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Biomedical subjects

B Oberg

Publications and source records attributed to B Oberg.

At least 19 recordsLinked to original sources
PubMed1995

Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is the major target for antiretroviral therapy of the acquired immunodeficiency syndrome (AIDS). While some inhibitors exhibit activity against most retroviral RTs, others are specific for the HIV-1 enzyme. To develop an animal model for the therapy of the HIV-1 infection with RT inhibitors, the RT of the simian immunodeficiency virus (SIV) was replaced by the RT of HIV-1. Macaques infected with this SIV/HIV-1 hybrid virus developed AIDS-like symptoms and pathology. The HIV-1-specific RT inhibitor LY300046.HCl, but not zidovudine [3'-azido-3'-deoxythymidine (AZT)] delayed the appearance of plasma antigenemia in macaques infected with a high dose of the chimeric virus. Infection of macaques with the chimeric virus seems to be a valuable model to study the in vivo efficacy of new RT inhibitors, the emergence and reversal of drug resistance, the therapy of infections with drug-resistant viruses, and the efficacy of combination therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Enhancement of HIV-1 proteinase activity by HIV-1 reverse transcriptase.

HIV-1 reverse transcriptase (RT) was found to increase the activity of HIV-1 proteinase in vitro and in eukaryotic cells. The effect of RT on proteinase activity was dose-dependent and independent of pH or salt concentration. The cleavage of sequences corresponding to all the naturally occurring cleavage sites that could be tested in vitro was enhanced. The effect of RT on cleavage was greatest at the cleavage site between RT and integrase. The enhancement of viral proteinase activity by the virus RT may contribute to regulation of the order and/or efficiency of cleavage at different sites during virus replication and maturation.

Base Sequence↗
PubMed1995

The effect of nasal oxygen flow and catheter position on the accuracy of end-tidal carbon dioxide measurements by a pharyngeal catheter in unintubated, spontaneously breathing subjects.

Reliable recordings of carbon dioxide concentrations during spontaneous respiration can be obtained from a catheter positioned in the hypopharynx. The present study investigated the possible influence on end-tidal carbon dioxide measurement of nasal oxygen administration, position of the sampling catheter and mouth breathing. The study demonstrated that not only can reliable capnographic tracings be obtained from a thin catheter placed in the unintubated airway, but the subject may also receive up to 6 l.min-1 of oxygen via the nasal route without interference with the accuracy of the measurements. Furthermore, the exact position of the sampling catheter tip in the airway is not critical, which means that it may be placed where it causes the patient least discomfort. Finally, mouth breathing caused a mean decrease in end-tidal carbon dioxide of 0.25 kPa compared to nose breathing.

Administration, Intranasal↗
PubMed1995

Reliability of CO2 measurements from the airway by a pharyngeal catheter in unintubated, spontaneously breathing subjects.

Although several short communications have appeared describing attempts to record the concentrations of carbon dioxide (cCO2) from the unintubated airway by a catheter placed in the nose, so far only few reports have documented the reliability of the method. To evaluate the reliability of CO2 measurements by a catheter in the open, unintubated airway during spontaneous respiration, a 12 CH PVC catheter was forwarded through the nostril to the hypopharynx and connected to a capnograph in nine healthy volunteers. Another capnograph was connected to a tightly fitting face mask and simultaneous CO2 recordings were attained from the two parts of the airway during normoventilation, hyperventilation and rebreathing. A corresponding blood sample was drawn from the radial artery for blood gas analysis. The configurations of the capnograms recorded from the pharyngeal catheter were similar to those recorded from the face mask. The results were analysed by a multifactor analysis of variance. The carbon dioxide tension (pCO2) was significantly influenced by degree of ventilation (P < 0.0001), subject (P < 0.0001), measurement site (P = 0.030) and interaction subject-ventilation (P = 0.015). In spite of the significant influence of the measurement site, the difference between end tidal carbon dioxide tension (pCO2(ET)) and carbon dioxide tension in arterial blood (pCO2(a)) was small. The mean differences between paired measurements (pCO2(ET)-pCO2(a)) were -0.10 kPa +/- 0.41 kPa (mean +/- SD) for the catheter and -0.20 kPa +/- 0.43 kPa for the face mask. The study demonstrates that reliable recordings of CO2 concentrations during spontaneous respiration can be obtained by a thin catheter positioned in the hypopharynx.

