Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used the enhancer-binding protein C/EBP as a model to study the nature and the complexity of interaction of an enhancer-binding protein with its target DNA. We found that bacterially expressed C/EBP binds the hepatitis B virus enhancer at multiple sites in a hierarchic and cooperative manner. At low concentrations, only the E element is occupied, but at higher concentrations, additional sites are filled including a site that binds EP, a crucial enhancer-activating protein. This pattern of C/EBP binding may explain the concentration-dependent effect of C/EBP on enhancer activity.
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PMID:Hierarchic and cooperative binding of the rat liver nuclear protein C/EBP at the hepatitis B virus enhancer. 237 Aug 72

In the last few years, plasma fractionation has been subjected to major technological changes which have contributed to improve the viral safety and overall purity of plasma derivatives. New viral inactivation treatments, primarily solvent-detergent and pasteurization, have been introduced in the manufacturing processes of plasma derivatives to ensure the inactivation of major plasma-borne viruses, including HIV and hepatitis B and C viruses. Concurrently, new highly purified products obtained by chromatographic methods (mainly ion exchange and/or immunopurification) have been developed in the last five years and have replaced former preparations, providing a significantly higher safety level in terms of purity and viral risks. For an example, the new generation of Factor VIII and Factor IX concentrates (to treat hemophilia A and hemophilia B, respectively), which have been introduced in the last five years, are purified over 10,000- to 20,000-fold from plasma, as compared to only 50- to 100-fold for the former products. Similarly, new, standardized, clotting factor or protease inhibitor concentrates have been made available, thus permitting to carry out selective hemotherapy of specific diseases. Examples include the development of von Willebrand factor, factor XI, protein C, or alpha 1-antitrypsin concentrates for the substitutive therapy of congenital or acquired deficiencies. In addition, the concept of good manufacturing practices has been implemented, whereas carefully controlled, validated processes are contributing to the consistency in the quality of those products. Current major problems in plasma fractionation relate to the potential occurrence of new pathogenic agents that could resist present viral inactivation treatments and to the potential effect of given purification technologies on the development of immunogenic properties of proteins. Current trends indicate that significant progress in viral safety of plasma derivatives (for example through the introduction of new concept such as viral filtration) are to be expected very soon. Further research in this very important field is mandatory as plasma should remain the starting material of important therapeutic products in the coming years.
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PMID:[Plasma fractionation. Progress, problems and perspectives]. 799 59

Using the polymerase chain reaction (PCR), we designed a study concept to evaluate the safety of plasma derivatives in previously treated patients who are non-infected by the specific viruses studied. Several product lots can be studied in a single patient, with a study period for each lot of 3 months. In the present study 19 patients were included for treatment with Baxter Hyland Immuno's PCR-screened factor VIII concentrate Immunate (n=7), factor IX concentrate Immunine (n=10), the by-passing agent FEIBA plus Immunine (n=1), and the protein C concentrate Ceprotin (n=1). PCR testing for hepatitis B, C or HIV genomic material in patient samples was done as well as serological testing. All patients remained negative for the tested markers. All seven Immunate patients completed three treatment periods with three different lots of the study drug. The median study period was 282 days and the median dose 115 000 units, with a median of 115 exposure days. Five of the 10 Immunine patients completed three treatment periods and four patients, two treatment periods. One Immunine patient was discontinued from the study for reasons unrelated to the study drug administration. The median study period was 305 days and the median total dose 82 200 units, with a median of 88 exposure days. Our study presents a new design to approach the evaluation of viral safety of new plasma derivatives in previously treated, non-infected patients (NIPs) and offers several advantages over the currently recommended studies using testing for serological markers of infection in previously untreated patients (PUPs).
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PMID:An approach to study the viral safety of plasma-derived products in previously treated, non-infected patients. 1144 39

