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Biomedical subjects

G Haas

Publications and source records attributed to G Haas.

At least 19 recordsLinked to original sources
PubMed2000

Comparative proteome analysis of Helicobacter pylori.

Helicobacter pylori, the causative agent of gastritis, ulcer and stomach carcinoma, infects approximately half of the worlds population. After sequencing the complete genome of two strains, 26695 and J99, we have approached the demanding task of investigating the functional part of the genetic information containing macromolecules, the proteome. The proteins of three strains of H. pylori, 26695 and J99, and a prominent strain used in animal models SS1, were separated by a high-resolution two-dimensional electrophoresis technique with a resolution power of 5000 protein spots. Up to 1800 protein species were separated from H. pylori which had been cultivated for 5 days on agar plates. Using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) peptide mass fingerprinting we have identified 152 proteins, including nine known virulence factors and 28 antigens. The three strains investigated had only a few protein spots in common. We observe that proteins with an amino acid exchange resulting in a net change of only one charge are shifted in the two-dimensional electrophoresis (2-DE) pattern. The expression of 27 predicted conserved hypothetical open reading frames (ORFs) and six unknown ORFs were confirmed. The growth conditions of the bacteria were shown to have an effect on the presence of certain proteins. A preliminary immunoblotting study using human sera revealed that this approach is ideal for identifying proteins of diagnostic or therapeutic value. H. pylori 2-DE patterns with their identified protein species were added to the dynamic 2D-PAGE database (http://www.mpiib-berlin.mpg.de/2D-PAGE/). This basic knowledge of the proteome in the public domain will be an effective instrument for the identification of new virulence or pathogenic factors, and antigens of potentially diagnostic or curative value against H. pylori.

Bacterial Proteins↗
PubMed1999

Immunoglobulin A1 protease, an exoenzyme of pathogenic Neisseriae, is a potent inducer of proinflammatory cytokines.

A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-alpha and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.

Adjuvants, Immunologic↗
PubMed1999

Synthesis and cytostatic activities of didemnin derivatives.

The highly cytostatic didemnins contain a 23-membered cyclopeptolide with a side chain attached to the backbone through the amine group of threonine. Thirty-six derivatives varying the side chain were prepared, but only compounds with D-MeLeu attached to threonine show remarkable biological activities. To protect the macrocycle from degradation by lipases the two ester bonds were replaced successively by amide bonds. Although these variations have a major effect on the conformation and rigidity of the ring, the compound which contains exclusively amide bonds is highly active, equivalent to acetyl-didemnin A.

Antineoplastic Agents↗
PubMed1998

Cytotoxic T-cell responses to HIV-1 reverse transcriptase, integrase and protease.

OBJECTIVES: To determine immunodominant regions and new epitopes for cytotoxic T cells (CTL) directed against the HIV-1 pol products reverse transcriptase (RT), integrase and protease in a large cohort of patients at different stages of disease. DESIGN AND METHODS: Cross-sectional analysis of 98 patients from the French IMMUNOCO cohort (CD4 counts: 125-1050 x 10(6) cells/l), monitored for CTL recognition of HIV-1 pol products using recombinant vaccinia virus constructs and synthetic peptides. RESULTS: Memory CTL responses against HIV-1 pol products were detected in 78% of all patients whatever the stage of disease. RT was more immunogenic (81%, 30 out of 37 patients) than integrase and protease (51% and 24%, respectively). CTL recognition of RT was more frequent against Pol amino acids 310-460 (61%, 11 out of 18 patients) than against the other three portions (Pol 168-310, Pol 450-600, Pol 590-728) in patients with CD4 counts > 400 x 10(6)/l, whereas in patients at advanced stages no prominent differences were observed. Two new clusters of antigenic regions were found in the NH2 segment: three epitopes between amino-acids Pol 200 and 217 and four epitopes between amino-acids Pol 346 and 387, using five different HLA-restricting elements. A new cluster of three conserved epitopes was found in the COOH segment of RT. CONCLUSIONS: This study shows that memory CTL responses against HIV-1 RT, integrase and protease are detectable in most patients at different stages of disease. The capacity of CTL to recognize simultaneously clusters of epitopes may become important for the immune control to reinforce antiretroviral drug efficiency.

