR gel-filtration columns were performed with scaled-down models of the production-scale chromatographic Albumex(R) process. Production samples collected before each of the chromatographic steps were spiked with HAV and processed through each of the scaled-down chromatographic columns. Samples collected during processing were assayed and the log10 reduction factors calculated. Inactivation kinetics of HAV were examined during the pasteurization of Albumex(R) 5 and 20 [5% and 20% (w/v) albumin solutions] held at 60 degrees C for 10 h. Log10 reductions for HAV through the DEAE-Sepharose(R) FF, CM-Sepharose(R) FF and Sephacryl(R) S200 HR chromatographic columns were 5.3, 1.5 and 4.2 respectively, whereas a 4.4 and a greater than 3.9 log10 reduction in HAV in Albumex(R) 5 and 20 respectively were achieved during pasteurization.

Chromatography, Gel↗