Adult↗
PubMed1995

Pelvic floor exercises for children: a method of treating dysfunctional voiding.

OBJECTIVE: To evaluate the clinical effect of a pelvic floor exercise programme developed for children. PATIENTS AND METHODS: Sixteen girls with non-neurogenic dysfunctional voiding were treated by a physiotherapist, mostly in small groups. The exercises were designed to increase the child's awareness of their pelvic floor musculature and to teach them how to contract and relax these muscles at will. The emphasis on pelvic floor relaxation served to improve the child's voiding pattern. RESULTS: After 1 year, nine girls were cured and seven improved. Another three girls were cured at the 3-4 year follow-up, giving a total cure rate of 12/16. CONCLUSION: This non-invasive method seems to be a useful alternative or complement to other treatments of children with dysfunctional voiding.

Adolescent↗
PubMed1994

Enzymatic properties and sensitivity to inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase with Glu-138-->Arg and Tyr-188-->His mutations.

Two mutants of HIV-1 reverse transcriptase (RT), Tyr-188-->His and Glu-138-->Arg have been prepared and their catalytic properties and sensitivities to inhibitors studied. As compared to wild type RT, a reduction in catalytic efficiency and turn over number was observed, especially for the Tyr-188-->His mutant. The non-nucleoside inhibitors nevirapine, L-697,661 and 9-Cl-TIBO caused a mixed type of inhibition of RT (Arg-138) with respect to substrate, and with the exception of a non-competitive inhibition by nevirapine, also a mixed type of inhibition of RT (His-188). Foscarnet (PFA) caused a non-competitive type of inhibition of RT (Arg-138) and a mixed inhibition of RT (His-188). The inhibition by ddG-TP was competitive with both mutant RTs. Inhibition by nevirapine gave IC50 values of 0.15, 0.23 and 0.72 microM; by 9-Cl-TIBO of 0.20, 2.50 and 10.3 microM; by L-697,661 of 0.064, 0.28 and 0.60 microM; by ddGTP of 0.13, 0.14 and 0.02 microM; by PFA of 17.0, 48.0 and 15.0 microM for RT wt, RT (Arg-138) and RT (His-188), respectively.

Amino Acids↗
PubMed1994

Validity and reliability of a new assessment of lower-extremity dysfunction.

BACKGROUND AND PURPOSE: A 20-variable assessment system for evaluation of lower-extremity dysfunction has been constructed with special consideration of the needs of the physical therapist. The variables are classified into five subgroups: hip impairment, knee impairment, physical disability, social disability, and pain. SUBJECTS: One hundred five patients with osteoarthrosis of the hip and knee, all accepted for total joint replacement arthroplasty, were tested. The mean age of the patients was 69 years (SD = 9.0, range = 46-91). METHODS: The original grouping of the variables was analyzed for content validity with a factor analysis. The results from a subgroup of 42 patients were tested for intertester reliability with the Goodman-Kruskal gamma coefficient. RESULTS: The factor analysis indicated a factor solution consistent with the primary grouping except for two variables. The correlation between two independent physical therapists was .99 to 1.00 for different variables, indicating excellent intertester reliability. CONCLUSION AND DISCUSSION: In the authors' opinion, the new assessment system provides a reasonably valid, reliable, inexpensive, and easy-to-use measurement and fulfills the needs of the physical therapist for functional evaluation of the lower extremity.

Activities of Daily Living↗
PubMed1993

Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-1-specific [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D-pentofurano syl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific nonnucleoside inhibitors.

