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Biomedical subjects

H Ireland

Publications and source records attributed to H Ireland.

At least 37 records · Page 2Linked to original sources
PubMed1996

Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group.

Protein S is a protein C-dependent and independent inhibitor of the coagulation cascade. Deficiency of protein S is an established risk factor for venous thromboembolism. We have used a strategy of specific amplification of the coding regions and intron/exon boundaries of the active protein S gene (PROS1) and direct single-strand solid phase sequencing, to seek mutations in 35 individuals with phenotypic protein S deficiency. Nineteen point mutations (16 novel) in 19 probands (or relatives of probands) with venous thromboembolism are reported here. Fifteen of the 19 mutations were expected to be causal and included 10 missense mutations (Lys9Glu, Glu26Ala, Gly54Glu, Cys145Tyr, Cys200Ser, Ser283Pro, Gly340Asp, Cys408Ser, Ser460Pro, and Cys625Arg). Three of the 15 mutations resulted in premature stop codons (delete T 635 producing a stop codon at position 126, Lys368stop and Tyr595stop) and two were at intron/exon boundaries (+1 G to A in intron d and +3 A to C in intron j). Of the remaining four mutations, three were within intronic sequence and one was a silent mutation within the coding region and did not alter amino acid composition. In two of the 10 missense mutations, reduced plasma protein S activity compared with antigen level suggested the presence of variant (type II) protein S.

Alleles↗
PubMed1996

TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice.

TGFbeta1 has been implicated in cell cycle control and carcinogenesis. To address the exact function of TGFbeta1 in skin carcinogenesis in vivo, mice with TGFbeta1 expression targeted to keratinocytes were subjected to long-term chemical carcinogenesis treatment. TGFbeta1 showed biphasic action during multistage skin carcinogenesis, acting early as a tumor suppressor but later enhancing the malignant phenotype. The transgenics were more resistant to induction of benign skin tumors than controls, but the malignant conversion rate was vastly increased. There was also a higher incidence of spindle cell carcinomas, which expressed high levels of endogenous TGFbeta3, suggesting that TGFbeta1 elicits an epithelial-mesenchymal transition in vivo and that TGFbeta3 might be involved in maintenance of the spindle cell phenotype. The action of TGFbeta1 in enhancing malignant progression may mimic its proposed function in modulating epithelial cell plasticity during embryonic development.

Animals↗
PubMed1996

Prenatal diagnosis in combined antithrombin and factor V gene mutation.

We report prenatal diagnosis in a family with combined antithrombin deficiency (type II heparin binding site) and factor V 506 Arg to Gln mutation. Both clinically unaffected parents are heterozygous for the antithrombin mutation, which results in a 99 Leu to Phe substitution, and the father is also heterozygous for the factor V gene defect. There is one daughter, homozygous for the antithrombin and heterozygous for the factor V mutations, who suffered a right-sided hemiparesis at the age of 4 months due to occlusion of the left middle cerebral artery and a large left sided infarct followed by further thromboembolic events. The family requested prenatal diagnosis and chorionic villi was sampled at 12 weeks gestation. The fetus was shown to be heterozygous for the antithrombin and factor V gene mutations, the same genotype as the unaffected father. No further intervention was considered necessary. To our knowledge this is the first report of prenatal diagnosis in antithrombin deficiency.

Antithrombins↗
PubMed1996

Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden.

In 29 patients (17 females) homozygous Arg 506 Gln mutation (FV Leiden) was identified. 25 had been investigated because of venous thromboembolism (VTE); four asymptomatic patients were found during family studies. The first VTE had occurred significantly earlier in females (median age [m] 26 years, range 17-49) than in males (m=38 years, range 21-82) (P=0.01). 12 females (80%) had taken oral contraceptives (OC, estrogen content 0.02-0.1 mg) for 6-150 months prior to thrombosis. Further triggering conditions in females were hormone replacement (n=1) and pregnancy (n=2). In 8/10 males the first VTE had occurred spontaneously--in two after surgery. The sites of VTE were deep vein thrombosis, pulmonary embolism, caval vein thrombosis and superficial thrombophlebitis. From our data we conclude that OC medication is the most important precipitating factor for VTE in females with homozygous FV Leiden.

Adolescent↗
PubMed1996

Directed search for thrombomodulin gene mutations.

