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At least 685 records · Page 38Linked to original sources
PubMed2001

Exploring the unique pharmacology of a novel opioid receptor, ZFOR1, using molecular modeling and the 'message-address' concept.

Previous studies have probed the structural basis of ligand selectivity in the mu, delta and kappa opioid receptors through the application of molecular modeling techniques in concert with the 'message-address' concept. Here, this approach was used in an attempt to rationalize the unique pharmacological profile of a recently cloned novel opioid receptor, ZFOR1 (ZebraFish Opioid Receptor 1). Specifically, a model of the transmembrane domains of ZFOR1 was constructed and used to explore the binding modes of various prototypical opioid ligands. The results show that the 'message' portion of the binding pocket of ZFOR1 is highly conserved; hence, the binding modes of non-selective opioid ligands are well preserved. In contrast, a small number of variant residues at the extracellular end of the binding pocket, particularly Lys288 (VI:26) and Trp304 (VII:03), are shown to create adverse steric interactions with all delta and kappa selective ligands examined, thereby disrupting their binding modes. These results are consistent with, and serve as an explanation for, the observed pharmacology of this receptor, lending support to both the validity of the 'message-address' concept itself and to the use of molecular modeling approaches in its application.

Animals↗
PubMed1994

Isolation of a novel cDNA encoding a putative membrane receptor with high homology to the cloned mu, delta, and kappa opioid receptors.

A rat brain cDNA library was screened for clones homologous to the recently cloned mouse delta-opioid receptor (DOR-1). Among the clones isolated was Hyp 8-1, a clone with a unique nucleotide sequence capable of encoding a putative protein which is 57-58% identical to the amino acid sequences of the cloned delta, mu and kappa opioid receptors, indicating a close relationship of Hyp 8-1 with the opioid receptor family. Several cDNAs representing possible splice variants of Hyp 8-1 were also isolated. Binding studies of COS-7 cells transfected with clone Hyp 8-1 failed to demonstrate specific binding with several 3H-opioid ligands. In situ hybridization studies indicate that the mRNA for Hyp 8-1 is distributed discretely throughout the rat brain, in an overall pattern which is different from that of several other G-protein-coupled seven transmembrane receptors. Thus, it is likely that the Hyp 8-1 cDNA encodes a novel peptide receptor.

Amino Acid Sequence↗
PubMed2026

Differential impacts of exon 1-associated and exon 11-associated variants of the rat mu opioid receptor gene, Oprm1, on buprenorphine- and morphine-induced analgesia and respiratory depression in male rats.

Buprenorphine has long been recognized as a mu opioid agonist with a distinctive and intricate pharmacological profile. It is a partial agonist at the mu opioid receptor, an antagonist at the kappa and delta opioid receptors, and an agonist at the nociception opioid receptor. Similar to other mu agonists such as morphine and fentanyl, buprenorphine can produce side effects, including tolerance, physical dependence, respiratory depression, and addiction. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating an array of splice variants or isoforms, which are conserved from rodents to humans. These splice variants can be categorized into 2 main types, exon 1 (E1)-associated variants and exon 11 (E11)-associated variants. E1-associated variants primarily consist of full-length, 7-transmembrane C-terminal variants, whereas E11-associated variants are typically truncated 6-transmembrane variants. Previous studies established that buprenorphine analgesia in mice is dependent on both E1- and E11-associated variants. However, the role of these variants in buprenorphine analgesia and respiratory depression in rats remains unclear. In this study, we used CRISPR/Cas9 technology to develop 2 rat Oprm1 gene-targeting models in which E1- and E11-associated variants were selectively disrupted, aiming to investigate their roles in buprenorphine and morphine's actions. The results showed that both E1- and E11-associated variants are essential for buprenorphine's analgesic and respiratory depressional effects in rats, whereas morphine's effects are solely attributed to the E1-associated variants. These findings provide new and important insights into the distinct contributions of the E1- and E11-associated variants to the pharmacological actions of buprenorphine and morphine. SIGNIFICANCE STATEMENT: Differential dependences of buprenorphine and morphine analgesia and respiratory depression on Oprm1 exon 1- and exon 11-associated variants revealed in rat gene-targeting models provide new and important insights into unique contributions of these variants to buprenorphine and morphine actions.