We recently reported that a newly discovered class of nucleoside analogues--[2',5'-bis-O-(tert-butyldimethylsilyl)- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D - pentofuranosyl derivatives of pyrimidines and purines (designated TSAO)--are highly specific inhibitors of human immunodeficiency virus type 1 (HIV-1) and targeted at the nonsubstrate binding site of HIV-1 reverse transcriptase (RT). We now find that HIV-1 strains selected for resistance against three different TSAO nucleoside derivatives retain sensitivity to the other HIV-1-specific nonnucleoside derivatives (tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine, nevirapine, and pyridinone L697,661, as well as to the nucleoside analogues 3'-azido-3'-deoxythymidine, ddI, ddC, and 9-(2-phosphonylmethoxyethyl)adenine. Pol gene nucleotide sequence analysis of the TSAO-resistant and -sensitive HIV-1 strains revealed a single amino acid substitution at position 138 (Glu-->Lys) in the RT of all TSAO-resistant HIV-1 strains. HIV-1 RT in which the Glu-138-->Lys substitution was introduced by site-directed mutagenesis and expressed in Escherichia coli could not be purified because of rapid degradation. However, HIV-1 RT containing the Glu-138-->Arg substitution was stable. It lost its sensitivity to the TSAO nucleosides but not to the other HIV-1-specific RT inhibitors (i.e., TIBO and pyridinone). Our findings point to a specific interaction of the 4''-amino group on the 3'-spiro-substituted ribose moiety of the TSAO nucleosides with the carboxylic acid group of glutamic acid at position 138 of HIV-1 RT.

Antiviral Agents↗
PubMed1993

HIV-1-specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase.

Serial passage of HIV-1 in CEM or MT-4 cell cultures in the presence of different HIV-1-specific reverse transcriptase (RT) inhibitors yielded mutant viruses which were resistant (i.e., 200- to 1000-fold less sensitive) to the homologous compounds. The RT of these mutant HIV-1 strains showed different amino acid substitutions depending on the class of the HIV-1-specific RT inhibitors. The following amino acid substitutions were found: 138 Glu-->Lys (TSAO-T), 181 Tyr-->Cys (nevirapine), 181 Tyr-->Cys (pyridinone), and 100 Leu-->Ile (TIBO R82150). Four TIBO (R82913)-resistant HIV-1 strains contained different amino acid substitutions: 103 Lys-->Asn (strain 2), 100 Leu-->Ile and 138 Glu-->Lys (strain B02), 100 Leu-->Ile and 181 Tyr-->Cys (strain 1), 100 Leu-->Ile and 188 Tyr-->His (strain B22). The level of cross-resistance (or sensitivity) highly depends on the nature of the amino acid substitutions. As a rule, the TSAO-resistant HIV-1 strains (138 Glu-->Lys) and TIBO (R82150 or R82913)-resistant HIV-1 strains (Leu 100-->Ile or 103 Lys-->Asn) are sensitive to the other HIV-1-specific RT inhibitors, whereas the amino acid change 181 Tyr-->Cys results in a significant reduction of sensitivity to all classes of the HIV-1-specific RT inhibitors.

Amino Acid Sequence↗
PubMed1993

Disruption of a salt bridge between Asp 488 and Lys 465 in HIV-1 reverse transcriptase alters its proteolytic processing and polymerase activity.

The conserved aspartic acid residue 488 in the RNase H domain of HIV-1 reverse transcriptase (RT) was mutated to alanine. RT was expressed in Escherichia coli alone or with the entire pol-gene polyprotein consisting of proteinase, RT, and integrase and processed by the HIV-1 proteinase in the bacterial cell. Expression of mutant RT together with the proteinase resulted in an overproduction of RT p51 vs p66. The mutation also altered the conformation of the RT p66/p51 heterodimer as shown by the loss of binding of monoclonal antibodies to mutant RT in ELISA. Crystallographic data shows that a salt bridge exists between Asp 488 and Lys 465 of RNase H which stabilizes the uncleavable form of RT p66, and that substitution of Asp for Ala would prevent the formation of this salt bridge. Our results indicate that disruption of this salt bridge through mutation of Asp 488 interferes with the conformational changes that regulate the limited processing of p66 to 51 by the virus proteinase. Homology data suggest that such a bridge may be present in other lentiviruses. The mutation introduced caused a moderate decrease in both the RNase H activity and the polymerase activity of RT, indicating that the proper folding of the RNase H domain of RT is necessary to achieve full polymerase activity.

