Gene Literature Dashboard

The dynamic haemostatic balance between blood coagulation and fibrinolysis and its influence on the development of disseminated intravascular coagulation are described. The effects of heparin and antithrombin-III are illustrated by clinical cases.

The synthesis of a phosphotriester, an inhibitor of acetylcholinesterase, was performed by the coupling reaction of diethylphosphate with various phenolic compounds using dicyclohexylcarbodiimide (DCC). All of the compounds synthesized inhibited housefly acetylcholinesterase activity. Derivatives including an electronegative part as a nitro group in the phenol ring showed strong inhibition towards housefly acetylcholinesterase, but those with hydrophobic derivatives of the phenol group, such as cresol, naphthol and biphenol, showed relatively low inhibition. In experiments with housefly, the value of LD50 for each chemical correlated with the I50 value for acetylcholinesterase except alpha-naphthyl diethylphosphate, beta-naphthyl diethylphosphate and p,p'-biphenyl diethylphosphate.

Using Southern DNA hybridization techniques, restriction enzyme site polymorphisms have been used to correlate the molecular maps of the murine major histocompatibility complex (MHC) I region with the genetic map derived from analyses of recombinant mouse strains. The data indicated that the DNA that maps between the I-A and I-E subregions is limited to 3.4 kilobases (kb) and includes the 3' end of the E beta gene. According to classical genetic mapping by recombinational analysis of serological markers, this region should encode the I-B and I-J subregions. These observations are surprising in two respects. First, 3.4 kb is a small amount of DNA to encode even one complete murine gene. Second, this region, which putatively encodes the I-J gene, appears to reside at least partially within the E beta gene. To analyze these apparent paradoxes, further, we cloned the 3.4-kb region in question from six I-region combinant strains [B10.A(3R), B10.a(5R), B10.A(4R), B10.GD, B10.HTT, and B10.S(9R)] and four strains used in the derivation of the recombinants (B10.D2, B10.A, C57BL/10, and ASW) into a lambda phage vector. By direct restriction enzyme mapping of polymorphic sites, we have confirmed the previously identified boundaries of the I-A and I-E subregions and have narrowed the estimate of the distance between these subregions to approximately 2.0 kb of DNA. This 2.0-kb region encompasses part of the intron between the first- (beta 1) and second-domain (beta 2) exons and the second-domain exon (beta 2) of the E beta gene.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously demonstrated that the murine humoral immune responses to the group-specific a and subtype-specific d/y determinants of hepatitis B surface antigen (HBsAg) are controlled by H-2-linked immune response (Ir) genes. High responder (H-2d,q), intermediate responder (H-2a greater than b greater than k) and nonresponder (H-2f,s) haplotypes have been identified (8, 9). The kinetics and specificity of in vivo antibody production after HBsAg immunization in congeneic, H-2-recombinant strains was analyzed to further define relevant Ir genes and their influence on the immune response to distinct antigenic determinants. These studies indicate that the humoral anti-HBs response is regulated by at least two Ir genes, one in the I-A subregion (Ir-HBs-1) and one in the I-C subregion (Ir-HBs-2) of the murine H-2 complex. Ir-HBs-1 regulates the primary responses to all HBsAg determinants, whereas the influence of Ir-HBs-2 is determinant specific, affecting the responses to the d or y determinants. The anti-a response is regulated exclusively by Ir-HBs-1. Strains possessing only the Ir-HBs-2 gene [B10.S(9R) and B10.HTT] produce no anti-a response and a subtype-specific antibody response is detected only after secondary or tertiary immunization. In contrast, the influence of Ir-HBs-2 in the presence of Ir-HBs-1 is detected upon primary immunization and is additive rather than exclusive. There is also suggestive evidence that the presence of the Ek molecule, at least in the context of I-Ak, may have a suppressive influence on the anti-HBs response. Additionally, HBsAg-specific, T cell proliferative responses were H-2 restricted and the kinetics and specificity of T cell proliferative responses paralleled in vivo antibody production. These data indicate that, although the I-A subregion exerts a dominant influence, distinct Ir-HBs genes, mapping in separate I subregions, control immune responses to alternate HBsAg determinants on the same protein molecule.