Animals↗
PubMed2006

Molecular interactions between dipeptides, drugs and the human intestinal H+ -oligopeptide cotransporter hPEPT1.

The human intestinal proton-coupled oligopeptide transporter hPEPT1 has been implicated in the absorption of pharmacologically active compounds. We have investigated the interactions between a comprehensive selection of drugs, and wild-type and variant hPEPT1s expressed in Xenopus oocytes, using radiotracer uptake and electrophysiological methods. The beta-lactam antibiotics ampicillin, amoxicillin, cephalexin and cefadroxil, the antineoplastics delta-aminolevulinic acid (delta-ALA) and bestatin, and the neuropeptide N-acetyl-Asp-Glu (NAAG), were transported, as judged by their ability to evoke inward currents. When the drugs were added in the presence of the typical substrate glycylsarcosine (Gly-Sar), the inward currents were equal or less than that induced by Gly-Sar alone. This suggests that the drugs are transported at a lower turnover rate than Gly-Sar, but may also point towards complex interactions between dipeptides, drugs and the transporter. Gly-Sar and the drugs also modified the kinetics of hPEPT1 presteady-state charge movement, by causing a reduction in maximum charge (Qmax) and a shift of the midpoint voltage (V0.5) to more negative potentials. Our results indicate that the substrate selectivity of hPEPT1 is: Gly-Sar > NAAG, delta-ALA, bestatin > cefadroxil, cephalexin > ampicillin, amoxicillin. Based on steady-state and presteady-state analysis of Gly-Sar and cefadroxil transport, we proposed an extension of the 6-state kinetic model for hPEPT1 function that globally accounts for the observed presteady-state and steady-state kinetics of neutral dipeptide and drug transport. Our model suggests that, under saturating conditions, the rate-limiting step of the hPEPT1 transport cycle is the reorientation of the empty carrier within the membrane. Variations in rates of drug cotransport are predicted to be due to differences in affinity and turnover rate. Oral availability of drugs may be reduced in the presence of physiological concentrations of dietary dipeptides in the gut, suggesting that oral delivery drugs should be taken on an empty stomach. The common hPEPT1 single-nucleotide polymorphisms Ser117Asn and Gly419Ala retained the essential kinetic and drug recognition characteristics of the wild type, suggesting that neither variant is likely to have a major impact on oral absorption of drugs.

Animals↗
PubMed1986

HBsAg, HBcAg and delta-Ag in liver tissue: simultaneous visualization in a single tissue section by triple immunostaining.

The distribution pattern of HBsAg, HBcAg and Delta-Ag was investigated by immunohistochemistry in a series of paraffin embedded liver tissue specimens from 45 subjects with serum HBsAg and anti-Delta antibody positivity. An indirect immunoperoxidase technique was used. Stains for HBsAg, HBcAg and Delta-Ag were alternatively carried out on serial tissue sections and, for the first time, consecutively in a single section (triple immunostaining). Simultaneous presence of all antigens occurred in 7 out of 45 cases, and of two antigens (HBsAg and Delta-Ag) in the remaining 38. Two antigens (either HBsAg and HBcAg or HBcAg and Delta-Ag) could also be shown in the same cell. A series of new observations was forwarded by the successful application of triple immunostaining in the present series: 1) high frequence of simultaneous presence of HBcAg and Delta-Ag (7 out of 45 cases = 16%); 2) cytoplasmic localization of Delta-Ag; 3) localization of HBcAg on the cell membrane of HBsAg positive Ground-Glass (G-G) hepatocytes; 4) Ground-Glass appearance of hepatocytic cytoplasm associated with exclusive content of HBcAg (HBcAg-Ground-Glass: a new variant of G-G-hepatocytes).