Amino Acid Sequence↗
PubMed1993

Antiviral therapy in human immunodeficiency virus infections. Current status (Part I).

Antiviral therapy has in the past met with limited success and only a few antiviral drugs have been available. The human immunodeficiency virus (HIV) epidemic has created an urgent need for the development of antiviral therapy against this infection. HIV replication offers several targets for inhibitory compounds, the foremost presently being the HIV reverse transcriptase and protease enzymes. Despite the short time since the beginning of the epidemic, 3 nucleoside analogue drugs (zidovudine, didanosine and zalcitabine) which act at the reverse transcriptase site are already licensed for use against HIV, and others (stavudine, alovudine and 3-TC) are still under clinical evaluation. Part II of this article discusses non-nucleoside reverse transcriptase inhibitors undergoing investigation, protease inhibitors, and compounds active against various other targets in HIV. Treatment guidelines are also provided in Part II.

Animals↗
PubMed1993

Antiviral therapy in human immunodeficiency virus infections. Current status (Part II).

Part I of this article reviewed the targets against which anti-HIV drugs can be directed, problems in assessing active compounds (e.g. resistance development and use of surrogate end-points). and nucleoside analogues effective against HIV reverse transcriptase. Intensive research is currently being undertaken in laboratories and hospitals to design and evaluate new inhibitors of HIV. In this work, combining different drugs is one important approach, both to decrease toxicity and to offset the rate of resistance development, which seems to be a major problem associated with therapy directed against the ever-changing HIV. Therapeutic vaccines and immunomodulators are other modalities being actively evaluated against HIV and AIDS, although this effort has not yet yielded any licensed treatment. It appears likely that new antiviral drugs and immunotherapies will be forthcoming during the next 5 years, that they will be used in a variety of combinations, and that the treatment options available for opportunistic infections will increase. These developments should improve the survival and the quality of life of patients with HIV infection.

Antiviral Agents↗
PubMed1992

The HIV replication inhibitor 3'-fluoro-3'-deoxythymidine blocks sialylation of N-linked oligosaccharides.

The ability of 3'-fluoro-3'-deoxythymidine (FLT) to interfere with glycosylation was investigated in an experimental system, where the effects on the herpes simplex virus type 1-specified glycoprotein gC were determined. By adding FLT to HSV-infected cells after the peak of DNA synthesis, it was possible to segregate possible effects on nucleic acid metabolism from the effects on glycosylation of gC. It was found that FLT treatment of HSV-infected cells at concentrations of 20-500 micrograms/ml resulted in a significant increase in the electrophoretic mobility of gC, indicating a reduction of the amount of carbohydrates incorporated into gC. Lectin-binding assays demonstrated that the FLT treatment blocked addition of sialic acid to complex type N-linked glycans. The effects on glycosylation were observed in cells infected with an HSV mutant, deficient in thymidine kinase (TK), but not in cells infected with wild type virus. The cells infected with the wild type virus contained five times more total FLT metabolites than the cells infected with the TK-deficient mutant, whereas the latter cell type contained significantly higher amounts of unmetabolized FLT. This result indicates that FLT itself, and not a metabolite, was responsible for the effects on glycosylation.

Antibodies, Monoclonal↗
PubMed1992

Early appearance of simian immunodeficiency virus (SIV) antigen and antibodies as variables in evaluating antiviral drugs in macaques.