Functional properties of the carbohydrate chain of human thrombin were examined by quantitating the activity of the enzyme before and after partial removal of its oligosaccharide by exoglycosidases. The following activities were studied: fibrinogen clotting, factor VIII coagulant (VIII:C) activation, inhibition by defibrinated plasma (anti-thrombin-III and alpha 2-macroglobulin), binding to polymerized fibrin, and stimulation of platelet release and aggregation. In general, the published information about the activity of native thrombin in these interactions was confirmed, though differences were observed in the association constants describing thrombin binding to fibrin. Partial deglycosylation had no apparent effect on any of these activities. It is concluded, therefore, that the oligosaccharide of human thrombin is located outside the major protein and platelet-binding regions of the molecule.

It is here proposed that disordered redox balance leads to congestive heart failure in a variety of diverse clinical situations. These conditions include those associated with an excess of reducing agents, such as catecholamines and thyroid hormone, or impaired oxidant defenses, such as in selenium deficiency. The clinical situations include hypertension, hyperthyroidism, progressive congestive heart failure, amphetamine overdose and hemochromatosis. The molecular damage to the cardiac muscle is postulated to be mediated via reaction oxygen radicals.

The authors study three cytotoxicity system in psoriasis: direct cytotoxicity (DCC), antibodies mediated cytotoxicity (ADCC) and activated lymphocytes mediated cytotoxicity (PCC). The results of DCC and PCC are in the normal values, while ADCC are a somewhat increased, showing a hyperactivity of this system, which could explain some physiopathological phenomena of this disease. We consider this finding as secondary to an alteration of the immune system by dysbalance of B-T lymphocytes.

The frequency of HLA-A3 and HLA-B14 antigens was found to be significantly (P = less than 0.0001) higher in a series of 50 unrelated and unselected Swedish patients with idiopathic hemochromatosis (IH) than in controls, being 66% and 32% for A3 and 22% and 2% for B14. The haplotype A3B14 was associated with the highest risk in this material (relative risk 23.4). One family with this haplotype was traced back to the end of the seventeenth century. The pattern of HLA antigens associated with IH in Sweden shows remarkable similarity to those reported from England and Brittany.

The absence of fibrinogen and the presence of plasmic fragments X, Y, D, and E were demonstrated in a patient bitten by a western diamondback rattlesnake, Crotalus atrox. The factor VIII level and the platelet count were within normal limits. There were distinct changes of protease inhibitors in the patient's plasma. Alpha-1-protease inhibitor was elevated. Antithrombin-III was only slightly decreased after the envenomation, but alpha 2-antiplasmin and alpha 2-macroglobulin were initially significantly lowered, returning to normal values in 38 and 3 days, respectively. Plasmin-alpha 2-antiplasmin complex was present until day 10 after the envenomation. However, purified plasminogen was not activated in vitro by the venom. Cultured endothelial and smooth muscle cells from human blood vessels released an increased amount of plasminogen activator upon incubation with the venom. The release did not result from cell lysis. Platelets in normal human platelet-rich plasma were aggregated by 10 micrograms/ml of the venom, without serotonin secretion. The aggregation kinetics and serotonin secretion induced by adenosine diphosphate (ADP) or arachidonate were not significantly affected by the venom at 1-10 micrograms/ml. It is concluded that the predominant mechanism of afibrinogenemia in the patient after Crotalus atrox bite resulted from primary fibrinogenolysis and not from a consumptive coagulopathy. The lytic state seemed to be induced through an indirect activation of plasminogen by vascular plasminogen activator, which was probably released from endothelial cells and smooth muscle cells by the snake venom.