Antigens, Viral↗
PubMed1990

Characterization of thymus-derived lymphocytes expressing Ti alpha-beta CD3 gamma delta epsilon zeta-zeta, Ti alpha-beta CD3 gamma delta epsilon eta-eta or Ti alpha-beta CD3 gamma delta epsilon zeta-zeta/zeta-eta antigen receptor isoforms: analysis by gene transfection.

To characterize the function of the CD3 eta subunit of the T cell receptor (TCR), we have used cDNAs encoding CD3 zeta, CD3 eta, or both to reconstitute a variant of a cytochrome c-specific, I-Ek-restricted murine T cell hybridoma, termed MA5.8, which lacks CD3 zeta and CD3 eta proteins. We provide direct evidence that assembly and surface expression of TCRs can be mediated by either of these subunits separately or together. However, the level of TCR expression on zeta transfectants is up to one order of magnitude greater than that on eta transfectants, implying that CD3 eta is weakly associated with the pentameric Ti alpha-beta CD3 gamma delta epsilon complex and/or inefficient at salvaging the incomplete TCR from lysosomal degradation. As a component of the TCR, the CD3 eta subunit preferentially forms a heterodimer with CD3 zeta, but is also able to form a CD3 eta-eta homodimer. Crosslinking of Ti alpha-beta CD3 gamma delta epsilon zeta-zeta, Ti alpha-beta CD3 gamma delta epsilon eta-eta, or Ti alpha-beta CD3 gamma delta epsilon zeta-zeta/zeta-eta TCR isotypes with anti-CD3 epsilon monoclonal antibody or a cytochrome c peptide epitope on I-Ek antigen-presenting cells mediates signal transduction resulting in reversible cell-cycle arrest of transfected clones. Given the potential for diversity of signals generated by these functional TCR isotypes and the expression of the CD3 eta gene product in the thymus, CD3 eta is likely to play a role in selection and/or activation of thymocytes during development.

Animals↗
PubMed2002

Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis.

Over 90 different mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) cause approximately 2% of amyotrophic lateral sclerosis (ALS) cases by an unknown mechanism. We engineered 14 different human ALS-related SOD1 mutants and obtained high yields of biologically metallated proteins from an Sf21 insect cell expression system. Both the wild type and mutant "as isolated" SOD1 variants were deficient in copper and were heterogeneous by native gel electrophoresis. By contrast, although three mutant SOD1s with substitutions near the metal binding sites (H46R, G85R, and D124V) were severely deficient in both copper and zinc ions, zinc deficiency was not a consistent feature shared by the as isolated mutants. Eight mutants (A4V, L38V, G41S, G72S, D76Y, D90A, G93A, and E133 Delta) exhibited normal SOD activity over pH 5.5-10.5, per equivalent of copper, consistent with the presumption that bound copper was in the proper metal-binding site and was fully active. The H48Q variant contained a high copper content yet was 100-fold less active than the wild type enzyme and exhibited a blue shift in the visible absorbance peak of bound Cu(II), indicating rearrangement of the Cu(II) coordination geometry. Further characterization of these as-isolated SOD1 proteins may provide new insights regarding mutant SOD1 enzyme toxicity in ALS.

Amino Acid Substitution↗
PubMed1984

Heterocellular hereditary persistence of fetal hemoglobin (HPFH). Molecular mechanisms of abnormal gamma-gene expression in association with beta thalassemia and linkage relationship with the beta-globin gene cluster.

We report a study of four families of Italian origin in which heterocellular HPFH is inherited linked to beta thalassemia over two or three generations. The HPFH + beta thalassemia carriers showed thalassemic blood pictures and elevated HbF and F-cell number without increase in the HbF/F-cell content. Association of this gene complex with a second beta thalassemia trait gives rise to a mild clinical picture characterized by 9-12 g/dl of mainly HbF in peripheral blood and no transfusion requirement. In two families, independent segregation of the HPFH or beta-thal trait was observed, and in one case the study of the DNA polymorphisms within the gamma delta beta gene cluster indicated that the HPFH mutation lies outside that DNA region. In one family the coexistence of a polymorphic variant of the A gamma chain (the A gamma T chain) allowed us to demonstrate that the increased gamma chain synthesis caused by the heterocellular HPFH determinant is directed by both chromosomes.

