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Biomedical subjects

M Katzman

Publications and source records attributed to M Katzman.

At least 19 recordsLinked to original sources
PubMed1999

Engagement and outcome in the treatment of bulimia nervosa: first phase of a sequential design comparing motivation enhancement therapy and cognitive behavioural therapy.

Despite the major advances in the development of treatments for bulimia nervosa, drop-outs and a lack of engagement in treatment, continue to be problems. Recent studies suggest that the transtheoretical model of change may be applicable to bulimia nervosa. The aim of this study was to examine the roles of readiness to change and therapeutic alliance in determining engagement and outcome in the first phase of treatment. One hundred and twenty five consecutive female patients meeting DSM-IV criteria for bulimia nervosa took part in a randomised controlled treatment trial. The first phase of the sequential treatment compared four sessions of either cognitive behavioural therapy (CBT) or motivational enhancement therapy (MET) in engaging patients in treatment and reducing symptoms. Patients in the action stage showed greater improvement in symptoms of binge eating than did patients in the contemplation stage. Higher pretreatment scores on action were also related to the development of a better therapeutic alliance (as perceived by patients) after four weeks. However, pretreatment stage of change did not predict who dropped out of treatment. There were no differences between MET and CBT in terms of reducing bulimic symptoms or in terms of developing a therapeutic alliance or increasing readiness to change. The results suggest that the transtheoretical model of change may have some validity in the treatment of bulimia nervosa although current measures of readiness to change may require modification. Overall, readiness to change is more strongly related to improvement and the development of a therapeutic alliance than the specific type of treatment.

Adult↗
PubMed1999

Substrate recognition by retroviral integrases.

Substrate recognition by the retroviral IN enzyme is critical for retroviral integration. To catalyze this recombination event, IN must recognize and act on two types of substrates, viral DNA and host DNA, yet the necessary interactions exhibit markedly different degrees of specificity. Although particular sequences at the viral DNA termini are recognized by IN, many host DNA sequences can serve as the target for integration. Over the last decade, both in vitro and in vivo data have contributed to our understanding of how IN recognizes its substrates. This review provides an overview of the sequence and structure requirements for recognition of viral and host DNA by different retroviral INs and discusses recent progress in mapping protein domains involved in these interactions.

Animals↗
PubMed1998

Analysis of a large collection of natural HIV-1 integrase sequences, including those from long-term nonprogressors.

A large collection of natural HIV-1 integrase (IN) sequences has not previously been described. We reasoned that analysis of such sequences would address whether natural variation of HIV-1 IN contributes to the pathogenesis of AIDS and might also identify amino acid residues important for IN function. Sequences encoding HIV-1 IN were amplified from cryopreserved lymphocytes or plasma obtained at different times from 10 hemophilia patients who had been observed for up to 17 years. The region of the HIV-1 genome that encodes the 288-amino acid IN protein was sequenced from a total of 102 clones; information was obtained for 99.97% of 29,478 amino acid positions. Phylogenetic analysis indicated that patient samples were unique. Interpatient nucleic acid distances ranged from 0.8% to 4.9%, highlighting the tight conservation of this genomic region. No major differences were found between DNA and RNA or between early and late time points from the same patient. Significantly, no amino acid changes that might account for the variable rate of disease progression between patients were evident. Only one amino acid substitution involved a highly conserved residue known to be important for enzymatic activity. However, several interesting amino acid substitutions were noted, including residues within the C-terminal region of the protein for which sequence comparisons between animal retroviruses have not been very informative. These results should encourage the pursuit of anti-integrase therapies, especially inasmuch as the apparent biologic constraints on the IN sequence may deter the development of drug resistance.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Mapping viral DNA specificity to the central region of integrase by using functional human immunodeficiency virus type 1/visna virus chimeric proteins.

