Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0019158 (hepatitis)
30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nine infants suffering from congenital cytomegalovirus infection were studied for clinical features with special reference to hematological manifestations. The mean age of appearance of first clinical symptom of disease was 14 days and mean age at presentation was 58 days. Significant pallor, thrombocytopenia and evidence of hemolysis were present in 8 (89%), 4 (44%) and 4 (44%) patients respectively out of three bone marrow examination performed, paucity of erythroid and megakaryocytic cells were seen in two. The other clinical features included hepatomegaly in a (100%) splenomegaly in 6 (66%) each, petachial rash in 5 (55%), Hepatitis in 4 (44%) optic atrophy and corneal opacities in one patient each. Two patients died. Remaining patients showed symptomatic improvement without specific therapy.
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PMID:Hematological manifestations of congenital cytomegalovirus infection. 1082 8

Use of oncoretroviral vectors in gene therapy for hemoglobinopathies has been impeded by low titer vectors, genetic instability, and poor expression. Fifteen self- inactivating (SIN) lentiviral vectors using 4 erythroid promoters in combination with 4 erythroid enhancers with or without the woodchuck hepatitis virus postregulatory element (WPRE) were generated using the enhanced green fluorescent protein as a reporter gene. Vectors with high erythroid-specific expression in cell lines were tested in primary human CD34(+) cells and in vivo in the murine bone marrow (BM) transplantation model. Vectors containing the ankyrin-1 promoter showed high-level expression and stable proviral transmission. Two vectors containing the ankyrin-1 promoter and 2 erythroid enhancers (HS-40 plus GATA-1 or HS-40 plus 5-aminolevulinate synthase intron 8 [I8] enhancers) and WPRE expressed at levels higher than the HS2/beta-promoter vector in bulk unilineage erythroid cultures and individual erythroid blast-forming units derived from human BM CD34(+) cells. Sca1(+)/lineage(-) Ly5.1 mouse hematopoietic cells, transduced with these 2 ankyrin-1 promoter vectors, were injected into lethally irradiated Ly5.2 recipients. Eleven weeks after transplantation, high-level expression was seen from both vectors in blood (63%-89% of red blood cells) and erythroid cells in BM (70%-86% engraftment), compared with negligible expression in myeloid and lymphoid lineages in blood, BM, spleen, and thymus (0%-4%). The I8/HS-40-containing vector encoding a hybrid human beta/gamma-globin gene led to 43% to 113% human gamma-globin expression/copy of the mouse alpha-globin gene. Thus, modular use of erythroid-specific enhancers/promoters and WPRE in SIN-lentiviral vectors led to identification of high-titer, stably transmitted vectors with high-level erythroid-specific expression for gene therapy of red cell diseases.
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PMID:High-level erythroid-specific gene expression in primary human and murine hematopoietic cells with self-inactivating lentiviral vectors. 1167 36

Gene therapy of many genetic diseases requires permanent gene transfer into self-renewing stem cells and restriction of transgene expression to specific progenies. Human immunodeficiency virus (HIV)-derived lentiviral vectors are very effective in transducing rare, nondividing stem cell populations (e.g., hematopoietic stem cells) without altering their long-term repopulation and differentiation capacities. We developed a strategy for transcriptional targeting of lentiviral vectors based on replacing the viral long terminal repeat (LTR) enhancer with cell lineage-specific, genomic control elements. An upstream enhancer (HS2) of the erythroid-specific GATA-1 gene was used to replace most of the U3 region of the LTR, immediately upstream of the HIV type 1 (HIV-1) promoter. The modified LTR was used to drive the expression of a reporter gene (the green fluorescent protein [GFP] gene), while a second gene (a truncated form of the p75 nerve growth factor receptor [DeltaLNGFR]) was placed under the control of an internal constitutive promoter to monitor cell transduction, or to immunoselect transduced cells, independently from the expression of the targeted promoter. The transcriptionally targeted vectors were used to transduce cell lines, human CD34+ hematopoietic stem-progenitor cells, and murine bone marrow (BM)-repopulating stem cells. Gene expression was analyzed in the stem cell progeny in vitro and in vivo after xenotransplantation into nonobese diabetic-SCID mice or BM transplantation in coisogenic mice. The modified LTR directed high levels of transgene expression specifically in mature erythroblasts, in a TAT-independent fashion and with no alteration in titer, infectivity, and genomic stability of the lentiviral vector. Expression from the modified LTR was higher, better restricted, and showed less position-effect variegation than that obtained by the same combination of enhancer-promoter elements placed in a conventional, internal position. Cloning of the woodchuck hepatitis virus posttranscriptional regulatory element at a defined position in the targeted vector allowed selective accumulation of the genomic transcripts with respect to the internal RNA transcript, with no loss of cell-type restriction. A critical advantage of this targeting strategy is the use of a spliced, major viral transcript to express a therapeutic gene and that of an internal, independently regulated promoter to express an additional gene for either cell marking or in vivo selection purposes.
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PMID:Transcriptional targeting of lentiviral vectors by long terminal repeat enhancer replacement. 1190 39

