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C Hoffmann

Publications and source records attributed to C Hoffmann.

At least 37 records · Page 2Linked to original sources
PubMed2000

COX-2 in brain and spinal cord implications for therapeutic use.

Following the discovery of inducible COX-2 in arthritic joint fluid and immunocompetent cells a revolution in the field of antiinflammatory treatment was expected. The detection of a constitutive COX-2 in the kidney, in stomach and central nervous system destroyed this hypotheses. Further experiments in animal models were done to elucidate the role of the constitutive COX-2 in different physiological and pathophysiological states. In central nervous system was shown that the constitutive COX-2 is the predominant isoform of cyclooxygenases in brain and spinal cord and is highly regulated by different mediators. After experimental induction of peripheral inflammation a significant induction of COX-2 gene, protein expression and synthesis of prostaglandins in the spinal cord was detected. It was concluded that COX-2 is strongly involved in pain mediation processing in the spinal cord. The detection of COX-2 in the brain endothelial cells and its role in fever led to new insights of development and time course of temperature elevation. Probably, the use of selective COX-2 inhibitors decreases fever more effective than classical antipyretics. Furthermore, newer results show a role of COX-2 in differentiation and maturation processes in brain. These findings implicate new ways for the treatment of Alzheimer's disease and other degenerative brain disorders. Clinical and experimental results with selective COX-2 inhibitors show a better safety profile than non-selective COX inhibitors. The clinical use after drug registration will be decide on the further role of this new class of drugs in analgesic/antiinflammatory therapy and on new fields of clinical use.

Animals↗
PubMed1999

[Common effect measures in medical and health economics studies? Results of an exploratory survey of physicians].

BACKGROUND: In economic evaluation studies quality-adjusted life years (QALYs) are often used as measure of effects. QALYs are calculated by weighting survival time with a valuation of health-related quality of life (HRQoL). The results may support clinical decisions for patient groups provided that physicians consider QALYs acceptable and clinically relevant. This study investigates whether physicians accept the various methodological steps of the calculation of QALYs and whether effect measures that result from these steps are useful in clinical studies, too. METHODS: In summer 1998, 41 physicians (21 principal investigators of clinical studies in oncology, 12 surgeons, 8 primary care physicians) completed a questionnaire. RESULTS: 90% of the physicians considered HRQoL a relevant measure of clinical effectiveness but only 54% were familiar with the concept of HRQoL. 80% accepted the creation of an index of HRQoL, 68% accepted the integration of HRQoL and survival time into a single effect measure, but only 44% accepted the multiplicative way of calculating QALYs. According to most physicians, HRQoL should be valued either by study patients or health care professionals rather than general population samples. 92% of the physicians considered identical effect measures in clinical and economic studies necessary or desirable. CONCLUSIONS: QALYs are not generally rejected by the responding physicians. The integration of HRQoL is largely accepted. The multiplicative way of combining survival time and HRQoL values is rejected by many physicians. The findings can be used to define a starting point for the development of common effect measures in medicine and health economics.

Attitude of Health Personnel↗
PubMed1999

The role of amino acids in extracellular loops of the human P2Y1 receptor in surface expression and activation processes.

The P2Y1 receptor is a membrane-bound G protein-coupled receptor stimulated by adenine nucleotides. Using alanine scanning mutagenesis, the role in receptor activation of charged amino acids (Asp, Glu, Lys, and Arg) and cysteines in the extracellular loops (EL) of the human P2Y1 receptor has been investigated. The mutant receptors were expressed in COS-7 cells and measured for stimulation of phospholipase C induced by the potent agonist 2-methylthioadenosine-5'-diphosphate (2-MeSADP). In addition to single point mutations, all receptors carried the hemagglutinin epitope at the N- terminus for detection of cell-surface expression. The C124A and C202A mutations, located near the exofacial end of transmembrane helix 3 and in EL2, respectively, ablated phospholipase C stimulation by </=100 microM 2-MeSADP. Surface enzyme-linked immunosorbent assay detection of both mutant receptors showed <10% expression, suggesting that a critical disulfide bridge between EL2 and the upper part of transmembrane 3, as found in many other G protein-coupled receptors, is required for proper trafficking of the P2Y1 receptor to the cell surface. In contrast, the C42A and C296A mutant receptors (located in the N-terminal domain and EL3) were activated by 2-MeSADP, but the EC50 values were >1000-fold greater than for the wild-type receptor. The double mutant receptor C42A/C296A exhibited no additive shift in the concentration-response curve for 2-MeSADP. These data suggest that Cys42 and Cys296 form another disulfide bridge in the extracellular region, which is critical for activation. Replacement of charged amino acids produced only minor changes in receptor activation, with two remarkable exceptions. The E209A mutant receptor (EL2) exhibited a >1000-fold shift in EC50. However, if Glu209 were substituted with amino acids capable of hydrogen bonding (Asp, Gln, or Arg), the mutant receptors responded like the wild-type receptor. Arg287 in EL3 was impaired similarly to Glu209 when substituted by alanine. Substitution of Arg287 by lysine, another positively charged residue, failed to fully restore wild-type activity.