Thrombomodulin is a principle thrombin receptor located on the vascular endothelium. Thrombomodulin alters the specificity of thrombin, redirecting its procoagulant function to an anticoagulant function by making it a more efficient activator of protein C. While mutation of the genes of other components of this anticoagulant mechanism, protein C, protein S and factor V, is known to predispose towards venous thromboembolism, there are only a few reports of the investigation of thrombomodulin gene mutation. We present the design and evaluation of a strategy to investigate thrombomodulin gene mutation in arterial and venous thrombosis.

Cerebrovascular Disorders↗
PubMed1996

Gene mutations in 21 unrelated cases of phenotypic heterozygous protein C deficiency and thrombosis. Protein C Study Group.

Mutations have been identified in the protein C gene in 21 patients with venous thromboembolism and phenotypic heterozygous protein C deficiency. In 20 probands, single mutations were the only abnormalities identified by sequencing all coding regions, intron exon boundaries and the promoter region back to -1540. In one proband 2 mutations were identified and in another family 2 mutations were identified (but not both in the proband). Of the 23 mutations, 18 resulted in predicted amino acid substitutions, 3 were mutations resulting in stop codons, one was a mutation within a consensus splice sequence and another a 9 base pair insertion within exon 5 (this region within exon 5 is proposed as a deletion/insertion hot spot). A novel polymorphism was also, uniquely, identified in the propeptide region of the molecule (Pro-21Pro; CCT to CCC) in a kindred from Hong Kong. Cosegregation of the protein C gene mutation with protein C deficiency could be determined in 13 families. In a further family, phenotypic protein C deficiency and the genetic mutation cosegregated in only 4/5 members. The first thrombotic incident occurred in the probands between the ages of 11 and 59 years and 12 individuals suffered recurrent thrombosis. Thrombosis occurred in at least one other family member in 9/21 families, but in 2 of these it was inconsistently associated with protein C deficiency. An independent genetic risk factor, factor V Arg506Gln (FV Leiden) was identified in 2 probands (and 3 family members) and in 4 protein C deficient members of a third family but not in the proband. The results suggest that in the majority of probands with thrombosis and phenotypic protein C deficiency, a single protein C gene mutation is associated with thrombosis. However, it is also possible that additional unknown genetic risk factors contribute to the thrombotic risk. An added, acquired, risk factor leads to thrombosis at an early age (< 25 years).

Adolescent↗
PubMed1995

Colour Doppler ultrasound in renal transplant artery stenosis: which Doppler index?

A prospective study comparing colour Doppler ultrasound (US) with the 'gold standard' of intra-arterial digital subtraction angiography in the evaluation of renal transplant artery stenosis was performed. Both the intrarenal vessels and the transplant renal artery were examined by Doppler US. Diagnostic arteriography was performed only if, on Doppler, the peak systolic velocity in the transplant renal artery exceeded 1.5 ms-1. Of 109 patients, the transplant artery could not be visualized using colour Doppler US in three, and these were omitted from statistical analysis. Of the remaining 106 patients, 31 had a peak systolic velocity greater than 1.5 ms-1 in the transplant renal artery and were referred for DSA. Of the multiple renal Doppler indices recorded, the peak systolic velocity in the transplant artery was the best discriminating measurement for the detection of renal artery stenosis. A peak systolic velocity of > or = 2.5 ms-1 in the transplant renal artery had a sensitivity of 100% and a specificity of 95% for the detection of renal artery stenosis ( > 50% diameter reduction). Although a significant difference in Pulsatility Index, Resistive Index, Acceleration Index and Acceleration Time was recorded from the intrarenal vessels in the angiographically normal and stenosed groups with Doppler, these measurements were less useful as discriminating diagnostic tests. In conclusion, the peak systolic velocity in the transplant renal artery is the most sensitive Doppler criterion for renal artery stenosis and is sensitive and specific enough to be used as a screening test. The intrarenal acceleration time and index should not be used in isolation.

Angiography, Digital Subtraction↗
PubMed1995

Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke.

To determine the prevalence of the factor V Leiden gene mutation in relation to the phenotypes of cerebral infarction and cerebral hemorrhage, we studied 386 randomly selected cases of acute stroke and 247 control subjects. Factor V genotype was determined by amplification of a 267-bp sequence of exon/intron 10 of the factor V gene. Levels of prothrombin fragment F(1 + 2), a marker of thrombin generation, were determined in both acute and convalescent stroke and related to factor V genotype. Prothrombin fragment F(1 + 2) was assessed by using an enzyme-linked immunosorbent assay. Sixteen stroke cases (4.1%) were identified as having the mutation compared with 14 (5.6%) control subjects. Prothrombin fragment F(1 + 2) levels were estimated in 191 cases and found to be elevated both acutely and after 3 months, but they were not related to factor V genotype. Prothrombin fragment F(1 + 2) is elevated in acute stroke and requires further evaluation in relation to cerebrovascular disease. These results suggest that the factor V Leiden gene mutation is not a risk factor for arterial thrombosis causing stroke.

