Calgranulin C is overexpressed in lesional psoriasis.
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Humans↗
Biomedical subjects
G Michel
Publications and source records attributed to G Michel.
A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and its consensus DNA sequence.
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor activated by hypoxia. When activated, HIF-1 mediates the differential expression of genes such as erythropoietin and Vascular Endothelial Growth Factor (VEGF) during hypoxia. It is composed of two different subunits, HIF-1alpha and ARNT (Aryl Receptor Nuclear Translocator). These two subunits belong to the bHLH (basic Helix-Loop-Helix) PAS (Per, Ahr/ARNT, Sim) family. The bHLH domain of these factors is responsible for dimerization through the two helices and for DNA binding through their basic domain. In this work, we used various methods of molecular modeling in order to develop a 3D structure for the HIF-1 bHLH domain bound to its DNA consensus sequence. Firstly, the 3D structure of the bHLH domain of both subunits based on their amino acid sequence was defined. Secondly, we compared this model with data from known crystal structures of basic leucine zipper-DNA and bHLH-DNA complexes in order to determine a potential canvas for HIF-1. Thirdly, we performed a manual approach of the HIF-1 bHLH domain onto the DNA recognition site using this canvas. Finally, the protein-DNA complex 3D structure was optimized using a Monte Carlo program called MONTY. The model predicted a pattern of interactions between amino acids and DNA bases which reflect for ARNT what is experimentally observed among different X-ray structures of other bHLH transcription factors possessing the H (His), E (Glu), R (Arg) triad, as ARNT does. On the other hand, only the Arg residue is conserved in HIF- 1alpha. We propose from this model that a serine replaces the histidine while an alanine and a lysine also make contacts with DNA. From these results, we postulate that the specificity of HIF-1 toward its DNA sequence could be driven by the HIF-1alpha subunit. The predicted model will be verified by X-Ray currently ongoing.
Alanine↗
Relationship between efficacy, tolerance, and plasma drug concentration of ritonavir in children with advanced HIV infection.
The relationship between ritonavir plasma concentration, efficacy, and tolerance was evaluated in 31 children with advanced HIV infection who were receiving a triple therapy with ritonavir as protease inhibitor. Median CD4+ lymphocyte count and median viral load before the initiation of ritonavir-containing combination therapy were 1320 cells/mL and 5 log10 copies/mL, respectively. Ritonavir was given at a dose ranging from 300 to 450 mg/m2 twice daily. The median follow-up of triple therapy was 19 months. Response was defined as a drop of viremia of more than 1 log. Plasma drug levels were determined twice during the observation period: after at least 4 weeks and after 3 months of combined treatment. Samples were collected before (residual) and 2 hours (T2) after drug intake. Cholesterol, triglycerides, alanine transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase were assessed at the same time. The median values of ritonavir residual and T2 levels were 1.64 mg/L and 5.9 mg/L at observation 1 and 3.35 mg/L and 6.29 mg/L at observation 2, respectively. According to virologic response, median residual concentrations of ritonavir were 3.17, 2.52, and 1.04 mg/L for the complete, the partial, and the no-response groups. The authors observed a wide intersubject variability of ritonavir concentrations with an increase in residual levels between the two observation periods. Residual levels were correlated with virologic response whereas there was no direct association between T2 levels and long-term response. Patients with complete or partial response displayed statistically significantly higher residual concentrations than the no-response group. No correlation could be demonstrated between elevated plasma drug concentrations and abnormal cholesterol or triglycerides values. These results emphasize the importance of a sustained high ritonavir concentration to achieve optimal treatment efficacy. Furthermore, these results prove the clinical benefit of therapeutic drug monitoring and could potentially improve patient evaluation in terms of treatment efficacy, compliance, and viral resistance.
Adolescent↗
Expression, purification, crystallization and preliminary X-ray analysis of the iota-carrageenase from Alteromonas fortis.