Pure red cell aplasia (PRCA) is a well-known although infrequent hematologic complication after allogeneic bone marrow transplantation. PRCA occurs in cases of major ABO-mismatch between donor and recipient and is believed to be due to inhibition of donor erythroid progenitors by residual host isohemagglutinins. We report a 10-year-old boy with post-hepatitis aplastic anemia (AA) who developed PRCA after HLA-matched familial peripheral blood stem cell transplantation (SCT) following conditioning with Cph 200 mg/kg + ATG 90 mg/kg. Granulocyte engraftment occurred on day +18, platelet engrafted on day +40, while reticulocytopenia at 0% persisted until day +118, and erythroid precursors were totally absent from bone marrow. After a single dose of rituximab 200 mg/m(2)administered on day +118 PRCA resolved and on day +132 the reticulocytes rose to 5.7%. On day +139 the Hb reached 137 g/l and the erythroid lineage in BM increased to 21%. We conclude that due to the rapid recovery from PRCA and lack of side effects, rituximab should be tried as first-line treatment of PRCA after allo-SCT.
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PMID:Successful treatment of pure red cell aplasia with a single dose of rituximab in a child after major ABO incompatible peripheral blood allogeneic stem cell transplantation for acquired aplastic anemia. 1223 27

3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS) and persons seropositive for human immunodeficiency virus (HIV). The National Cancer Institute nominated AZT for toxicity and carcinogenicity studies because of the impending large-scale use of AZT in the treatment of adult patients with AIDS or AIDS-related complex. alpha-Interferon A/D, which displays antiviral activity in mice, is a hybrid molecule composed of the N-terminal portion of human alpha-interferon A and the C-terminal portion of human alpha-interferon D. AZT and alpha-interferon A/D combination studies were conducted because in vitro studies of AZT and alpha-interferon have demonstrated that the combination is more effective in blocking HIV infection than either agent alone. Male and female B6C3F1 mice received AZT (approximately 98% pure) in 0.5% aqueous methylcellulose by gavage for 14 weeks or 2 years. In addition, male and female B6C3F1 mice received alpha-interferon A or alpha-interferon A/D by subcutaneous injection for 2 years, and male and female B6C3F1 mice received AZT in 0.5%% aqueous methylcellulose by gavage in combination with alpha-interferon A/D by subcutaneous injection for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow erythrocytes, and mouse peripheral blood erythrocytes. 14-WEEK AZT STUDY: Groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 50, 100, 200, 800, or 2,000 mg/kg daily for 14 weeks. Additional groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 100, 800, or 2,000 mg/kg daily for 14 weeks and then were held without treatment for an additional 4 weeks before necropsy. One female receiving 100 mg/kg and two females receiving 200 mg/kg died during week 1 as a result of gavage trauma; one female receiving 2,000 mg/kg also died prior to the end of the 14-week dosing period. One female receiving 2,000 mg/kg in the recovery study also died from gavage trauma during week 1. The final mean body weights of dosed mice were similar to those of the vehicle control groups at the end of the dosing period and at the end of the recovery period. Female mice receiving 200, 800, or 2,000 mg/kg gained less weight than the vehicle controls during the 14-week dosing period. Exposure to AZT was toxic to the bone marrow, resulting in significant changes in the peripheral blood (decreased hematocrit values, erythrocyte counts, and hemoglobin concentrations, and increased mean cell volume and mean cell hemoglobin) and bone marrow (erythroid hypoplasia) characteristic of a dose- and time-dependent, minimal to moderate, poorly regenerative macrocytic anemia. At the end of the 4-week recovery period, the hematology parameters had returned to normal, indicating that the hematotoxicity was reversible. 2-YEAR STUDIES: AZT Groups of 95 male and 95 female mice received AZT in 0.5% methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, administered as two equal doses at least 6 hours apart, 5 days per week for 105 weeks. Each group of 95 animals was composed of a core group of 50 animals for evaluation of carcinogenic response, a group of 30 animals for evaluation of hematology and bone marrow cellularity, and a group of 15 animals from which blood was drawn for determination of plasma AZT concentrations at week 54. alpha-Interferon A/D and AZT/alpha-Interferon A/D Studies Groups of 80 male and 80 female mice received AZT in 0.5% aqueous methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, given in two equal doses, 5 days per week for 105 weeks. Those groups receiving AZT also received sub-cutaneous injections of 500 or 5,000 U alpha-interferon A/D three times per week for 105 weeks. Additional groups of 80 male and 80 female mice received subcutaneous injections of the vehicle, 500 U alpha-interferon A/D, 5,000 Uutaneous injections of the vehicle, 500 U α-interferon A/D, 5,000 U α-interferon A/D, or 5,000 U α-interferon A, three times per week for 105 weeks. Each group of 80 animals was composed of a core group of 50 animals for evaluation of carcinogenic response and a group of 30 animals for evaluation of hematology and bone marrow cellularity. Because of the large number of animals involved, the 2-year studies were started in four phases and, for clarity, are presented as follows: the AZT study, the α-interferon A/D study, the AZT/500 U α-interferon A/D study, and the AZT/5,000 U α-interferon A/D study. Design of the 2-year AZT, AZT/α-Interferon A/D, and α-Interferon A/D Studies AZT Dose AZT Study AZT/500 U α-Interferon A/D Study AZT/5,000 U α-Interferon A/D Study 500 or 5,000 U α-Interferon A/D or 5,000 U α-Interferon A Study Vehicle Control 95 male and 