Amino Acid Sequence↗
PubMed1999

Role of the extracellular loops of G protein-coupled receptors in ligand recognition: a molecular modeling study of the human P2Y1 receptor.

The P2Y1 receptor is a G protein-coupled receptor (GPCR) and is stimulated by extracellular ADP and ATP. Site-directed mutagenesis of the three extracellular loops (ELs) of the human P2Y1 receptor indicates the existence of two essential disulfide bridges (Cys124 in EL1 and Cys202 in EL2; Cys42 in the N-terminal segment and Cys296 in EL3) and several specific ionic and H-bonding interactions (involving Glu209 and Arg287). Through molecular modeling and molecular dynamics simulations, an energetically sound conformational hypothesis for the receptor has been calculated that includes transmembrane (TM) domains (using the electron density map of rhodopsin as a template), extracellular loops, and a truncated N-terminal region. ATP may be docked in the receptor, both within the previously defined TM cleft and within two other regions of the receptor, termed meta-binding sites, defined by the extracellular loops. The first meta-binding site is located outside of the TM bundle, between EL2 and EL3, and the second higher energy site is positioned immediately underneath EL2. Binding at both the principal TM binding site and the lower energy meta-binding sites potentially affects the observed ligand potency. In meta-binding site I, the side chain of Glu209 (EL2) is within hydrogen-bonding distance (2.8 A) of the ribose O3', and Arg287 (EL3) coordinates both alpha- and beta-phosphates of the triphosphate chain, consistent with the insensitivity in potency of the 5'-monophosphate agonist, HT-AMP, to mutation of Arg287 to Lys. Moreover, the selective reduction in potency of 3'NH2-ATP in activating the E209R mutant receptor is consistent with the hypothesis of direct contact between EL2 and nucleotide ligands. Our findings support ATP binding to at least two distinct domains of the P2Y1 receptor, both outside and within the TM core. The two disulfide bridges present in the human P2Y1 receptor play a major role in the structure and stability of the receptor, to constrain the loops within the receptor, specifically stretching the EL2 over the opening of the TM cleft and thus defining the path of access to the binding site.

Amino Acid Sequence↗
PubMed1999

ATP depletion, purine riboside triphosphate accumulation and rat thymocyte death induced by purine riboside.

Purine riboside (purine-1-D-ribofuranoside, nebularine), an adenosine analog, exerts cytotoxic effect both in vivo and in vitro. However, exact biochemical mechanism for its toxicity and sensitivity of lymphoid cells remains unknown. The present experiments have examined the sequential metabolic changes leading to cell death, induced in cultured rat thymocytes during incubation with purine riboside. Among 22 analogs tested, purine-riboside and tubercidin were most toxic as determined by trypan blue exclusion and lactate dehydrogenase leakage from the cells. 2-Chloroadenosine and 2'-deoxyadenosine were only moderately toxic, whereas other analogs tested were without effect on cell viability. In the presence of purine riboside, more than 90% of ATP was lost after 2 h of incubation. Hypoxanthine accumulated in the medium and the formation of purine-riboside triphosphate exceeded 4-fold the physiological concentration of ATP in the cell. Inhibition of adenosine kinase by 5-iodotubercidin reversed the cytotoxic effect of purine riboside. Interestingly, cells virtually deprived of ATP after 2 h of incubation with purine riboside maintained high nucleotide energy charge value and high viability. Purine riboside triphosphate was capable to replace ATP in stimulation of glycolysis in cell-free thymus extract. We conclude that for a short time (a few hours) purine riboside triphosphate formed in the cell may serve in the absence of ATP as an intermediate of cellular energy metabolism in rat thymocytes. However, possibly due to toxic effects of purine-riboside triphosphate, cells were finally dying. Thus, ATP depletion and adenosine kinase mediated purine riboside phosphates formation are the principle causes of rat thymocytes death exposed to purine riboside.