SIV infection in macaques has become an important animal model for HIV-1 infection in humans. An antibody assay was therefore developed and compared to a commercially available antigen assay with respect to their usefulness to monitor the course of simian immunodeficiency virus (SIV) infection in cynomolgus monkeys. A peptide, JB6T, consisting of 21 amino acids with the sequence NSWGCAFRQVCHTTVPWVNDS corresponding to a segment in the env protein of human immunodeficiency virus (HIV) type 2 was used as antigen in an enzyme-linked immunosorbent assay (ELISA). JB6T was found to detect IgG and IgM antibodies to viral antigens with high specificity. The earliest anti-SIV IgM antibodies were detected at days 13-16, with a maximum at day 20 and subsequently the levels fell. Specific IgG antibody levels increased at day 16-20 after SIV infection and reached a plateau at day 60. The commercially available HIV-1 p24/26 antigen test could, due to cross-reactivity, be employed to detect SIV antigen delay, peak and duration.

Amino Acid Sequence↗
PubMed1992

Prevention of HIV-2 and SIV infections in cynomolgus macaques by prophylactic treatment with 3'-fluorothymidine.

The aim of this study was to determine the usefulness of human immunodeficiency virus type 2 (HIV-2) for in vivo evaluation of antiviral drugs in monkeys and to study if prophylactic treatment with 3'-fluorothymidine (FLT) could prevent infection against a low challenge dose of HIV-2 or simian immunodeficiency virus (SIV). Protection against infection was assessed by virus isolation and polymerase chain reaction (PCR) on monkey peripheral blood mononuclear cells (PBMC) as well as by antibody and viral antigen assays. Prophylactic treatment with FLT 3 x 5 mg/kg/day, starting 8 h prior to virus inoculation, prevented HIV-2 infection in 3 of 8 monkeys. In another experiment 2 of 4 monkeys resisted 2-10 monkey infectious doses (MID50) of SIV with the same prophylactic treatment. All control animals (HIV-2 n = 8, SIV n = 4) became infected. Thus, FLT treatment prevented HIV-2 and SIV infection in 5 of 12 animals.

Animals↗
PubMed1992

Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action.

Cynomolgus monkeys had microdialysis probes implanted under ketamine anesthesia into peripheral veins, thigh muscles, and the brain in order to sample the extracellular fluid for the concentrations of unbound nucleoside analogs. A dose of 25 mg of zidovudine or 3'-fluoro-3'-deoxythymidine (FLT) per kg was administered subcutaneously to each of three animals. Relatively high antiviral concentrations of FLT and zidovudine were present in peripheral tissues and in the brain. It was found that the concentration of zidovudine in the brain was approximately one-third of that in muscle and veins; the same relation was observed for FLT. The in vivo unbound concentrations of both drugs in the brain, muscle, and venous blood exceeded those reported to inhibit human immunodeficiency virus replication in vitro. In addition, in a correlative study we found that the appearance of p24 antigen in sera of monkeys infected with simian immunodeficiency virus was significantly delayed by both compounds (15 mg/kg three times daily for 9 days after infection). Thus, we have shown that the extracellular concentrations of unbound FLT and zidovudine in the brain and peripheral tissues attained with in vivo antiviral doses exceed in vitro antiviral concentrations.

Animals↗
PubMed1992

Pharmacokinetics and distribution over the blood brain barrier of two acyclic guanosine analogs in rats, studied by microdialysis.

The free extracellular concentrations of acyclovir and (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) in the blood and in brain tissue of rats were measured in microdialysis samples by high-pressure liquid chromatography with UV detection. The half-life of acyclovir in blood was 2 h, while that of H2G was 28 min. The concentration attained in the brain compared with the concentration in blood was slightly lower for H2G than for acyclovir. The results show that the pharmacokinetic profiles of acyclic nucleosides may vary as a consequence of the structure of the acyclic chain corresponding to the sugar moiety.

Acyclovir↗