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Mark Thomas

Publications and source records attributed to Mark Thomas.

43 records · Page 3Linked to original sources
PubMed2002

New Zealand's HIV infected population under active follow-up during 2000.

AIM: To audit New Zealand's HIV infected population currently under active follow-up. METHODS: Multiple sources were used to determine anonymously the demographic and management characteristics of HIV infected individuals being monitored with HIV viral load measurements and/or receiving antiretroviral therapy during 2000. RESULTS: 593 people (480 males and 113 females) were under active follow-up. The most common transmission risk was male homosexual contact (56%) followed by heterosexual contact (28%), injecting drug use (3%) and mother to infant transmission (1%). Ethnicity data showed a disproportionate number of Africans (13%) compared to recent census figures. Anti-retroviral therapy was used in 71% of the cohort of whom 62% had HIV viral load measurements below 400 copies/mL. An upper estimate of diagnosed HIV individuals living in New Zealand at 30/9/2000 was 801. CONCLUSIONS: This is the first time that the demographic and clinical state of HIV infected individuals has been assessed throughout New Zealand. The results suggest a slightly lower number of HIV infected individuals currently living in New Zealand than previously estimated. Anti-retroviral therapy is being used effectively within the HIV infected population. The changing demographics, with a higher proportion of people under care from Africa, increasing numbers of females, and an increase in the proportion with heterosexual risk factors are particular challenges.

Adolescent↗
PubMed2002

Mutation detection in the duplicated region of the polycystic kidney disease 1 (PKD1) gene in PKD1-linked Australian families.

Screening for disease-causing mutations in the duplicated region of the PKD1 gene was performed in 17 unrelated Australian individuals with PKD1-linked autosomal dominant polycystic kidney disease. Exons 2-21 and 23-34 were assayed using PKD1-specific PCR amplification and direct sequencing. We have identified 12 novel probably pathogenic DNA variants, including five truncating mutations (Q563X, c.5105delAT, c.5159delG, S2269X, c.9847delC), two in-frame deletions (c.7472del3, c.9292del39), and two splice-site mutations (IVS14+1G>C, IVS16+1G>T). Three of the mutations (G381C, Y2185D, G2785D) were predicted to lead to the replacement of conserved amino acid residues, with ensuing changes in protein conformation. Defects in the duplicated region of PKD1 thus account for 63% of our patients. Together with the previously detected mutations (Q4041X, R4227P) in the 3 region of the gene, the study has achieved an overall mutation detection rate of 74%. In addition, we have detected 31 variants (nine novel and 22 previously published) that did not segregate with the disease and were considered to be neutral polymorphisms. Three of the nine novel polymorphisms were missense mutations with a predicted effect on protein conformation, emphasizing the problems of interpretation in PKD1 mutation screening.

Amino Acid Sequence↗
PubMed2002

Titin-cap associates with, and regulates secretion of, Myostatin.

Myostatin, a secreted growth factor, is a key negative regulator of skeletal muscle growth. To identify modifiers of Myostatin function, we screened for Myostatin interacting proteins. Using a yeast two-hybrid screen, we identified Titin-cap (T-cap) protein as interacting with Myostatin. T-cap is a sarcomeric protein that binds to the N-terminal domain of Titin and is a substrate of the titin kinase. Mammalian two-hybrid studies, in vitro binding assays and protein truncations in the yeast two-hybrid system verified the specific interaction between processed mature Myostatin and full-length T-cap. Analysis of protein-protein interaction using surface plasmon resonance (Biacore, Uppsala, Sweden) kinetics revealed a high affinity between Myostatin and T-cap with a KD of 40 nM. When T-cap was stably overexpressed in C(2)C(12) myoblasts, the rate of cell proliferation was significantly increased. Western analyses showed that production and processing of Myostatin were not altered in cells overexpressing T-cap, but an increase in the retention of mature Myostatin indicated that T-cap may block Myostatin secretion. Bioassay for Myostatin confirmed that conditioned media from myoblasts overexpressing T-cap contained lower levels of Myostatin. Given that Myostatin negatively regulates myoblast proliferation, the increase in proliferation observed in myoblasts overexpressing T-cap could thus be due to reduced Myostatin secretion. These results suggest that T-cap, by interacting with Myostatin, controls Myostatin secretion in myogenic precursor cells without affecting the processing step of precursor Myostatin.

Animals↗
PubMed2002

The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD.