Adolescent↗
PubMed2000

Structure and organization of the rDNA intergenic spacer in lake trout (Salvelinus namaycush).

A total-genomic cosmid library was created to isolate complete copies of the rDNA cistron of lake trout (Salvelinus namaycush) in order to study the structure and organization of the intergenic spacer (IGS) in this species. A total of 60 rDNA-positive clones (average inserts > 25 kb) was recovered by screening the library with a rDNA-specific probe. Positive clones were assayed for the presence of the two internal rDNA spacers (ITS-1 and ITS-2) and the entire IGS fragment was successfully amplified from 42 clones by PCR. Length of the IGS fragments ranged from 9.4 to 17.8 kb. Comparative restriction mapping of the IGS-PCR products of several clones indicated two regions of extensive length variation surrounding a central region with sequence conservation. DNA sequence analysis was used to investigate the molecular basis of the IGS length variation and focused on identifying the region responsible for this variation. Over 9 kb of DNA sequence was obtained for one clone (A1) with a total IGS length of approximately 12.4 kb. Sequence of a conserved central region contained two open reading frames and a number of short direct repeats. Length variation in the IGS was determined by RFLP to result from differences in the number of copies of repetitive DNA sequences. These included an 89-bp tandem repeat (alpha repeats), an 82-bp element (beta repeats), a 168-177-bp element (chi repeats), and a 179-201-bp element (delta repeats). Overall nucleotide composition of the IGS was biased towards A and T (%GC = 47.4). Maintenance of discrete rDNA-length variants in lake trout suggests that the rate of gene conversion is insufficient to produce homogeneous copies across the genome.

Animals↗
PubMed2000

An in vitro rapid-turnover assay for human immunodeficiency virus type 1 replication selects for cell-to-cell spread of virus.

We have developed a rapid-turnover culture system where the life span of a human immunodeficiency virus type 1-infected cell is controlled by periodic addition of a cytotoxic agent, mitomycin C. These mitomycin C-exposed cells are cocultured with a constant number of uninfected cells as new targets for the virus. Passage of the virus-infected cells under these conditions led to the emergence of a viral variant that was able to replicate efficiently in this culture system. After biologic and molecular cloning, we were able to identify a single frameshift mutation in the vpu open reading frame that was sufficient for growth of the mutant virus in the rapid-turnover assay. This virus variant spread more efficiently by cell-to-cell transfer than the parental virus did. Electron micrographs of cells infected with the delta vpu virus revealed a large number of mature viral capsids attached to the plasma membrane. The presence of these mature virus particles on the cell surface led to enhanced fusion and formation of giant syncytia with uninfected cells. Enhanced cell-to-cell transfer of the delta vpu virus provides an explanation for the survival of this mutant virus in the rapid-turnover culture system. The in vitro rapid-turnover culture system is a good representation of the in vivo turnover kinetics of infected cells and their continual replacement by host lymphopoietic mechanisms.

Amino Acid Sequence↗
PubMed1998

Distribution of CCR5-delta 32 gene deletion across the Russian part of Eurasia.

32-bp inactivating deletion in the beta-chemokine receptor 5 (CCR5) gene, common in Nothern European populations, is associated with reduced HIV-1 transmission risk and delayed disease progression. We have studied the deletion distribution in many populations in Eurasia by polymerase chain reaction analysis of 531 DNA samples representing West and East Siberian, Central Asian, and Far Eastern parts of Russia. An unusually high frequency (11.1%) of the deleted variant in natives of West Siberia, of Finno-Ugrian descent, was observed. Furthermore, the deletion was infrequent in indigenous populations of Central Asia, East Siberia, the Russian Far East, and Canada. We conclude that the delta(ccr5) distribution is limited primarily to Europeans and related western Siberian Finno-Ugrian populations, with a sharp negative gradient toward the east along the territory of Russian Asia.