The dioxin receptor (DR) is a ligand-activated transcription factor that is activated upon binding of dioxins or structurally related forms of xenobiotics. Upon binding ligand the DR translocates from the cytoplasm to the nucleus where it complexes with the partner protein Arnt to form a DNA binding heterodimer, which activates transcription of target genes involved in xenobiotic metabolism. Latency of the DR signaling pathway is maintained by association of the DR with a number of molecular chaperones including the 90-kDa heat shock protein (hsp90), the hepatitis B virus X-associated protein (XAP2), and the 23-kDa heat shock protein (p23). Here we investigated the role of XAP2 in DR signaling and demonstrated that reduced levels of XAP2 labilize the DR, arguing for a function of XAP2 beyond its reported role as a cytoplasmic retention factor. In addition, we showed that a constitutively nuclear DR is degraded in the nucleus and does not require nuclear export for efficient degradation. We also provided evidence implicating the ubiquitin ligase protein C-terminal hsp70-interacting protein (CHIP) in the degradation of the DR, and we demonstrated that this degradation can be overcome by overexpression of XAP2. XAP2 protection of CHIP-mediated degradation is dependent on the tetratricopeptide repeat domain of XAP2 and suggests a mechanism whereby competition for the C-terminal tetratricopeptide repeat acceptor site of hsp90 guides the protein triage decision, the point of determination for either maturation of DR folding or DR degradation.
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PMID:Defining the role for XAP2 in stabilization of the dioxin receptor. 1283 59

A 54-year-old man of Persian origin presented to our department with a 1-year history of ulcers on the right leg that had been unresponsive to numerous topical treatments, accompanied by lymphedema of the right leg. Medical history included hypergonadotropic hypogonadism, which had not been further investigated. He was treated for 20 years with testosterone IM once monthly, which he stopped a year before the current hospitalization for unclear reasons. The patient reported no congenital lymphedema. Physical examination revealed two deep skin ulcers (Figure 1) on the right leg measuring 10 cm in diameter with raised irregular inflammatory borders and a boggy, necrotic base discharging a purulent hemorrhagic exudate. Bilateral leg pitting edema and right lymphangitis with lymphadenitis were noted. He had low head hair implantment, sparse hair on the body and head, hyperpigmentation on both legs, onychodystrophia of the toenails (mainly the large toe and less prominent on the other toes), which was atrophic lichen-planus-like in appearance and needed no trimming (Figure 2), normal hand nails, oral thrush, and angular cheilitis. Other physical findings were gynecomastia, pectus excavatum, small and firm testicles, long extremities, asymmetrical goiter, systolic murmur 2/6 in left sternal border, and slow and inappropriate behavior. The patient's temperature on admission was 39 degrees C. Blood cultures were negative for bacterial growth. Results of laboratory investigations included hemoglobin (11.2 g/dL), hematocrit (26.8%), normal mean corpuscular volume and mean corpuscular hemoglobin volume, and red blood cell distribution width (16%). Blood smear showed spherocytes, slight hypochromia, anisocytosis, macrocytosis, and microcytosis. Blood chemistry values were taken for iron (4 micro g/dL [normal range 40-150 micro g/dL]), transferrin (193 mg/dL [normal range 220-400 mg/dL]), ferritin (1128 ng/mL [normal range 14-160 ng/mL]), transferrin saturation (1.5% [normal range 20%-55%]), serum folate (within normal limits), and vitamin B12 (within normal limits). Direct Coombs' test equaled positive 2 + IgG. All these values indicated anemia of chronic diseases combined with hemolytic anemia. Further blood work-up tested antinuclear antibody (positive <1:80 homogeneous pattern), rheumatoid factors (143 IU/mL [positive >8.5 IU/mL]), C-reactive protein (286 mg/L [normal range 0-5 mg/L]), anticardiolipin IgM antibody (9.0 monophosphoryl lipid U/mL [normal range 0-7.00 MPL U/mL]) and antithrombin III activity (135% [normal range 74%-114%]). Results of other blood tests were within normal limits or negative, including lupus anticoagulant, beta2 glycoprotein, anticardiolipin IgG Ab, anti-ss DNA Ab, C3, C4, anti-RO, anti-LA, anti-SC-70, anti-SM Ab, P-ANCA, C-ANCA, TSH, FT4, anti-T microsomal, antithyroglobulin, protein C activity, protein S free, cryoglobulins, serum immunoelectrophoresis, VDRL, hepatitis C antibodies, hepatitis B antigen, and human immunodeficiency virus. Endocrinological work-up examined luteinizing hormone (22.9 mIU/mL [normal range for adult men 0.8-6 mIU/mL]), follicle stimulating hormone (49.7 mIU/mL [normal range for adult men 1-11 mIU/mL]), testosterone (0.24 ng/mL [normal range for adult men 2.5-8.0 ng/mL]), bioavailable testosterone (0.02 ng/mL [normal range for adult men >0.6 ng/mL]), and percent bioavailable test (8.1% [normal value >20%]). These results indicate hypergonadotropic hypogonadism. Plasminogen activator inhibitor 1 was 6 U (normal value 5-20 U/mL). Karyotyping performed by G-banding technique revealed a 47 XXY karyotype, which is diagnostic of Klinefelter's syndrome. Doppler ultrasound of the leg ulcers disclosed partial thrombus in the distal right femoral vein. X-rays and bone scan displayed osteomyelitis along the right tibia. Histological examination of a 4-mm punch biopsy from the ulcer border revealed hyperkeratosis, acanthosis, hypergranulosis, and mixed inflammatory infiltrate containing eosinophils compatible with chronic ulcer. Multiple vessels were seen, compatible with a healing process. Direct immunofluorescence of the biopsy revealed granular IgM in the dermo-epidermal junction. Indirect immunofluorescence was negative. Thyroid function tests showed normal thyroid stimulating hormone and free throxine4. Multinodular goiter was seen on thyroid scan and ultrasound. Thyroid fine needle aspiration was compatible with multinodular goiter (normal follicular cells, free colloid, macrophages with pigment). IV treatment with amoxicillin-clavulanic acid 1 g t.i.d. was administered for 2 weeks, with a decrease in temperature and normalization of the leukocyte level. Oral antibiotic treatment with amoxicillin-clavulanic acid was continued for 10 more days, followed by 25 days of ciprofloxacin for the osteomyelitis. Local treatment included saline soakings followed by application of Promogran (Johnson & Johnson, New Brunswick, NJ) and Kaltostat (ConvaTec Ltd., a Bristol-Myers Squibb Company, New York, NY) with slight improvement. At the same time, the patient was treated with warfarin sodium due to deep vein thrombosis under international normalized ratio 2-3. The patient was treated with IM testosterone once monthly for 1 year, which resulted in a reduction in the diameter and depth of the leg ulcers (Figure 3). Blood tests were not performed for follow-up of the immune state.
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PMID:Klinefelter's syndrome presenting with leg ulcers. 1536 65