95 female micea 80 male and 80 female miceb 80 male and 80 female miceb 80 male and 80 female miceb 30 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 60 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 120 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none aFor the AZT study, there were 95 male and 95 female mice; these were divided into 50 males and 50 females in the core groups, 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only), and 15 males and 15 females for plasma AZT concentration determinations. bFor the α-interferon A/D study and the AZT/α-interferon A/D studies, there were 80 male and 80 female mice for each study; these were divided into 50 males and 50 females in the core groups and 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only). Survival and Body Weights Survival and mean body weights of mice exposed to AZT, α-interferon A, α-interferon A/D, or AZT plus α-interferon A/D were generally similar to those of the vehicle control groups. Hematology and Bone Marrow Analyses All groups of male and female mice receiving AZT exhibited changes in peripheral blood and bone marrow characteristic of a dose- and time-dependent, minimal to mild, macrocytic, nonresponsive anemia. In females, these changes were evident throughout the study. In males, the macrocytic anemia had resolved by week 80 in the 30 mg/kg group; at study termination erythrocyte macrocytosis was present only in males receiving 60 or 120 mg/kg AZT or AZT plus α-interferon A/D. There were no treatment-related alterations in hematology or bone marrow parameters in groups that received only α-interferon A or A/D. Pathology Findings Incidences of squamous cell carcinoma and squamous cell papilloma or carcinoma (combined) of the vagina occurred with a positive trend and were significantly increased in groups of female mice receiving 60 or 120 mg/kg AZT alone or in combination with α-interferon A/D. Epithelial hyperplasia was observed in all dosed groups of females, and the incidence was significantly increased in the 120 mg/kg AZT group. Three renal tubule adenomas and one renal tubule carcinoma were observed in male mice receiving 120 mg/kg AZT; the combined incidence in this group exceeded the range in historical controls. A renal tubule adenoma was observed in one male receiving 60 mg AZT/kg and 500 U α-interferon A/D; how ever, none were observed in other groups. Evaluation of step sections revealed a few more renal tubule hyperplasias but no additional neoplasms. The incidence of harderian gland adenoma was increased in male mice receiving 120 mg/kg AZT and exceeded the range in historical controls. Harderian gland neoplasms were observed in other groups but did not follow a treatment-related pattern. Overall Incidences of Vaginal Neoplasms and Hyperplasia of the Vaginal Epithelium in Female Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 2/197 (1%)b 1/197 0/49 (0%) 3/49 5/45 (11%%) 4/45 11/49 (22%%) 11/49 500 U α-Interferon A/D 0/49 (0%%) 0/49 0/44 (0%) 4/44 5/48 (10%) 8/48 6/48 (13%) 12/48 5,000 U α-Interferon A/D 1/50 (2%) 1/50 1/48 (2%) 4/48 5/48 (10%) 8/48 4/50 (8%) 15/50 aData are presented as number of vaginal neoplasms/number of animals microscopically examined (first line) and number of vaginal hyperplasias/number of animals microscopically examined (second line) bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidences in the vehicle control group from the AZT alone study are 0/50 (0%%) (neoplasms) and 0/50 (hyperplasia) Overall Incidence of Harderian Gland Neoplasms in Male Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 13/200 (6%%)b 5/50 (10%%) 2/50 (4%) 10/50 (20%%) 500 U α-Interferon A/D 3/50 (6%) 3/50 (6%) 1/50 (2%%) 4/50 (8%%) 5,000 U α-Interferon A/D 3/50 (6%) 9/50 (18%%) 4/50 (8%%) 4/50 (8%) aData are presented as number of harderian gland neoplasms/number of animals necropsied bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidence in the vehicle control group from the AZT alone study is 3/50 (6%) Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver consistent with an infection with Helicobacter hepaticus. An organism compatible with H. hepaticus was confirmed by polymerase chain reaction-restriction fragment length polymorphism-based assays. Detection of dose-related differences in neoplasm incidences in these studies was not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: AZT is mutagenic in vitro and in vivo. It induced gene mutations in Salmonella typhimurium strain TA102, with and without S9; no increases in mutations were noted in the other tested strains of S. typhimurium. AZT induced sister chromatid exchanges, but not chromosomal aberrations, in cultured Chinese hamster ovary cells, with and without S9. In vivo studies with male mice administered AZT by gavage showed highly significant increases in micronucleated erythrocytes in bone marrow and peripheral blood after exposure periods that ranged from 72 hours to 14 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of AZT in male mice based on increased incidences of renal tubule and harderian gland neoplasms in groups receiving AZT alone. There was clear evidence of carcinogenic activity of AZT in female mice based on increased incidences of squamous cell neoplasms of the vagina in groups that received AZT alone or in combination with α-interferon A/D. Hematotoxicity occurred in all groups that received AZT. Treatment with AZT alone and AZT in combination with α-interferon A/D resulted in increased incidences of epithelial hyperplasia of the vagina in all dosed groups of females. Synonyms: AZT; 3'-azido-2',3'-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3'-azidothymidine; 3'-deoxy-3'-azidothymidine; 3'-deoxy-(8CI) (9CI); BW A509U; Compound S; ZDV; zidovudine Trade name: Retrovir®
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PMID:NTP Toxicology and Carcinogenesis Studies of AZT (CAS No. 30516-87-1) and AZT/alpha-Interferon A/D B6C3F1 Mice (Gavage Studies). 1257 4