Adolescent↗
PubMed2004

Apolipoprotein E genotype and changes in serum lipids and maximal oxygen uptake with exercise training.

Physical activity improves lipid levels by altering triglyceride (TG) metabolism. Apolipoprotein E (Apo E) facilitates TG clearance by mediating lipoprotein binding to hepatic receptors, but Apo E also has less defined roles in skeletal muscle and nervous tissue. This study examined if variants in Apo E genotype affect the lipid and physiologic response to exercise training. Seven centers genetically screened 566 individuals to recruit 120 subjects into 6 gender-specific cohorts equal for the most common Apo E genotypes: E2/3, E3/3, and E3/4. Anthropometics, exercise capacity (Vo(2)max), serum lipids, and post heparin (PH) plasma lipase activities were measured before and after 6 months of supervised exercise training. Difference in the response (Delta) to training among the Apo E genotypes was the primary outcome variable. Differences in pretraining serum lipids among the Apo E genotypes mimicked those observed in population studies: TGs were slightly higher in E2/3 subjects, whereas low-density lipoprotein (LDL)-cholesterol (C) was lower (P = not significant [NS] ). TGs decreased 11% with training for the entire cohort (P <.0001) and 7%, 12%, and 14% for the Apo E 2/3, 3/3 and 3/4 groups, respectively (P = NS for Delta). LDL-C did not change in the entire cohort, but decreased slightly in the 2/3 and 3/3 subjects and increased 4% in the 3/4 group (P = NS for Delta). High-density lipoprotein (HDL)-C increased 2% for the entire cohort (P =.06) due to a 6% increase in the 3/3 group (P =.07 for Delta). Total cholesterol (TC)/HDL and LDL/HDL decreased with training in the 2/3 and 3/3 groups, but increased in the 3/4 subjects and these responses differed among the genotypes (P <.05 for Delta). Vo(2)max increased 9% to 10% for the entire cohort, but only 5% in the 3/3 subjects versus 13% in the 2/3 and 3/4 groups and these differences were significantly different among the genotypes (P <.01 for Delta). This is the first prospective study to demonstrate that the serum lipid response to exercise training differs by Apo E genotype in a pattern consistent with known metabolic differences among the variants. Surprisingly, Apo E genotype also affected the increase in aerobic capacity produced by exercise training possibly via undefined effects on nerve and skeletal muscle function.

Adult↗
PubMed2001

Functional properties of Cav1.3 (alpha1D) L-type Ca2+ channel splice variants expressed by rat brain and neuroendocrine GH3 cells.

Ca(2+) enters pituitary and pancreatic neuroendocrine cells through dihydropyridine-sensitive channels triggering hormone release. Inhibitory metabotropic receptors reduce Ca(2+) entry through activation of pertussis toxin-sensitive G proteins leading to activation of K(+) channels and voltage-sensitive inhibition of L-type channel activity. Despite the cloning and functional expression of several Ca(2+) channels, those involved in regulating hormone release remain unknown. Using reverse transcription-polymerase chain reaction we identified mRNAs encoding three alpha(1) (alpha(1A), alpha(1C), and alpha(1D)), four beta, and one alpha(2)-delta subunit in rat pituitary GH(3) cells; alpha(1B) and alpha(1S) transcripts were absent. GH(3) cells express multiple alternatively spliced alpha(1D) mRNAs. Many of the alpha(1D) transcript variants encode "short" alpha(1D) (alpha(1D-S)) subunits, which have a QXXER amino acid sequence at their C termini, a motif found in all other alpha(1) subunits that couple to opioid receptors. The other splice variants identified terminate with a longer C terminus that lacks the QXXER motif (alpha(1D-L)). We cloned and expressed the predominant alpha(1D-S) transcript variants in rat brain and GH(3) cells and their alpha(lD-L) counterpart in GH(3) cells. Unlike alpha(1A) channels, alpha(1D) channels exhibited current-voltage relationships similar to those of native GH(3) cell Ca(2+) channels, but lacked voltage-dependent G protein coupling. Our data demonstrate that alternatively spliced alpha(1D) transcripts form functional Ca(2+) channels that exhibit voltage-dependent, G protein-independent facilitation. Furthermore, the QXXER motif, located on the C terminus of alpha(1D-S) subunit, is not sufficient to confer sensitivity to inhibitory G proteins.