Adenosine↗
PubMed1999

Pelvic Ewing sarcoma: a retrospective analysis of 241 cases.

BACKGROUND: This article reports on 241 patients each with pelvic Ewing sarcoma registered for studies in Germany, Austria, and the Netherlands from January 1, 1981, until January 31, 1994. One hundred sixty-four patients had localized disease and 87 had metastases at diagnosis (PMP). Eighty-four patients with localized disease were entered on protocol (PP) and 80 were followed (FP). METHODS: Statistics included an analysis of event free survival by the Kaplan-Meier method and a Cox regression analysis of factors influencing prognosis. RESULTS: In the Kaplan-Meier analysis, on February 1, 1995, the event free survival (EFS) rate was 32% at 12 years for all patients, 54% for PP, 25% for FP, and 13% for PMP. Cox regression analysis showed that response to chemotherapy, initial metastases, and less intense therapy were significant prognostic factors. Among patients who had surgery for local control, the histologic response to chemotherapy was analyzed in the surgical specimen and had a significant influence on survival: EFS 69% for PP with good response compared with 47% (P = 0.11) for patients with poor response, and for FP 56% versus 13% (P = 0.002). All PP with small tumors had relapse free survival, compared with 69% of patients with medium-sized tumors and 36% of patients with tumors larger than 200 mL (P = 0.006). The initial tumor volume was a significant predictor of survival. CONCLUSIONS: Combined modality treatment has resulted in definitive improvement of prognosis for patients with localized pelvic Ewing sarcoma. However, the results for patients with metastases at diagnosis are still discouraging, and their treatment requires new approaches. Tumor load, responsiveness to chemotherapy, and adequate surgical margins are the major factors influencing the prognosis of patients with localized Ewing sarcoma of the pelvis.

Adolescent↗
PubMed1999

Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study.

BACKGROUND: The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (> or = 100 ml), where ifosfamide was substituted for cyclophosphamide. PROCEDURE: From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Cox's proportional hazard model. RESULTS: The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). CONCLUSIONS: Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.

Adolescent↗
PubMed1999

Adverse reactions after cosmetic lip augmentation with permanent biologically inert implant materials.

Augmentation of lips is a common aesthetic procedure that is mostly performed with alloplastic materials or autologous tissue. Various alloplastic injectable implants have been developed for soft tissue augmentation without surgery. Most biologic materials are resorbed within a few months, fluid silicone may migrate, and autologous fat is not ideal for fine contouring of the lips. The search for a biocompatible, permanent, nontoxic, and biologically inert filler material led to the development of some new materials for subdermal or intradermal implantation. Recently Bioplastique, Artecoll, and Gore-Tex have been well established and recommended by many authors. Although these materials meet most of the characteristics that constitute an ideal injectable prosthetic material, we describe 3 examples of adverse reactions after their implantation into lips.

Adult↗
PubMed1999

Expanded polytetrafluoroethylene threads for lip augmentation induce foreign body granulomatous reaction.

Especially in cases of facial aesthetic surgery, the demands of the patients are high. The formation of a visible and painful nodule will cause not only discomfort but also dissatisfaction. When alloplastic materials are used for facial and lip augmentation, the possibility of migration, allergic reaction, and formation of a foreign body granuloma is always present. Although e-PTFE is the most bioinert alloplastic material available, the authors could show the formation of a foreign body granuloma. When using e-PTFE threads for facial augmentation, the surgeon should keep in mind and inform the patients that the threads can induce a foreign body granulomatous reaction.