Cohort Studies↗
PubMed1998

Gender differences in premorbid social adjustment and intimacy motivation in schizophrenia.

The present study compared the relationship between motivation for intimacy and level of premorbid adjustment for men and women with schizophrenia. A sample of 34 schizophrenic patients (14 male and 20 female) were studied. Stories told in response to six TAT cards were scored for Intimacy Motivation (IM). Levels of Premorbid adjustment (PA) and Asociality (ASOC) were assessed. A statistically significant interaction between gender and level of PA indicated that males with good PA had higher IM than those with poorer whereas females with good PA had lower IM than females with poor PA. The same interaction was obtained for the measure of ASOC. Findings are discussed in relation to sociocultural expectations for women. Some implications for differential treatment needs of male and female schizophrenics are suggested.

Adolescent↗
PubMed1997

Dynamics of HIV variants and specific cytotoxic T-cell recognition in nonprogressors and progressors.

Infection with the human immunodeficiency virus (HIV) results in a disease characterized by a rapid viral replication, immunodeficiency and chronic immune activation. The vigorous polyspecific cytotoxic T-cell (CTL) response directed against multiple HIV epitopes reduces HIV-infected cell numbers, although unable to eradicate the virus. The plasticity of the specific CTL repertoire ensures adaptation to the high rate of viral variation that can be found in CTL epitopes of several HIV-1 proteins. However, viral persistence occurs despite continuous CTL recognition and although functional importance of conserved sites in the different HIV proteins may impose constraints to viral variation. In the reverse transcriptase (RT) which is a major target for antiretroviral therapy, the impact of the continuous pressure of drug therapy is more obvious than that of the CTLs. Shifts in immunodominant RT regions seem to allow the maintenance of the HIV-1 RT CTL recognition with disease progression and antiretroviral therapy. In respect to new highly active drug combinations, understanding the capacity of virus-specific CTLs to control residual viral variants seems very important and may allow development of efficient immunotherapies to prevent drug-induced viral resistance.

Adaptation, Physiological↗
PubMed1997

[Vancomycin resistant enterococci in Austria].

This study reports pheno- and genotypical analysis of 9 isolates of vancomycin-resistant enterococci (VRE) and 5 vancomycin-sensitive enterococci (VSE) in Austria: 5 E, faecium isolates of 4 patients (the sole patients demonstrating VRE at the University Hospital of Innsbruck in 1994 and 1995), 3 glycopeptide-sensitive isolates collected in Innsbruck in February 1996 for epidemiological analysis, and 6 enterococcus isolates from the University Hospitals of Vienna and Graz. The pheno- and genotypical analyses of all glycopeptide highly resistant E. faecium and E. faecalis isolates indicated the presence of VanA type resistance. One E. casseliflavus strain with intrinsic VanC-1 resistance showed a characteristic constitutive low-level resistance to vancomycin and susceptibility to teicoplanin. Genotyping with macro-restriction analysis demonstrated that 3 VRE isolates of the 5 E. faecium specimens were identical; the same applied to 2 VSE isolates. The two patients with VRE had been cared for at the same time in a surgical ICU and likewise, the two patients with VSE were simultaneously treated at a neurological ICU. The genotyping of E. faecalis strains showed that two strains of the three VRE isolates exhibited identical patterns. Epidemiological investigation did not reveal a mode of transmission for this cluster. Two of the 8 patients with VRE died within 60 days after isolation of the bacteria; the doctors in charge did not consider that the enterococci had been the cause of death. The results of our study indicate that oral vancomycin administration to humans is a primary cause of VRE in Austrian hospitals. In Austria approximately 66 kg vancomycin, 20% of it given orally, are administered to patients per year. Approx. 18-20 tons Avotan (active ingredient Avoparcin-10%)/year were used in Austria; as of April 1, 1997 the use of this animal foodstuff supplement is prohibited by the European Commission.

Administration, Oral↗
PubMed1997

Hopelessness and first-episode psychosis: a longitudinal study.