We previously described the construction and analysis of the first set of functional chimeric lentivirus integrases, involving exchange of the N-terminal, central, and C-terminal regions of the human immunodeficiency virus type 1 (HIV-1) and visna virus integrase (IN) proteins. Based on those results, additional HIV-1/visna virus chimeric integrases were designed and purified. Each of the chimeric enzymes was functional in at least one oligonucleotide-based IN assay. Of a total of 12 chimeric IN proteins, 3 exhibit specific viral DNA processing, 9 catalyze insertion of viral DNA ends, 12 can reverse that reaction, and 11 are active for nonspecific alcoholysis. Functional data obtained with the processing assay indicate that the central region of the protein is responsible for viral DNA specificity. Target site selection for nonspecific alcoholysis again mapped to the central domain of IN, confirming our previous data indicating that this region can position nonviral DNA for nucleophilic attack. However, the chimeric proteins created patterns of viral DNA insertion distinct from that of either wild-type IN, suggesting that interactions between regions of IN influence target site selection for viral DNA integration. The results support a new model for the functional organization of IN in which viral DNA initially binds nonspecifically to the C-terminal portion of IN but the catalytic central region of the enzyme has a prominent role both in specific recognition of viral DNA ends and in positioning the host DNA for viral DNA integration.

Amino Acid Sequence↗
PubMed1996

Issues and concerns associated with different risk models for eating disorders.

OBJECTIVE: The present paper examines issues and concerns associated with different risk models in identifying individuals who may be vulnerable for eating disorders. METHOD: Studies were located by computerized search and the authors' knowledge of the literature. For the purposes of this paper, different risk models are grouped according to three types of sample selection criteria: exposure to environmental pressures toward thinness, parental psychopathology, and intraindividual characteristics. Intraindividual characteristics were subdivided into biological and behavior vulnerability markers, and within the behavior risk approach, symptom and nonsymptom risk models were further identified. RESULTS: Our literature review indicates that risk research on eating disorders is still in its formative years. More well-planned prospective risk studies are needed. CONCLUSIONS: Among these risk models, the nonsymptom risk approach, which defines risk on the basis of nonsymptom vulnerability markers, represents one of the more promising avenues for future risk research and deserves further exploration.

Anorexia Nervosa↗
PubMed1996

Influence of subterminal viral DNA nucleotides on differential susceptibility to cleavage by human immunodeficiency virus type 1 and visna virus integrases.

A comparison of the extents of site-specific cleavage of U5 and U3 viral DNA termini by the integrases of human immunodeficiency virus type 1 and visna virus guided the quantitative testing of oligonucleotide substrates containing specific base substitutions. The simultaneous exchange of positions 5 and 6 between U3 substrates switched the patterns of differential susceptibility to the two integrases. The activity of visna virus integrase was more dependent on the identity of position 5 adjacent to the invariant CA bases than on position 6, whereas human immunodeficiency virus type 1 integrase appeared to interact even more critically with position 6. Although the paired natural substrates of most lentiviral integrases match at positions 7 and 8, these bases were not important for susceptibility of U5 substrates. In fact, the final six U5 positions contained all of the sequence information necessary for susceptibility. These results suggest that constraints other than integration influence the terminal inverted repeats of retroviral DNA.

Animals↗
PubMed1996

Nonspecific alcoholysis, a novel endonuclease activity of human immunodeficiency virus type 1 and other retroviral integrases.

Retroviral integrase (IN) exhibits a previously unrecognized endonuclease activity which we have termed nonspecific alcoholysis. This action occurred at every position in nonviral DNA sequences except those near 5' ends and is clearly distinguished from, and was not predicted by, the site-specific alcoholysis activity previously described for IN at the processing site near viral DNA termini. The integrases of human immunodeficiency virus type 1, visna virus, and Rous sarcoma virus exhibited different target site preferences in this new assay. The isolated central domain of human immunodeficiency virus type 1 IN preferred the same sites as the full-length protein. Nonspecific alcoholysis may provide insights into the structure and function of IN and other endonucleases and suggests that stimulators of some activities possessed by retroviral enzymes should be sought as antiviral agents.

Alcohols↗
PubMed1995

Human immunodeficiency virus type 1 quantitative cell microculture as a measure of antiviral efficacy in a multicenter clinical trial.

A quantitative cell microculture assay (QMC) was used to measure the human immunodeficiency virus type 1 (HIV-1) peripheral blood mononuclear cell (PBMC)-associated titer in 109 subjects rolled in an open-label phase I/II study of didanosine monotherapy or combination therapy with zidovudine. The titer was inversely correlated with CD4+ cell count at baseline (r = .37, P = .001). After 12 weeks of therapy, subjects showed a significant decreases in virus titer and those with the highest baseline virus titers had the greatest increase in CD4+ cell number (r = .430, P = .002). The QMC assay was more sensitive (98%) for assessing the antiretroviral effect of therapy than was immune complex-dissociated HIV p24 antigen (32%) or plasma culture (3.4%). Estimated sample sizes for phase I/II clinical trials were derived using the within-subject QMC SD of .72 log10 infectious units per 10(6) PMBC.