Adult↗
PubMed1999

Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationplasty. Functional outcome and quality-of-life measurements.

BACKGROUND: The present study was performed to determine whether there is a difference, with regard to functional outcome and quality of life, between endoprosthetic replacement and rotationplasty for the treatment of malignant tumors of the distal part of the femur or the proximal part of the tibia. METHODS: Sixty-seven patients, between the ages of eleven and twenty-four years at the time of the diagnosis, had a malignant tumor of the distal part of the femur or the proximal part of the tibia. A rotationplasty was performed in thirty-three patients, and an endoprosthetic replacement was done in thirty-four patients. The median duration of follow-up was six years and one month (range, two years to sixteen years and two months). The scale developed by the Musculoskeletal Tumor Society was used to evaluate the functional results. Quality-of-life issues were assessed with the questionnaire developed by the European Organization for Research and Treatment of Cancer. RESULTS: The patients who had had a rotationplasty had a mean functional score, according to the system of the Musculoskeletal Tumor Society, of 24 points, and the patients who had had an endoprosthetic replacement had a mean score of 25 points. This difference was not found to be significant, with the numbers available (p = 0.47). Only one patient who had had a rotationplasty used an assistive device when walking long distances, whereas six patients who had had an endoprosthetic replacement used an assistive device. This difference was significant (p<0.001). The quality-of-life questionnaire revealed that the patients who had had a rotationplasty could participate in hobbies such as carpentry and sports as well as in other daily activities to a significantly greater degree than those who had had an endoprosthetic replacement (p = 0.001). Restriction in daily activities due to pain was significantly less common in the group that had had a rotationplasty than it was in the group that had had an endoprosthetic replacement (p = 0.047). CONCLUSIONS: Rotationplasty was not associated with any disadvantages with regard to function or quality of life in comparison with endoprosthetic replacement. It is possible that the psychosocial outcome is influenced by the fact that patients who have a rotationplasty know that additional operative intervention is not usually necessary. Despite good functional and quality-of-life results, the cosmetic appearance may be the most serious disadvantage of rotationplasty. The decision to perform this procedure must be made on a case-by-case basis.

Adolescent↗
PubMed1999

Parallel Synthesis and Testing of Catalysts under Nearly Conventional Testing Conditions.

Acceleration by one to two orders of magnitude for catalyst development without much loss of information: Parallelized synthesis and screening has been used to evaluate catalysts for the room-temperature oxidation of CO. The overall process was highly reproducible, and the data quality is comparable to that of conventional testing. The graph shows the results of parallel testing of Au/Co(3)O(4) catalyts at 25 degrees C (y=yield of CO(2)).

Journal Article↗
PubMed1998

Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy.

OBJECTIVE: To evaluate the impact of different antiretroviral therapies on the prognosis of AIDS patients affected by progressive multifocal leukoencephalopathy (PML). METHODS: A retrospective analysis of all HIV-infected patients admitted to hospital between 1988 and 1996 found 29 patients (25 men) with histologically or PCR-confirmed PML. Their mean age was 39.3 years. The median CD4 cell count was 40 x 10(6)/l (mean, 106 x 10(6)/l). Six patients had CD4 cell counts > 200 x 10(6)/l. Fourteen patients never received or stopped antiretroviral therapy following diagnosis (group A), 10 patients were treated with nucleoside analogues alone (group B), and five patients started highly active antiretroviral therapy (HAART) including protease inhibitors (group C). RESULTS: The median survival following the onset of symptoms was 131 days, but differed significantly between the three groups: group A, 127 days; group B, 123 days; group C, > 500 days (P < 0.0002 for the difference between group C versus group A and B, stratified log-rank test). As of July 1997, four out of five patients on HAART were still alive 391, 500, 543, and 589 days after diagnosis of PML and have either experienced a resolution of the symptoms (three patients) or had progressed very slowly (one patient). A multivariate analysis using Cox regression found younger age at diagnosis to be the only other variable associated with improved survival (P < 0.02). CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, or interferon-alpha did not affect survival in this cohort (P > 0.1). CONCLUSION: This study of a large cohort of patients with confirmed PML indicates that AIDS patients with PML may benefit significantly from HAART. All patients with PML should be offered optimal antiretroviral combination therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Chromosome structure and human immunodeficiency virus type 1 cDNA integration: centromeric alphoid repeats are a disfavored target.