The function of regulatory regions of DNA, which flank the genes for prostatic steroid binding protein, is being analysed by introducing the cloned genes into heterologous cells. Two non-allelic genes for the C3 polypeptide, C3(1) and C3(2) have been transfected into androgen-responsive S115 cells using SV2-gpt vectors. The genes have been introduced either intact or as so-called fusion genes consisting of putative C3 promoters plus human beta-interferon cDNA. Both genes for C3 were accurately transcribed and their expression was stimulated 5-10-fold with 10(-8) M testosterone. Thus we should be able to define at least one region of DNA which confers androgen sensitivity to the genes. Although both genes were expressed similarly in S115 cells only C3(1) is responsible for C3 in vivo and C3(2) is transcribed poorly, if at all. The most likely explanation for the difference is that in vivo the C3(2) gene remains hypermethylated whereas the DNA which was introduced into S115 cells was unmethylated. This result supports the notion that the state of DNA methylation is important for controlling the transcription of genes.

Prekallikrein (Prekk), antithrombin III (ATIII), plasminogen and alpha 2-antiplasmin were evaluated in chronic active hepatitis and in liver cirrhotic patients and correlated with Normotest. Prekk, ATII and plasminogen were significantly decreased in chronic active hepatitis as well as in liver cirrhosis. Alpha 2-antiplasmin levels in chronic active hepatitis patients did not differ from controls; liver cirrhotic patients, on the contrary, showed significantly low values of alpha 2-antiplasmin, Prekk, ATIII and plasminogen were significantly correlated with Normotest in both groups, but when cirrhotic patients were divided into the compensated and decompensated state only Prekk was correlated with Normotest in the decompensated state. The investigation seems to suggest that Prekk could be a reliable index for protein liver failure.

The study of genetic markers linked and associated with disease has provided important evidence of a genetic contribution to numerous diseases and has helped to establish their modes of inheritance. However, this information has not been fully utilized in counseling individuals at risk for these disorders. In the case of recessive, marker-linked diseases, such as idiopathic hemochromatosis linked to HLA in family studies and associated with specific HLA alleles in population surveys, the only current clinical application has been to identify siblings who share both HLA-marker haplotypes with the affected proband. They are considered to be presymptomatically affected, and more definitive invasive investigations are considered appropriate. All other relatives, including parents, offspring, and other siblings, who share only one marker with the proband, have been counseled only that their risk is equivalent to the gene frequency of the disease allele, for example, 3%-6% for hemochromatosis. We have developed a generally applicable method to utilize population association data to derive more specific and accurate risk figures for these other relatives of patients with marker-linked and associated diseases. We have applied this method to idiopathic hemochromatosis. If the offspring of a patient with hemochromatosis lacks A3, B7, and B14, the risk to that offspring for developing hemochromatosis is less than 2%. On the other hand, if they receive HLA A3 from their unaffected parent, their risk climbs to 9%-10%; if they receive an A3-B14 haplotype, their risk increases to virtually 100%. As demonstrated by our example, the application of association data to family members already at a basal increased risk for marker-linked disease can significantly refine the disease risk estimates given to those relatives. This information can be utilized to select individuals in whom invasive diagnostic testing or preventative intervention is indicated.

Antithrombin III is an important element of the endogenous thrombosis protection system. Congenital Anti-thrombin III deficiencies are associated with increased incidence of thrombo-embolisms. If Antithrombin III is determined at the time of operation, postoperative deficiencies resulting from an increased turnover rate can be identified. Determination of Antithrombin III is not suitable for prognosticating the occurrence of thrombo-embolic complications in isolated cases. Antithrombin III can be administered in the form of fresh frozen plasma (FFP), though it is also available as Antithrombin III concentrate. So far no investigations have been carried out to establish whether it is possible to improve thrombosis protection with or without heparin prophylaxis by concentrated Antithrombin III substitution.