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Frits R Rosendaal - One of the best experts on this subject based on the ideXlab platform.
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increased risk of venous thrombosis in carriers of hereditary protein c deficiency defect
The Lancet, 1993Co-Authors: C F Allaart, S R Poort, Pieter H Reitsma, Rogier M Bertina, E Briet, Frits R RosendaalAbstract:Abstract The relevance of heterozygosity for hereditary protein C deficiency as a risk factor for venous thrombosis has been disputed because Heterozygotes without symptoms have been identified among blood donors and relatives of homozygotes. As a result, clinicians do not know whether to offer prophylaxis or not. We have compared thrombosis-free survival in 161 heterozygous and normal members of the families of 24 Heterozygotes for protein C deficiency referred from several centres in the Netherlands and with a history of symptoms. We studied the influence of heterozygosity and of putative additional risk factors on the occurrence of thrombotic events noted when a medical history was taken. Protein C activities were measured but a diagnosis of heterozygosity was based on the presence of the specific mutation in one of the protein C genes identified in the proband of the family. We found a significant difference in the thrombosis-free survival of the 77 Heterozygotes and 84 normals: by age 45, 50% of Heterozygotes and 10% of normal relatives can be expected to have had a manifestation of venous thromboembolism. The presence of such a mutation was clearly associated with an increased risk of venous thrombotic events. Thrombotic events occurred more often in years in which the patient had been immobile for more than a week or had had surgery. Other putative risk factors showed no significant effect in the incidence of thrombotic events. About 50% of all first episodes and 65% of recurrences of venous thromboembolism in the Heterozygotes were spontaneous—ie, there was no predisposing event such as surgery or pregnancy. There was no increased risk for arterial occlusions in Heterozygotes. We conclude that members of the family of a symptomatic Heterozygote proband who are heterozygous for the mutation in the protein C gene have an increased risk of venous thrombotic events compared with their normal family members. For such individuals prophylactic anticoagulation should be considered; the decision will need to be taken on an individual basis.
Takashi Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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Biochemical and Immunochemical Study of Seven Families with 3-Ketothiolase Deficiency: Diagnosis of Heterozygotes Using Immunochemical Determination of the Ratio of Mitochondrial Acetoacetyl-CoA Thiolase and 3-Ketoacyl-CoA Thiolase Proteins
Pediatric Research, 1993Co-Authors: Seiji Yamaguchi, Akihiro Wakazono, Atsuko Sakai, Takashi Kuwahara, Tadao Orii, Toshiyuki Fukao, Takashi HashimotoAbstract:ABSTRACT: The possibility of identifying Heterozygotes of 3-ketothiolase deficiency, an inborn error of metabolism caused by a defect of mitochondrial acetoacetyl-CoA thiolase (T2), was tested in seven unrelated families by using enzymatic assay of thiolase activity and immunoblot analysis. The ratio of acetoacetyl-CoA thiolase activities, in the presence and absence of K^+ ion (+K/-K ratio), in fibroblasts from 15 normal controls was around 2.0 (1.8 to 2.4), whereas the +K/-K ratio in eight patients was always 1.0. The ratio for the 13 obligate carriers ranged from 1.4 to 1.9, causing a minor overlap with control. Identification of Heterozygote cells by immunoblot analysis, using anti-T2 antibody alone as a probe, was difficult, as previously reported. We therefore carried out immunoblot analysis, using as probes a mixture of anti-T2 antibody and the antibody against mitochondrial 3-ketoacyl-CoA thiolase (T1), another mitochondrial thiolase, and determined the ratio of the intensities of the T2 and T1 bands (T2/T1 ratio) using a densitometer. When the T2/T1 ratio was calculated, there was no overlap between the Heterozygotes and normal controls. Hence, the Heterozygotes can be unambiguously identified using this method. The thiolase activities and T2/T1 proteins in immunoblotting were detectable in peripheral lymphocytes, rectal mucosa, amniocytes, and liver. Thus, the postnatal diagnosis of 3-ketothiolase deficiency can be readily made using lymphocytes or rectal mucosa. The applicability of these methods in amniocytes indicates that prenatal diagnosis of this disease should be possible.
Hiroaki Onda - One of the best experts on this subject based on the ideXlab platform.