This is the first crystallization report of a glycoside hydrolase which belongs to family 82. A recombinant form of His-tagged iota-carrageenase from Alteromonas fortis was expressed, purified and crystallized. Crystals were obtained by the vapour-diffusion method using polyethylene glycol (M(W) = 6000) as a precipitant. They belong to space group P2(1), with unit-cell parameters a = 56. 75, b = 91.04, c = 125.01 A, beta = 93.41 degrees. The unit cell contains two molecules in the asymmetric unit related by a non-crystallographic twofold axis. Crystals diffracted to 2.0 A resolution on a synchrotron beamline.
Alteromonas↗
Alteration of the lipopolysaccharide structure affects the functioning of the Xcp secretory system in Pseudomonas aeruginosa.
Pseudomonas aeruginosa secretes a wide range of hydrolytic enzymes into the external medium by the Xcp secretion machinery. To better understand the role played by envelope constituents in the functioning of this type II secretory system, we have studied the influence of lipopolysaccharide (LPS) on the secretion of two extracellular enzymes, the elastase LasB and the lipase LipA. Strains with defective LPS decreased production of LasB and altered the secretion processes of both LasB and LipA without any apparent effect on the composition of the Xcp machinery. The PAO1algC strain, defective in the outer core of LPS, was leaky, as shown by the extracellular release of the periplasmic beta-lactamase. Generation of an xcpR mutation in this mutant led only to a partial accumulation of LasB within the cells, indicating that in strain PAO1algC with a functional xcpR gene, LasB was released in the extracellular medium partly by leakage and partly by secretion. The pool of LasB released into the medium by leakage was not recovered in an active form, while extracellular LasB was active when secreted via the secretory machinery. Further analysis revealed that the presence of a functional Xcp machinery is strictly required for the activation process of LasB. Our results provide evidence that the Xcp system is not fully functional when the LPS structure of P. aeruginosa is altered.
Aspartic Acid Endopeptidases↗
Cefadroxil in hyperimmunoglobulin E syndrome.
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Bronchiectasis↗
Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia.
PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.
Adolescent↗
Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review).
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor first identified as being activated by hypoxia but also in normoxic conditions by insulin and IGF-2. It is able to induce the expression of glycolytic genes and hence the ATP production, it also regulates the expression of the angiogenic factor VEGF and stimulates erythropoiesis via EPO production. HIF-1 is a protein necessary for the normal embryonic and cardiovascular system development, but seems to be also involved in cancer progression and apoptosis. Thus, it appears that HIF-1 plays a central role in normal cellular functions and in tissue metabolism but it is also involved in pathological evolutions raising its interest as a therapeutic target. In this review, we summarize the dual role of HIF-1 as a major component of the embryo development, as well as an element of tumor progression and of anoxia-induced apoptosis.
Animals↗
[Concerning the article "the need for examination as seen by the radiologist, the report as seen by the clinician"].
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Humans↗
The quantitative measurement of autoantibodies to thyroglobulin and thyroid peroxidase by automated microparticle based immunoassays in Hashimoto's disease, Graves' disease and a follow-up study on postpartum thyroid disease.
The aim of this study was to investigate the association between various autoimmune thyroid diseases and the presence of anti-TPO and anti-Tg antibodies using two novel automated microparticle based immunoassays developed for the AxSYM analyzer. Serum samples from 65 individuals with Hashimoto's Disease, 38 with Graves' Disease and 80 UK blood donors were assayed. In addition, samples were taken from 50 women known to be positive for TPO antibodies, for up to 24 weeks following delivery. Precision for both assays ranges from 5.7-9.1% CV, while analytical sensitivity was determined to be 1.0 IU/ml for Anti-Tg and 0.3 IU/ml for Anti-TPO. The Anti-TPO test showed positive results in 86% of Hashimoto's Disease and 87% of Graves' Disease. The figures obtained for Anti-Tg were 58% and 73% respectively. Specificity was 94% with Anti-TPO and 99% with Anti-Tg. The postpartum women were divided into 2 groups, group A remained symptomless while group B developed thyroid dysfunction. Within the 2 groups, medians calculated at each time point were compared between and within groups using the Mann-Whitney Rank Sum Test or the Kruskal-Wallis One Way ANOVA on Ranks. Anti-TPO baseline levels (week 6) were statistically different between both groups (median 36 vs. 167 IU/ml, p = 0.002). In group A, the median values increased from 36 to 87 IU/ml within the observation period, although the difference was not statistically significant. In group B, antibody titres showed a statistically significant increase from 168 IU/ml (week 6) up to 676 IU/ml after 20 weeks (p < 0.001). Anti-Tg baseline levels were not statistically different between the two groups. In group A, the median values did not change significantly over time (range: 47-86 IU/ml) whereas antibody titres in group B showed a statistically significant increase from 79 IU/ml (week 6) to 276 IU/ml after 24 weeks (p = 0.002). Results obtained indicate that these assays provide useful tools for the quantitative determination of autoantibodies in both primary diagnosis as shown with the Hashimoto's disease and Graves' disease samples and patient follow-up as demonstrated with the postpartum samples. The automation and high precision of the assays make them perfectly suited to routine diagnostic use.