Alternative Splicing↗
PubMed1993

The common variant of cystic fibrosis transmembrane conductance regulator is recognized by hsp70 and degraded in a pre-Golgi nonlysosomal compartment.

The most common cause of cystic fibrosis is deletion of Phe-508 (delta F508) from the cystic fibrosis transmembrane conductance regulator (CFTR). Previous studies have suggested that delta F508 CFTR is an unstable protein that retains a pattern of glycosylation specific to the endoplasmic reticulum. This report examines the mechanism responsible for the mislocalization of delta F508 CFTR in a human cystic fibrosis epithelial cell line overexpressing recombinant CFTR by virtue of adenovirus-mediated gene transfer. Immunoelectron microscopy confirmed that wild-type CFTR is delivered to the plasma membrane of these cells and that delta F508 CFTR is retained in the endoplasmic reticulum. Pulse-chase studies showed that newly synthesized CFTR complexes with the chaperone hsp70. The wild-type protein dissociates from hsp70 before its transport to the Golgi, and the protein is subsequently degraded in lysosomes. By contrast, the complex formed between delta F508 CFTR and hsp70 is retained in the endoplasmic reticulum and delta F508 CFTR is rapidly degraded in a pre-Golgi nonlysosomal compartment. Thus, hsp70 discriminates between the normal form of CFTR and the form of the protein that most commonly causes cystic fibrosis (delta F508). These findings clarify the mechanism by which mutation causing delta F508 affects the intracellular trafficking of CFTR and suggest another function for hsp70 in ensuring quality control during the biosynthesis of plasma-membrane proteins.

Biological Transport↗
PubMed1993

Allele-specific amplification for the identification of several hemoglobin variants.

Eight known abnormal hemoglobins in more than 40 patients have been identified with an allele-specific amplification procedure. These are mutants of the A gamma (Hb F-Sardinia), the delta (Hb B2), the alpha (Hb G-Philadelphia), and the beta (Hbs S, C, E, D-Los Angeles, O-Arab) globin genes. Adjustment to an unusually high annealing temperature improves the procedure greatly, allowing excellent discrimination between normal and mutant alleles, irrespective of the particular mismatch. The discrimination includes the Hbs C and E in the same reaction mixture-multiplex allele-specific amplification. The procedure can successively use primers with 3'-penultimate critical nucleotides, degenerative ends, and potentially dimerizing properties.

Alleles↗
PubMedDate not supplied

Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid.

The enantiomers of 2-[( 3-13C]-n-propyl)pentanoic acid [(R)- and (S)-[13C]VPA] were employed as metabolic probes to investigate stereochemical aspects of the biotransformation of valproic acid (VPA) to 2-n-propyl-4-pentenoic acid (delta 4-VPA), a hepatotoxic metabolite of VPA. When incubated with hepatocytes freshly isolated from untreated male rats, each labeled substrate (initial concentration 1.0 mM) underwent metabolism to [13C]-delta 4-VPA, the formation of which was time-dependent and occurred at a rate of ca. 20 ng/(10(6) cells.4-h incubation). Analysis of this unsaturated metabolite by GC-MS techniques revealed that, following incubation of (R)-[13C]VPA, desaturation had taken place preferentially (by a factor of approximately 4) on the labeled propyl group (i.e., on the R side chain). Parallel incubations with (S)-[13C]VPA supported this conclusion, in that metabolism of this isotopic variant of VPA led to a terminal olefin that also was predominantly (83 +/- 2%) of R configuration (in this case oxidized selectively on the unlabeled side chain). Hence, biotransformation of VPA to delta 4-VPA in rat hepatocytes occurs with marked enantiotopic differentiation, favoring production of the R enantiomer of this chiral metabolite. When rats were pretreated with phenobarbital (80 mg kg-1 day-1 ip for 3 days) prior to isolation of hepatocytes, the overall rate of metabolism of VPA to delta 4-VPA over the 4-h incubation period increased approximately 3-fold, while the degree of product enantioselectivity was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Hemoglobin Evanston (alpha 14 Trp----Arg). An unstable alpha-chain variant expressed as alpha-thalassemia.