Base Sequence↗
PubMed1994

Risk factors for cardiovascular disease in IDDM. A study of identical twins.

Patients with insulin-dependent diabetes mellitus (IDDM) have an excess mortality, predominantly attributable to cardiovascular disease. To determine the effect of IDDM on potential risk factors for cardiovascular mortality, we studied subjects from the British Diabetic Twin Study Group. Forty-five identical twin pairs discordant for IDDM were recruited in addition to 45 matched nondiabetic singleton control subjects. All were selected to be normotensive and to have normal albumin excretion rates. Four variables differed significantly between the diabetic twins and their nondiabetic identical co-twins: diabetic twins had higher systolic blood pressure (sBP) ([mean +/- SD] 127 +/- 17 vs. 123 +/- 18 mmHg, P < 0.05), high-density lipoprotein (HDL) cholesterol (1.36 +/- 0.31 vs. 1.25 +/- 0.29 mM, P < 0.05) and fibrinogen (3.23 +/- 0.81 vs. 2.98 +/- 0.71 mg/ml, P < 0.05) but lower factor VII (114 +/- 34 vs. 122 +/- 31%, P < 0.05). All four of these risk factors were significantly correlated (P < 0.001) within the identical twin pairs, as were the other risk factors. These significant correlations within twins for the risk factors studied reflects the impact of shared genetic and environmental influences. IDDM affects sBP, HDL cholesterol, fibrinogen, and factor VII, but only sBP and fibrinogen are affected adversely.

Adult↗
PubMed1992

Antithrombotic properties of dermatan sulphate (MF 701) in haemodialysis for chronic renal failure.

The therapeutic potential of the glycosaminoglycan (GAG), dermatan sulphate (DS), as an antithrombotic agent in humans has yet to be established. We have performed dose ranging studies of DS to determine its effectiveness as an antithrombotic agent in patients (n = 6-8) undergoing haemodialysis for chronic renal failure. In an initial study, Study 1, i.v. bolus doses of 2-4 mg/kg and 5-6 mg/kg DS were given to patients dialysing with polyacrylonitrile hollow fibre (PAN HF) membranes. In a second crossover study, Study 2, performed using cuprophane hollow fibre (CHF) membranes, i.v. bolus doses of 3 mg/kg and 6 mg/kg DS were compared to a standard unfractionated heparin (UFH) regime that has been shown previously to inhibit fibrin formation. Further infusion studies, Study 3 and Study 4 evaluated the antithrombotic efficacy of an i.v. DS bolus of 3 mg/kg plus an i.v. infusion of DS 0.6 mg kg-1 h-1 and a DS bolus of 5 mg/kg plus an infusion of 1 mg kg-1 h-1 over 5 h, respectively. These studies were compared to standard UFH regimes in a randomised crossover design. Plasma levels of fibrinopeptide A (FPA) and thrombin-antithrombin (TAT) were used as markers of fibrin formation and thrombin generation during dialysis using both membranes. The changes in DS concentration following administration of the different doses were similar in Studies 1 and 2. However, the effectiveness of DS as an anticoagulant appeared to depend markedly on the different dialyser types used in the two studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Dermatan sulphate in haemodialysis.

Experimental work suggests that dermatan sulphate has potential as an antithrombotic agent: it can inhibit venous thrombi yet has less effect upon bleeding than heparin. While heparin functions as an anticoagulant primarily by its ability to accelerate the action of the plasma protein inhibitor antithrombin III, dermatan sulphate acts selectively through a structurally related inhibitor, heparin co-factor II, to inhibit thrombin. We have done a series of dose-finding studies of the use of dermatan sulphate as an anticoagulant/antithrombotic agent in patients on maintenance haemodialysis. Dermatan sulphate proved to be an effective anticoagulant in this setting.

Dermatan Sulfate↗
PubMed1992

Pleiotropic effects of antithrombin strand 1C substitution mutations.

Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to s1C proximity to highly conserved internal beta strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, s1C is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of s1C variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function.

Adolescent↗