Autoanalysis↗
[Hepatitis C virus and chronic hepatopathies in Dakar: case-control study].
In Black Africa, the role of hepatitis C virus (HCV) in the onset of chronic hepatic disease is unclear. This is particularly true in Senegal where the prevalence of HCV is moderate. To gain insight into this question, a case-control study including 73 patients and 73 controls was carried out at Principal Hospital in Dakar in 1995. The patients included in this study presented chronic hepatitis in 2 cases cirrhosis in 25 and hepatocellular carcinoma in 46. Patients and controls underwent serologic testing for HCV (ELISA screening test followed by 3rd generation ELISA test in case of positive results and confirmation by immunoblot) with determination of HCV serotype using the immunoenzymatic method. Testing also included research for infection by hepatitis B virus and for anti-delta antibodies. Anti-HCV antibodies were detected in two patients (3 p. 100) and serology was suspicious in two others. Serotype 2 was detected in one of these patients. No positive results were recorded in controls. Fifty-four patients (74 p. 100) and 15 controls (21 p. 100) presented the HBs antigen including 13 patients (24 p. 100) and I control (7 p. 100) with anti-delta antibodies. This study shows that HCV currently plays a minor role in the onset of hepatic disease in hospitalized patients in Senegal. It also confirms the predominant role of hepatitis B and complicating effect of the delta hepatitis virus. These findings are compared with reported data for Black African countries. The impact of HCV appears to be lower in Senegal than in central Africa.
Adult↗
[Criteria for the appointment for a full professorship in the course of history at the School of Veterinary Medicine of Dresden/Leipzig].
First the history of the appointment for a full professorship is described in the various stages of development of the School of Veterinary Medicine Dresden. Then the significance of the habilitation degree introduced in 1903 is discussed in terms of the development of the School of Veterinary Medicine Dresden and the Faculty of Veterinary Medicine of the University of Leipzig, respectively. Commentary follows on the current discussion about the discontinuation of further development of the habilitation and possible alternatives to it, the Ph.D. and the assistant professorship.
Faculty↗
Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction.
The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear translocator (ARNT)-Sim (PAS) factors Sim and aryl hydrocarbon receptor (Ahr). The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), involved in the response to hypoxia, also belongs to the bHLH-PAS family. This work was aimed to investigate the putative role of Hsp90 in HIF-1 activation by hypoxia. Using a EGFP-HIF-1alpha fusion protein, co-immunoprecipitation experiments evidenced that the chimeric protein expressed in COS-7 cells interacts with Hsp90 in normoxia but not in hypoxia. We also demonstrated that Hsp90 interacts with the bHLH-PAS domain of HIF-1alpha. Moreover, Hsp90 is not co-translocated with HIF-1alpha into the nucleus. At last, we showed that Hsp90 activity is essential for HIF-1 activation in hypoxia since it is inhibited in the presence of geldanamycin. These results indicate that Hsp90 is a major regulator in HIF-1alpha activation.
Animals↗
Cloning and characterization of hurpin (protease inhibitor 13): A new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family.