CD4 Lymphocyte Count↗
PubMed1995

Mapping domains of retroviral integrase responsible for viral DNA specificity and target site selection by analysis of chimeras between human immunodeficiency virus type 1 and visna virus integrases.

Human immunodeficiency virus type 1 (HIV-1) and visna virus integrases were purified from a bacterial expression system and assayed on oligonucleotide substrates derived from each terminus of human immunodeficiency virus type 1 and visna virus linear DNA. Three differences between the proteins were identified, including levels of specific 3'-end processing, patterns of strand transfer, and target site preferences. To map domains of integrase (IN) responsible for viral DNA specificity and target site selection, we constructed and purified chimeric proteins in which the N-terminal, central, and C-terminal regions of these lentiviral integrases were exchanged. All six chimeric proteins were active for disintegration, demonstrating that the active site in the central region of each chimera maintained a functional conformation. Analysis of endonucleolytic processing activity indicated that the N terminus of IN does not contribute to viral DNA specificity; this function must reside in the central region or C terminus of IN. In the viral DNA integration assay, chimeric proteins gave novel patterns of strand transfer products which did not match that of either wild-type IN. Thus, target site selection with a viral DNA terminus as nucleophile could not be mapped to regions of IN defined by these boundaries and may involve interactions between regions. In contrast, when target site preferences were monitored with a new assay in which glycerol stimulates IN-mediated cleavage of nonviral DNA, chimeras clearly segregated between the two wild-type patterns. Target site selection for this nonspecific alcoholysis activity mapped to the central region of IN. This report represents the first detailed description of functional chimeras between any two retroviral integrases.

Amino Acid Sequence↗
PubMed1994

In vitro activities of purified visna virus integrase.

Although integration generally is considered a critical step in the retrovirus life cycle, it has been reported that visna virus, which causes degenerative neurologic disease in sheep, can productively infect sheep choroid plexus cells without detectable integration. To ascertain whether the integrase (IN) of visna virus is an inherently defective enzyme and to create tools for further study of integration of the phylogenetically related human immunodeficiency virus type 1 (HIV-1), we purified visna virus IN by using a bacterial expression system and applied various in vitro oligonucleotide-based assays to studying this protein. We found that visna virus IN demonstrates the full repertoire of in vitro functions characteristic of retroviral integrases. In particular, visna virus IN exhibits site-specific endonuclease activity following the invariant CA found two nucleotides from the 3' ends of viral DNA (processing activity), joins processed oligonucleotides to various sites on other oligonucleotides (strand transfer or integration activity), and reverses the integration reaction by resolving a complex that mimics one end of viral DNA integrated into host DNA (disintegration activity). In addition, although it has been reported that purified HIV-1 IN cannot specifically nick visna virus DNA ends, purified visna virus IN does specifically process and integrate HIV-1 DNA ends.

Base Sequence↗
PubMed1992

Hepatobiliary infections caused by Haemophilus species.

Haemophilus species are rarely associated with hepatobiliary infections. We report a case of hepatic abscess caused by Haemophilus paraphrophilus and review the English-language literature for reports of infections of the liver and biliary system caused by Haemophilus species. Most patients identified had predisposing conditions. The pathogenesis of hepatobiliary infections due to Haemophilus species may involve ascending spread from the gastrointestinal tract or hematogenous seeding following oropharyngeal colonization.

Adult↗
PubMed1992

High incidence of bronchospasm with regular administration of aerosolized pentamidine.

A systematic evaluation of changes in pulmonary status by objective spirometric assessment and subjective rating using visual analog scale was performed in a cohort of 134 patients receiving aerosolized pentamidine (AP) for the prevention of Pneumocystis carinii pneumonia. Significant bronchospasm defined as greater than or equal to 15 percent reduction in the forced expiratory volume in 1 s was noted in 26 of 100 (26 percent) of patients receiving AP alone. Despite the use of salbutamol (albuterol) as concurrent aerosolized treatment in 34 subjects, bronchospasm developed in 9 of 34 (26 percent) of the patients. The subjective respiratory status rating scale was found to be unreliable in correctly predicting the development of bronchospasm. We conclude that a high incidence of bronchospasm is present in patients receiving regular AP administration using an ultrasonic nebulizer as studied, and concurrent administration of salbutamol is not fully protective of this acute adverse pulmonary reaction.