Myostatin is a negative regulator of myogenesis, and inactivation of myostatin leads to heavy muscle growth. Here we have cloned and characterized the bovine myostatin gene promoter. Alignment of the upstream sequences shows that the myostatin promoter is highly conserved during evolution. Sequence analysis of 1.6 kb of the bovine myostatin gene upstream region revealed that it contains 10 E-box motifs (E1 to E10), arranged in three clusters, and a single MEF2 site. Deletion and mutation analysis of the myostatin gene promoter showed that out of three important E boxes (E3, E4, and E6) of the proximal cluster, E6 plays a significant role in the regulation of a reporter gene in C(2)C(12) cells. We also demonstrate by band shift and chromatin immunoprecipitation assay that the E6 E-box motif binds to MyoD in vitro and in vivo. Furthermore, cotransfection experiments indicate that among the myogenic regulatory factors, MyoD preferentially up-regulates myostatin promoter activity. Since MyoD expression varies during the myoblast cell cycle, we analyzed the myostatin promoter activity in synchronized myoblasts and quiescent "reserve" cells. Our results suggest that myostatin promoter activity is relatively higher during the G(1) phase of the cell cycle, when MyoD expression levels are maximal. However, in the reserve cells, which lack MyoD expression, a significant reduction in the myostatin promoter activity is observed. Taken together, these results suggest that the myostatin gene is a downstream target gene of MyoD. Since the myostatin gene is implicated in controlling G(1)-to-S progression of myoblasts, MyoD could be triggering myoblast withdrawal from the cell cycle by regulating myostatin gene expression.

Animals↗
PubMed2002

Single cysteine to tyrosine transition inactivates the growth inhibitory function of Piedmontese myostatin.

Myostatin, a member of the transforming growth factor-beta superfamily, is a secreted growth factor that is proteolytically processed to give COOH-terminal mature myostatin and NH2-terminal latency-associated peptide in myoblasts. Piedmontese cattle are a heavy-muscled breed that express a mutated form of myostatin in which cysteine (313) is substituted with tyrosine. Here we have characterized the biology of this mutated Piedmontese myostatin. Northern and Western analyses indicate that there is increased expression of myostatin mRNA and precursor myostatin protein in the skeletal muscle of Piedmontese cattle. In contrast, a decrease in mature myostatin was observed in Piedmontese skeletal muscle. However, there is no detectable change in the circulatory levels of mature myostatin in Piedmontese cattle. Myoblast proliferation assay performed with normal and Piedmontese myostatin indicated that mature wild-type myostatin protein inhibited the proliferation of C2C12 myoblasts. Piedmontese myostatin, by contrast, failed to inhibit myoblast proliferation. In addition, when added in molar excess, Piedmontese myostatin acted as a potent "competitive inhibitor" molecule. These results indicate that, in Piedmontese myostatin, substitution of cysteine with tyrosine results in the distortion of the "cystine knot" structure and a loss of biological activity of the myostatin. This mutation also appears to affect either processing or stability of mature myostatin without altering the secretion of myostatin.

Amino Acid Substitution↗
PubMedDate not supplied

Assessment of the efficiency of treatment of dyslipidaemia in renal outpatients.

BACKGROUND: Lipid abnormalities, together with other co-existent risk factors, contribute to the accelerated atherosclerotic process, and consequently to the high incidence of cardiovascular disease, observed in end-stage renal patients. The objectives of this study were to determine the prevalence of dyslipidaemia and to assess how it is managed in a range of patients at four UK renal units. METHODS: Patients with renal disease were recruited from the outpatient clinics of 4 UK hospitals. Individuals meeting the entry criteria were required to provide one sample of venous blood following a 12-hour fast. Lipid profiles were measured for each patient. RESULTS: The study population consisted of 677 patients of which 276 (40.8%) were pre-dialysis patients with existing renal disease, 233 patients (34.4%) were receiving haemodialysis and 168 patients (24.8%) were receiving CAPD. Analysis showed that 64% of all patients had hypercholesterolaemia (defined according to Joint British Societies guidelines as LDL-cholesterol [LDL-C] >3.0 mmol/L [115 mg/dL] and/or total cholesterol [TC] >5.0 mmol/L [190 mg/dLl). Despite the high incidence of hypercholesterolaemia, only 16% of study participants were receiving lipid-lowering therapy. An LDL-C goal of <3.0 mmol/L (115 mg/dL) was achieved in 50.0% of patients receiving lipid-lowering treatment. CONCLUSIONS: The widespread failure to treat hypercholesterolaemia in patients with renal dysfunction given their high risk of future cardiovascular events is a major cause for concern. The observation that many dialysis patients receiving lipid-lowering therapy had not achieved recommended LDL-C and TC levels suggests that more efficient treatment of dyslipidaemia may be indicated in this patient population.

Adult↗