The liver plays a central role in haemostasis, being the site of synthesis of most of the clotting factors, coagulation inhibitors and fibrinolytic parameters, in addition to its clearance of activated clotting and fibrinolytic factors. Nonetheless, no haemostatic test(s) is included among the routine liver function tests and this study aims to probe this possibility. The liver disease group (n=258) included acute hepatitis (n=25), chronic viral hepatitis (n=128), hepatitis B (HB) carriers (n=25), liver cirrhosis (n=67), and hepatocellular carcinoma (HCC) (n=13). The prothrombin time was significantly prolonged in acute hepatitis, liver cirrhosis and HCC. However, the reptilase time was prolonged in all the groups except in HB carriers, while the thrombin time was prolonged only in the HCC group. Antithrombin III and protein C levels exhibited significant reduction in acute hepatitis, liver cirrhosis and HCC. On the other hand, protein S levels (total and free) were reduced significantly in all the patients groups, including HB carriers when compared with healthy controls. Derangement of haemostatic tests is a common feature in liver disease, being most significant in acute hepatitis, liver cirrhosis and hepatocellular carcinoma. The most sensitive markers of hepatocyte malfunction are protein S (total and free) and the reptilase time as they were abnormal, in the mildest liver affections, when other biochemical tests as well as other haemostatic tests were normal. Further studies are needed to see whether these two tests qualify for inclusion among the routine liver function tests.
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PMID:Haemostatic abnormalities in liver disease: could some haemostatic tests be useful as liver function tests? 1597 Jul 16

Cytoplasmic hepatitis B virus (HBV) capsids are not enveloped and secreted unless the packaged RNA pregenome is reverse transcribed. The expression of the capsid protein C, together with envelope proteins in the absence of pregenomic RNA, produced normal amounts of intracellular capsids, but the secretion of virion-like particles was greatly reduced. The I97L C protein mutant, allowing immature nucleocapsid envelopment in the background of an HBV genome, did not promote the envelopment of capsids lacking a pregenome, suggesting that this mutation is not sufficient to induce secretion competence independently of the pregenome.
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PMID:Hepatitis B virus particle formation in the absence of pregenomic RNA and reverse transcriptase. 1657 36