Limitin has sequence homology with alpha interferon (IFN-alpha) and IFN-beta and utilizes the IFN-alpha/beta receptor. However, it has no influence on the proliferation of normal myeloid and erythroid progenitors. In this study, we show that limitin has antiviral activity in vitro as well as in vivo. Limitin inhibited not only cytopathic effects in encephalomyocarditis virus- or herpes simplex virus (HSV) type 1-infected L929 cells, but also plaque formation in mouse hepatitis virus (MHV) type 2-infected DBT cells. In addition, administration of limitin to mice suppressed MHV-induced hepatitis and HSV-induced death. The antiviral activity may be mediated in part by 2',5'-oligoadenylate synthetase, RNA-dependent protein kinase, and Mx protein, which inhibit viral replication or degrade viral components, because limitin induced their mRNA expression and enzyme activity. While limitin has antiviral activity as strong as that of IFN-alpha in vitro (the concentration that provided 50% inhibition of cytopathic effect is approximately 30 pg/ml), IFN regulatory factor 1 (IRF-1) dependencies for induction of an antiviral state were different for limitin and IFN-alpha. In IRF-1-deficient fibroblasts, a higher concentration of limitin than of IFN-alpha was required for the induction of antiviral activity and the transcription of proteins from IFN-stimulated response element. The unique signals and the fewer properties of myelosuppression suggest that a human homolog of limitin may be used as a new antiviral drug.
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PMID:Antiviral activity of limitin against encephalomyocarditis virus, herpes simplex virus, and mouse hepatitis virus: diverse requirements by limitin and alpha interferon for interferon regulatory factor 1. 1291 74