Hopelessness has not been adequately studied in first-episode psychotic patients, although it is already present at the early stages, especially in schizophrenic patients. We have studied 96 neuroleptic-naive psychotic patients (49 schizophrenic patients and 47 other non-affective psychotic patients) over a period of 12 months after their first admission. The total score on the Hopelessness Scale (HS) at first admission was higher in the schizophrenic patients, and correlated with younger age and with negative symptoms. High HS scores at baseline predicted poor short-term outcome in schizophrenic patients, as evidenced by worse global functioning at the 12-month follow-up. These correlations were not observed in the other psychoses group. Our results suggest that young, severely affected schizophrenic patients who experience hopelessness might be at higher risk of poor outcome.

Adolescent↗
PubMed1996

Dynamics of viral variants in HIV-1 Nef and specific cytotoxic T lymphocytes in vivo.

The vigorous CTL response directed against HIV is considered to be important in reducing HIV viral load, although it is unable to stop ongoing viral replication, which generates new antigenic variants. We analyzed the impact of sequential changes in five epitopes of HIV-1 Nef on CTL recognition in four stable patients. A high rate of variation was found, and in all these patients we could detect CTL specific for 32 out of 36 autologous viral variants occurring in 5 HLA-A2- or HLA-B7-restricted Nef epitopes at two time points. Two distinct patterns for dynamics of CTL responses to viral variation were observed: 1) temporary amplification of viral variants followed by expansion of variant-specific CTL, ultimately leading to the disappearance of 12 out of the 14 initial epitope variants within two years. A second set of viral variants that had replaced the initial ones could also stimulate specific CTL precursors in the context of the same or an alternative HLA molecule; and 2) persistence of 2 viral variants in relatively conserved epitopes despite specific CTL recognition. Therefore, a remarkable flexibility of the immune system allows constant adaptation of CTL to multiple HIV variants and thus elimination of HIV variant-producing cells in slow progressors.

Amino Acid Sequence↗
PubMed1996

Synthetic peptides coupled to the lipotripeptide P3CSS induce in vivo B and Thelper cell responses to HIV-1 reverse transcriptase.

To evaluate the ability of the lipotripeptide P3CSS to increase peptide-specific immune responses in vivo, we immunized mice from different inbred strains (BALB/c, C3H/HeJ, C57BL/6) with the 22-mer lipopeptide conjugates P3CSS-[RT-(522-543)] and P3CSS-[RT-(528-549)] of HIV-1 reverse transcriptase (RT) which included an immunodominant Th epitope [i.e. RT-(528-543)] characterized previously. Analysis of T and B cell responses to these lipopeptide conjugates indicated that specific Th responses could be readily induced in vivo. The peptide segments could also efficiently prime mice for secondary recognition of native RT. The use of shorter peptides permitted a delineation of the minimal T cell recognition site of this RT C-terminal region [i.e. RT-(528-540)]. Close to this T cell epitope we identified a B cell determinant containing the motif EQVD [RT-(546-549)] which was recognized in three different strains of mice (H-2b, H-2d and H-2k). A comparison with X-ray analysis of the C-terminal region of HIV-1 reverse transcriptase indicated exposed positions of these Th and B cell epitopes. Both the presence of T and B cell sites and its limited polymorphism make the region RT-(528-549) a promising candidate for vaccine design. The use of the P3CSS adjuvant/carrier principle as a nontoxic adjuvant may be of major importance in the development of vaccines applicable to humans.

Adjuvants, Immunologic↗
PubMed1996

Evolution and plasticity of CTL responses against HIV.

Exceptionally potent cytotoxic T lymphocyte responses are generated after HIV invasion and probably control the primary infection as well as the asymptomatic phase of HIV infection. The chronic phase appears as a quasi-equilibrium between waves of new HIV variants and variant-specific CTLs, thus sustaining continuous CTL activation which eventually fails to eradicate HIV disease progression and the reascension of viral replication. Meanwhile, both the host and the virus develop various strategies either to stop or to evade this potentially deleterious permanent CTL activity. The transient effectiveness of CTLs opens perspectives for understanding disease progression generally as well as for immune therapeutic strategies.

Carrier State↗