A new hematologic syndrome with phenotypic features of mild Hb H disease was identified in three children from two unrelated black American families. Erythrocytes from each of these children contained Hb H (beta 4) and Hb Barts (gamma 4), as well as a slowly migrating hemoglobin fraction that made up 7-10% of the total hemoglobin. The parents of the affected children all showed mild thalassemia-like changes, with one of the parents in each family also expressing the variant hemoglobin; in the latter individuals the mutant alpha-chains made up less than 2% of the total, and were present mainly or exclusively in combination with delta-chains in the form of a slowly migrating Hb A2. Purified Hb Evanston showed an increased oxygen affinity, but its Bohr effect, cooperativity, and 2,3-diphosphoglycerate effect were normal. The mutant hemoglobin appeared to have normal stability to heat and to isopropanol, and the stability of its alpha-chain in an extended time course synthesis study also appeared to be similar to that of alpha A. However, the results from short-term globin synthesis studies, and from mRNA translation in vitro, suggest that the two types of alpha-chains were synthesized at relatively equal rates, with a major fraction of the newly synthesized variant alpha-chains undergoing rapid catabolism. The hematologic data taken in combination with DNA hybridization and globin synthesis findings indicate that the proposita in each of these families has the genotype--, alpha A/--, alpha Ev. These observations suggest that two separate mechanisms are contributing to the alpha-thalassemia-like expression of Hb Evanston : the newly synthesized alpha EV-chains are unstable and are subject to early proteolytic destruction; and the mutant alpha-allele is linked to an alpha-globin gene deletion.

Child, Preschool↗
PubMed1997

Hepatitis B virus sequence changes evolving in liver transplant recipients with fulminant hepatitis.

BACKGROUND/AIMS: Patients undergoing liver transplantation for hepatitis B virus (HBV) related liver cirrhosis are at major risk of developing HBV recurrence, and occasionally fulminant hepatitis. Here we tested in a longitudinal study whether specific viral variants are associated with fulminant HBV infection in the graft. METHODS: The complete HBV genomes isolated from the sera of three patients with HBV and HBV and hepatitis delta virus (HDV) coinfection during chronic infection before and during fulminant reinfection after transplantation were amplified and directly sequenced. RESULTS: Twenty, 25 and 19 mutations, distributed over the entire genome, were identified which differed between the HBV genomes isolated from each patient during chronic and fulminant infection, respectively. This reflects a much higher rate of nucleotide sequence changes than expected from the natural variation of HBV. No common HBV mutation emerged in any of the three cases during fulminant infection. However, precore defective viruses were found to be present in all three patients at the time of fulminant infection and in two of the patients before fulminant infection. Two of the patients had preS2-defective HBVs both before and after transplantation. A point mutation in the 'a'-determinant of the surface protein emerged in one case after transplantation under treatment with polyclonal HBV specific immunoglobulins. CONCLUSIONS: Many new, but no specific common mutations emerged during fulminant HBV reinfection. Although HBeAg defective variants were found in all cases studied, the presence of these variants also during chronic infection in two cases demonstrates that they are not sufficient to cause fulminant hepatitis. Thus, other factors than the emergence of a specific viral strain seem to contribute to the development of fulminant reinfection in a liver graft.

Adult↗