Epidermal keratinocytes are the primary target of the midrange ultraviolet part (UVB, 280-320 nm) of terrestrial sunlight. Analysis of the resulting UV response at the transcriptional level by differential display PCR identified a formerly unrecognized large group of repressed genes. Among those UV-repressible genes, a novel serine proteinase inhibitor (serpin) termed hurpin (HaCaT UV-repressible serpin) has been identified. The isolated full-length cDNAs harbour a 1176 bp open reading frame encoding a potential protein with 391 amino acid residues and a predicted molecular mass of approximately 44 kDa. The novel serpin has nearly 59 % amino acid identity with the squamous cell carcinoma antigen 1 (SCCA1) and squamous cell carcinoma antigen 2 (SCCA2). In addition, it displays all of the structural features unique to the ovalbumin family of serpins (ov-serpins). The amino acid sequence of the hinge region in the reactive site loop suggests that hurpin has the potential for protease inhibition. The putative reactive center P1-P1'residues were identified as Thr356-Ser357 by alignment with other ov-serpins. The physiological target protease is unknown and the in vitro translated hurpin does not form SDS-stable complexes with a variety of known serine proteases. Expression of hurpin is restricted to epidermal cells where two distinct transcripts of 3.0 and 3.4 kb are detectable. Furthermore, expression of hurpin appears to be related to the activation or proliferation state of keratinocytes, since hurpin transcripts are more abundant in immortalized keratinocytes (HaCaT) and in cultured normal human keratinocytes, compared to the expression in normal skin. Moreover, in psoriasis, a skin disease characterized by hyperproliferation of keratinocytes and responsive to therapeutic UV irradiation, overexpression of hurpin is noted in psoriatic skin lesions compared to non-lesional skin.
Amino Acid Sequence↗
HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5'UTR.
Hypoxia inducible factor-1 (HIF-1) is a transcription factor composed of two subunits, HIF-1alpha and ARNT, which is activated under hypoxia. HIF-1alpha mRNA is expressed constitutively in a wide variety of cell types, whereas in some others HIF1A gene expression is upregulated by hypoxia. In this report, we show that in endothelial cells (HMEC-1) the HIF-1alpha mRNA expression level is the same in both normoxia and hypoxia. Deletion analysis experiments of the HIF1A promoter showed that in hypoxia HIF1A gene expression is upregulated through a short sequence located next to the transcription initiation site. We also show that in hypoxia another sequence located upstream from the +1 initiation site plays an inhibitory role on HIF1A transcription in HMEC-1 but not in hepatoma cells and brings back this expression level to that observed in normoxia. Finally, we demonstrate that HIF1A gene transcription is dependent on Sp1 binding sites and that the 5'UTR sequence also contains other important cis-acting elements.
5' Untranslated Regions↗
Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord-Cord Blood Transplant Group.
We have analyzed factors influencing the outcome of 102 children with acute leukemia given a cord blood transplantation (CBT) and reported to the Eurocord Registry. Seventy patients with acute lymphoblastic and 32 with acute myeloid leukemia were given either a related (n = 42) or an unrelated (n = 60) CBT. Children given CBT during first or second complete remission were considered as belonging to the good-risk group (n = 66), whereas those who received a transplant in a more advanced stage of disease were assigned to the poor-risk group (n = 36). In the related group (RCBT), 12 of 42 patients received transplantation from an HLA-disparate donor, whereas in the unrelated group (UCBT) 54 of 60 received an HLA mismatched CBT. Kaplan-Meier estimates for neutrophil recovery at day 60 were 84% +/- 7% in RCBT and 79 +/- 6% in UCBT (P =.16). In multivariate analysis, the most important factor influencing neutrophil engraftment in UCBT was a nucleated cell dose infused greater than 3.7 x 10(7)/kg (P =.05, relative risk [RR] of 1.85, 95% confidence interval [CI]: 0.98-3.4). The incidence of grade II through IV acute graft-versus-host disease was 41% +/- 8% in the RCBT group and 37% +/- 6% in the UCBT group (P =.59). Kaplan-Meier estimates of 2-year event-free survival (EFS) after RCBT or UCBT were 39% +/- 8% and 30% +/- 7%, respectively (P =.19). In multivariate analysis, the most important factor influencing EFS was disease status at time of transplantation: good-risk patients had a 2-year EFS of 49% +/- 7% as compared to 8% +/- 5% in patients with more advanced disease (P =.0003, RR: 0.40, 95% CI: 0.24 to 0. 65). This was a consequence of both an increased 1-year transplant related mortality and a higher 2-year relapse rate in the poor-risk group (65% +/- 9% and 77% +/- 14%, respectively), as compared with good risk patients (34% +/- 6% and 31% +/- 9%, respectively). These data confirm that allogeneic CBT from either a related or an unrelated donor is a feasible procedure able to cure a significant proportion of children with acute leukemia, especially if transplanted in a favorable phase of disease.