Sideroblastic anemia is an anemic condition characterized by chronic hypochromic anemia and the presence of large iron deposits in erythroid cells. Seven dogs with sideroblastic anemia were evaluated retrospectively. Historical, clinical, and clinicopathologic findings were reviewed to determine whether the condition was idiopathic or associated with disease conditions or drug or toxin exposure. Associated diseases were identified in 6 affected dogs and included acute hepatitis, pancreatitis, acute hepatitis and pancreatitis, inflammatory disease, glomerulonephritis, and myelofibrosis. None of the dogs had a history of recent exposure to drugs or toxins. One dog had no evidence of associated disease. Regardless of the associated disease condition, sideroblastic anemia was characterized by moderate to severe nonregenerative and frequently hypochromic anemia with prominent dysplastic features in bone marrow that were most prominent in the erythroid series. Survival varied from days to years. Identification of large numbers of siderocytes or sideroblasts in blood or bone marrow is inconsistent with a diagnosis of iron deficiency and should prompt a search for inflammatory disease conditions, including hepatitis, pancreatitis, and glomerulonephritis.
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PMID:Sideroblastic anemia in 7 dogs (1996-2002). 1595 46

We report a 6-year-old Iranian boy with silvery-gray hair, eyelashes and the eyebrows who was admitted because of seizures and subsequent stupor. He had previous history of acute hemiparesis at 1 year of age and hepatitis-like syndrome 3 months ago. Microscopic examination of the patient's hair shaft revealed different sized clumps of melanin seen in the center of the shafts. Bone marrow aspiration revealed erythroid hyperplasia and erythrophagocytic cells. Bilateral frontal cortical and subcortical high signal lesions, dirty white matter, high signal areas in the upper pons and in both caudates and lentiform nuclei in T2 WI were the brain MRI findings of the patient. He died in the accelerated phase of Griscelli Syndrome (GS) type 2. To our knowledge we report the first case of GS from Iran.
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PMID:Bilateral basal ganglia involvement in a patient with Griscelli syndrome. 1695 71

Viral infections are a common complication of pregnancy and in some cases, can have profound effects for the unborn fetus. The human herpesvirus family is composed of large, enveloped DNA viruses that have close structural similarity. The family includes the herpes simplex viruses types 1 and 2, varicella zoster virus, Epstein Barr virus, cytomegalovirus (CMV), and human herpes viruses types 6, 7 and 8. These viruses all share the ability to establish latency and reactivate at a later time. Structural fetal abnormalities can result from intrauterine infection and transmission of the infection during the pregnancy or at the time of delivery can result in important neonatal disease. Human parvovirus B19 is a DNA virus with strong tropism for erythroid precursors and infection during pregnancy can result in fetal hydrops and stillbirth. The causative agents of hepatitis are hepatotropic viruses termed hepatitis A, B, C, D (deltavirus) and E. All except hepatitis B virus are RNA viruses. Vertical transmission of maternal infection with hepatitis B and C can result in significant long term sequelae.
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PMID:Viral infections in pregnancy. 1750 58

A 57-year-old man consulted a local hospital because of a persistent slight fever. At the age of 37 years he was diagnosed having B-type hepatitis, but left the liver dysfunction untreated. Twenty years later, he was diagnosed having chronic hepatitis B, hepatocellular carcinoma (HCC) and macrocytic anemia, and referred to our hospital for further investigation. A HCC with a maximum diameter of 5.2 cm was detected in segment 8. Results of blood tests included 1.8 mg/dL serum total bilirubin, 0.9 mg/dL bilirubin, less than 10 mg/dL haptoglobin, 7.9 g/dL hemoglobin, 130 fL MCV, and 14.5% reticulocytes. A bone marrow sample showed erythroid hyperplasia. The direct Coombs test gave a positive result. We diagnosed the anemia as autoimmmune hemolytic anemia (AIHA), for which prednisolone could not be administered due to positivity for HBsAg and HBeAg. After preparation of washed blood cells for later transfusion, the patient underwent systematic resection of segment 8. The cut surface of the resected specimen demonstrated an encapsulated yellow-brownish tumor measuring 52 mm multiply 40 mm which was diagnosed pathologicaly as moderately differentiated HCC. On the 9th postoperative day, the patient's temperature rose to 38 centigrade, and exacerbated hemolysis was observed. The maximum total bilirubin value was 5.8 mg/dL and minimum hemoglobin level was 4.6 g/dL. He tolerated this period without blood transfusion. Currently he is being followed up as an outpatient, and shows no signs of HCC recurrence or symptoms of anemia. AIHA associated with HBV infection has been described in only three previous cases, and the present case is the first in which surgery was performed for accompanying HCC.
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PMID:Hepatocellular carcinoma with chronic B-type hepatitis complicated by autoimmune hemolytic anemia: a case report. 1770 20


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