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a mouse model of tsc1 reveals sex dependent lethality from liver hemangiomas and up regulation of p70s6 kinase activity in tsc1 null cells
Human Molecular Genetics, 2002Co-Authors: David J Kwiatkowski, Hongbing Zhang, Jennifer L Bandura, Kristina M Heiberger, Michael Glogauer, Nisreen Elhashemite, Hiroaki OndaAbstract:Tuberous sclerosis (TSC) is a autosomal dominant genetic disorder caused by mutations in either TSC1 or TSC2, and characterized by benign hamartoma growth. We developed a murine model of Tsc1 disease by gene targeting. Tsc1 null embryos die at mid-gestation from a failure of liver development. Tsc1 Heterozygotes develop kidney cystadenomas and liver hemangiomas at high frequency, but the incidence of kidney tumors is somewhat lower than in Tsc2 Heterozygote mice. Liver hemangiomas were more common, more severe and caused higher mortality in female than in male Tsc1 Heterozygotes. Tsc1 null embryo fibroblast lines have persistent phosphorylation of the p70S6K (S6K) and its substrate S6, that is sensitive to treatment with rapamycin, indicating constitutive activation of the mTOR-S6K pathway due to loss of the Tsc1 protein, hamartin. Hyperphosphorylation of S6 is also seen in kidney tumors in the Heterozygote mice, suggesting that inhibition of this pathway may have benefit in control of TSC hamartomas.
R Palmer - One of the best experts on this subject based on the ideXlab platform.
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cystic fibrosis Heterozygote screening in 5 161 pregnant women
American Journal of Human Genetics, 1996Co-Authors: David R Witt, C Schaefer, P Hallam, B Blumberg, A Fishbach, J Holtzman, S Kornfeld, R Lee, L Nemzer, R PalmerAbstract:A screening program for cystic fibrosis (CF) Heterozygotes was conducted in a large HMO prenatal population, to evaluate the level of interest among eligible patients, the effectiveness of prescreening education, attitudes toward the screening process, psychological effects, and utilization of prenatal diagnosis and its outcomes. The Heterozygote identification rate and frequency of specific CFTR mutations were also assessed. Identified carriers were offered genetic counseling and testing of male partners. Prenatal diagnosis was offered if both partners were identified as carriers. A total of 5,161 women underwent carrier testing; 947 others completed survey instruments only. The acceptance rate of screening was high (78%), and pretest education by videotape was generally effective. Adverse psychological effects were not reported. Participants generally found screening to be desirable and useful. Screening identified 142 female Heterozygotes, 109 couples in which the male partner was not a carrier, and 7 high-risk couples. The incidence of R117H mutations was much higher than expected. The number of identified carriers was much lower in Hispanics than in Caucasians. We conclude that large-scale prenatal screening for CF Heterozygotes in the absence of a family history of CF is an acceptable method for identifying couples at risk for affected fetuses. Sufficient pretestmore » education can be accomplished efficiently, test insensitivity is well accepted, adverse psychological events are not observed, and general patient satisfaction is high. 66 refs., 1 fig., 8 tabs.« less
Karl V Voelkerding - One of the best experts on this subject based on the ideXlab platform.
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instrument comparison for Heterozygote scanning of single and double Heterozygotes a correction and extension of herrmann et al clin chem 2006 52 494 503
Clinical Chemistry, 2007Co-Authors: Mark G Herrmann, Jacob D Durtschi, Kathryn L Bromley, Carl T Wittwer, Karl V VoelkerdingAbstract:We have discovered that the DNA sample used in our recent paper (1) as a control Heterozygote at the sickle cell locus of β-globin (17A→T, also known as HBB c.20A→T by HUGO nomenclature) contained an additional variant. Subsequent sequencing revealed a double Heterozygote, HBB c.[9C→T; 20A→T]. The HBB c. 9C→T is a silent variant for the 3rd amino acid, histidine. In view of this additional sequence variation, we reevaluated the heteroduplex scanning capabilities of the instruments, as reported in the original Fig. 3, to ascertain their ability to distinguish melting curves of heteroduplexes caused by single and double Heterozygotes from melting curves of homoduplexes. The c. 9C→T is a …