Protein products fractionated from human plasma are an essential class of therapeutics used, often as the only available option, in the prevention, management, and treatment of life-threatening conditions resulting from trauma, congenital deficiencies, immunologic disorders, or infections. Modern plasma product production technology remains largely based on the ethanol fractionation process, but much has evolved in the last few years to improve product purity, to enhance the recovery of immunoglobulin G, and to isolate new plasma proteins, such as alpha1-protease inhibitor, von Willebrand factor, and protein C. Because of the human origin of the starting material and the pooling of 10,000 to 50,000 donations required for industrial processing, the major risk associated to plasma products is the transmission of blood-borne infectious agents. A complete set of measures--and, most particularly, the use of dedicated viral inactivation and removal treatments--has been implemented throughout the production chain of fractionated plasma products over the last 20 years to ensure optimal safety, in particular, and not exclusively, against HIV, hepatitis B virus, and hepatitis C virus. In this review, we summarize the practices of the modern plasma fractionation industry from the collection of the raw plasma material to the industrial manufacture of fractionated products. We describe the quality requirements of plasma for fractionation and the various treatments applied for the inactivation and removal of blood-borne infectious agents and provide examples of methods used for the purification of the various classes of plasma protein therapies. We also highlight aspects of the good manufacturing practices and the regulatory environment that govern the whole chain of production. In a regulated and professional environment, fractionated plasma products manufactured by modern processes are certainly among the lowest-risk therapeutic biological products in use today.
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PMID:Modern plasma fractionation. 1739 61

Protein S (PS), protein C (PC), and antithrombin (AT) are produced by the liver, and their levels were previously shown to be reduced in chronic as well as acute liver disease. The aim of this study was to determine whether measurement of PS, PC, and AT levels in patients would be as good as the commonly used clinical and histological parameters of liver disease in discriminating early and advanced hepatocyte dysfunction. A total of 154 patients were recruited and categorized into five groups: hepatitis B inactive carriers in group 1 (n = 29), nonalcoholic steatohepatitis patients in group 2 (n = 30), chronic hepatitis B patients with elevated liver enzymes in group 3 (n = 29), chronic hepatitis C patients with elevated liver enzymes in group 4 (n = 30), liver cirrhosis patients in group 5 (n = 36). There were significant differences between groups in the levels of PC (P = 0.0001), total PS (P = 0.0001), and free PS (P = 0.0001) and AT (P = 0.0001). These parameters were least affected in the control group, then groups 1 and 2, followed by groups 3 and 4, and most affected in group 5. No differences in these tests were detected between groups 1 and 2 and between groups 3 and 4. Univariate and multivariate analyses showed that free PS was the only predictor of significant inflammation (P = 0.0001), and AT (P = 0.001) and PC (P = 0.003) were the most important factors associated with advanced fibrosis. Both PS and PC are sensitive markers of liver disease, but PS is a sensitive marker of liver inflammation, whereas PC may be a more sensitive marker for liver fibrosis.
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PMID:Natural anticoagulants can be useful predictors of severity in chronic liver disease. 2001 98

Vitamin K is frequently administered in cirrhotic patients to correct their coagulopathy, but evidence for such practice is lacking. We aimed to assess whether vitamin K administration increases the levels of the vitamin K-dependent factor VII (FVII), protein C, and protein S in patients with different stages of liver dysfunction. Eighty-nine patients were recruited into four groups: group 1 [hepatitis B virus (HBV) inactive carriers, n = 23]; group 2 [chronic HBV and hepatitis C virus (HCV) hepatitis, n = 21]; group 3 (cirrhosis, n = 24); group 4 (hepatocellular carcinoma, n = 21); and a healthy control group (n = 39). A single dose of 10 mg of vitamin K1 was administered subcutaneously to all patients. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, FVII, protein C, total and free protein S, and proteins induced by vitamin K absence (PIVKA)-II (des-gamma-carboxy prothrombin) were measured at baseline and 72 h after vitamin K administration. There was progressive increment in baseline PIVKA-II, and decrements in fibrinogen, FVII, protein C, and protein S across study groups (P < 0.0001). Compared to baseline, vitamin K administration did not affect the measured parameters, whereas TT showed no reduction in any of the groups. Protein C levels declined in group 2, whereas FVII, total and free protein S did not increase in any group, for all parameters. Vitamin K therapy does not cause significant improvements in the majority of coagulation parameters and hence does not seem to be routinely indicated in patients with liver disease.
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PMID:The coagulopathy of liver disease: does vitamin K help? 2308 Mar 65


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