Acute Disease↗
Combination antiretroviral therapy including ritonavir in children infected with human immunodeficiency.
OBJECTIVE: To assess the efficacy of combination therapy that includes ritonavir in HIV-1 infected children. DESIGN: A monocentric retrospective study. PATIENTS AND METHODS: Twenty-two children with a minimum follow-up of 6 months under triple therapy including ritonavir were analysed for treatment efficacy. At entry, all the patients were protease inhibitor naive and all but two had received previous antiretroviral therapy during a median period of 5 years. Their initial median CD4+ lymphocyte count and viral load were 121 x 10(6)/l and 5.08 log10 copies/ml, respectively. Clinical and biological evaluation included clinical assessment every 6 weeks and determination of CD4 cell count and HIV-RNA concentration every 3 months. RESULTS: Median length of follow-up on triple therapy was 15 months (range: 7-21 months). Neither progression in the CDC classification nor death occurred. No significant change in mean weight SD scores was noted when baseline values were compared with values obtained after 1 year of triple therapy. Median CD4 count increases were of 210 x 10(6)/l, 415 x 10(6)/l, and 472 x 10(6)/l cells at 6, 12, and 18 months, respectively. Among the patients baseline characteristics, neither age nor initial CD4 cells count influenced the magnitude of immunologic improvement. There were median decreases of 1.14, 0.95, and 1.5 log10 per ml of plasma in the concentration of viral RNA at 6, 12, and 18 months respectively. Seven patients maintained an undetectable viral load when under treatment. The introduction of at least one new reverse transcriptase inhibitor at the initiation of triple therapy correlated significantly with a greater viral suppression. CONCLUSION: Despite variable viral response, antiretroviral-experienced HIV-infected children demonstrated a substantial CD4 cell increase during a median period of 15 months of ritonavir containing combination therapy.
Adolescent↗
Prediction of successful outcome in a randomised controlled trial of the long-term efficacy of interferon alpha treatment for chronic hepatitis C.
To evaluate the efficacy of a 12-month course of recombinant interferon alpha (IFN-alpha2b), and to assess predictive factors of successful response to IFN therapy in chronic active hepatitis C (HCV CAH), 242 patients with histologically proven HCV CAH were assigned randomly to two groups, one treated with IFN-alpha2b (3 MU three times weekly, intramuscularly), the other untreated. To determine the efficacy of IFN-alpha2b 12 months after therapy, a second liver biopsy was carried out on 100 treated patients and 27 untreated patients. The biochemical, virological, and serological response of patients followed up for at least 50 months after treatment was also evaluated to confirm the efficacy of IFN-alpha2b. The genotypes of infecting HCV, anti-HCV core IgM, and HCV-RNA concentrations were also analysed and the predictors of response determined by univariate and multivariate analyses. Response was defined in terms of the normalisation of aminotransferase activities and the disappearance of HCV-RNA. The overall long-term response was 39.4%. Anti-HCV core IgM levels were significantly lower in long-term responders. Patients with increased levels of IgM anti HCV core (>3.8 sample/cut-off), infected with genotype 1b were nonresponders. Liver histology improved significantly in patients with long-term response. Multivariate analysis identified three independent predictors of the likelihood of long-term response to IFN therapy: age younger than 40 years, basal anti-HCV core IgM levels < or = 3.8, and genotypes other than 1b. These data indicate that the treatment with IFN-alpha2b used in this randomised controlled trial is effective in HCV CAH. Anti-HCV core IgM was the strongest predictor of long-term response in the present study.
Alanine Transaminase↗