Aerosols↗
PubMed1991

A covalent complex between retroviral integrase and nicked substrate DNA.

Purified retroviral integrase (IN) from avian sarcoma-leukosis viruses can appropriately process the termini of linear viral DNA, cleave host DNA in a sequence-independent manner, and catalyze integrative recombination; an exogenous source of energy is not required for these reactions. Using DNA substrates containing radioactive phosphate groups, we demonstrate that IN becomes covalently joined to the new 5' phosphate ends of DNA produced at sites of cleavage. Most of the phosphodiester linkages between IN and DNA involve serine, but some involve threonine. Computer-assisted alignment of 80 retroviral and retrotransposon IN sequences identified one serine that is conserved in all of these proteins and three less-conserved threonine residues. These results identify candidate active-site residues and provide support for the participation of a covalent IN-DNA intermediate in retroviral integration.

Amino Acid Sequence↗
PubMed1991

Overlapping retrovirus U5 sequence elements are required for efficient integration and initiation of reverse transcription.

A secondary structure in the 5' noncoding region of avian retrovirus RNA, called the U5-leader stem, was shown previously to have a role in initiation of reverse transcription (D. Cobrinik, L. Soskey, and J. Leis, J. Virol. 62:3622-3630, 1988). We now show that an additional RNA secondary structure near the U5 terminus, called the U5-IR stem, is also important for reverse transcription. Mutations that disrupt the U5-IR stem cause a replication defect associated with both a decrease in synthesis of viral DNA in infected cells and a decrease in initiation of reverse transcription in melittin-permeabilized virions. Structure-compensating base substitutions in the U5-IR restore reverse transcription efficiency. In viral DNA, U5-IR sequences are included in the U5 terminal region that functions as a viral integration donor site. When base substitutions are introduced into these sequences, a reduced efficiency of integration in vitro and in vivo is observed. These observations indicate that U5-IR sequences have a structural role in reverse transcription of viral RNA and a sequence-specific role in the integration of viral DNA.

Avian Sarcoma Viruses↗
PubMed1989

The avian retroviral integration protein cleaves the terminal sequences of linear viral DNA at the in vivo sites of integration.

The purified integration protein (IN) of avian myeloblastosis virus is shown to nick double-stranded oligodeoxynucleotide substrates that mimic the ends of the linear form of viral DNA. In the presence of Mg2+, nicks are created 2 nucleotides from the 3' OH ends of both the U5 plus strand and the U3 minus strand. Similar cleavage is observed in the presence of Mn2+ but only when the extent of the reaction is limited. Neither the complementary strands nor sequences representing the termini of human immunodeficiency virus type 1 DNA were cleaved at analogous positions. Analysis of a series of substrates containing U5 base substitutions has defined the sequence requirements for site-selective nicking; nucleotides near the cleavage site are most critical for activity. The minimum substrate size required to demonstrate significant activity corresponds to the nearly perfect 15-base terminal inverted repeat. This in vitro activity of IN thus produces viral DNA ends that are joined to host DNA in vivo and corresponds to an expected early step in the integrative recombination reaction. These results provide the first enzymatic support using purified retroviral proteins for a linear DNA precursor to the integrated provirus.

Avian Leukosis Virus↗
PubMed1989

Serious infectious complications of corticosteroid therapy for COPD.

We report seven elderly patients with COPD who developed serious infectious complications during prolonged treatment with high doses of corticosteroids. Infections included invasive pulmonary aspergillosis, Herpes simplex stomatitis and esophagitis, cytomegalovirus pneumonia, bacterial sepsis, fungemia and meningitis due to Cryptococcus neoformans. Each of the three patients who developed invasive aspergillus pneumonia died. The efficacy of prolonged therapy with high doses of corticosteroids in patients with COPD is not proven. These cases illustrate the potential for serious infections in patients with COPD treated with corticosteroids.

Aged↗