Integration of retroviral cDNA into host chromosomal DNA is an essential and distinctive step in viral replication. Despite considerable study, the host determinants of sites for integration have not been fully clarified. To investigate integration site selection in vivo, we used two approaches. (i) We have analyzed the host sequences flanking 61 human immunodeficiency virus type 1 (HIV-1) integration sites made by experimental infection and compared them to a library of 104 control sequences. (ii) We have also analyzed HIV-1 integration frequencies near several human repeated-sequence DNA families, using a repeat-specific PCR-based assay. At odds with previous reports from smaller-scale studies, we found no strong biases either for or against integration near repetitive sequences such as Alu or LINE-1 elements. We also did not find a clear bias for integration in transcription units as proposed previously, although transcription units were found somewhat more frequently near integration sites than near controls. However, we did find that centromeric alphoid repeats were selectively absent at integration sites. The repeat-specific PCR-based assay also indicated that alphoid repeats were disfavored for integration in vivo but not as naked DNA in vitro. Evidently the distinctive DNA organization at centromeres disfavors cDNA integration. We also found a weak consensus sequence for host DNA at integration sites, and assays of integration in vitro indicated that this sequence is favored as naked DNA, revealing in addition an influence of target primary sequence.

Binding Sites↗
PubMed1998

Relative bioavailability of rapidly dispersing, plain, and microencapsuled acetylsalicylic acid tablets after single dose administration.

UNLABELLED: Extent and rate of absorption of acetylsalicylic acid (ASA) from rapidly dispersing (Acesal Extra) and plain tablets (Acesal) relative to reference 1 (plain tablets, Aspirin) and from microcapsuled tablets (Micristin) relative to comparable listed tablets (reference 2, Colfarit) were assessed in 2 single-dose (0.5 g ASA), open, randomized, crossover studies with intervals of 14 days between 2 periods. Both studies were performed in 24 male and female healthy volunteers each (age 18-32 years, body weight 48-90 kg, body height 161-190 cm). ASA and its metabolite salicylic acid (SA) were measured with an HPLC method validated for ASA between 0.2 and 20 microg/ml and for SA between 0.4 and 40 microg/ml. The test tablets were considered bioequivalent with reference in extent of absorption if the 90% confidence limits of the AUC0 to infinity ratio were within the range of 0.80-1.25, and in rate of absorption if the confidence limits of the Cmax/AUC0 to infinity ratios were within 0.70-1.43. RESULTS: Geometric means and 90% confidence limits for the test/reference ratios of the comparisons Acesal vs reference 1, Acesal Extra vs reference 1 and Micristin vs reference 2 were 1.05 (0.97-1.13), 1.13 (1.05-1.22), 1.02 (0.92-1.14) for ASA AUC0 to infinity and 1.02 (0.96-1.07), 1.05 (0.99-1.11), 0.98 (0.91-1.04) for SA AUC0 to infinity, respectively. The results for Cmax/AUC of ASA were 1.16 (1.00-1.34), 1.72 (1.49-1.99), 0.83 (0.73-0.94) and of SA 1.02 (0.98-1.07), 1.07 (1.02-1.12), 0.93 (0.88-0.97). CONCLUSION: Acesal and Micristin were bioequivalent with the respective references in both extent and rate of absorption. Acesal Extra and reference 1 were bioequivalent with regard to extent only. Acesal Extra was absorbed faster.

Adult↗
PubMed1998

[Inverted Y partial ureteral duplication. Apropos of an unusual case].

Inverted Y partial ureteric duplication corresponds to the presence of a variable length of duplicated ureter before entering the bladder in an orthotopic or ectopic position. A case od inverted Y partial ureteric duplication with ureteric confluence in the hilum of the kidney associated with anastomosis of an ectopic ureter in the epididymis is reported. The description of this original case is compared with the data of the literature.

Adult↗
PubMed1998

[Laparoscopic cholecystectomy as routine intervention in acute cholecystitis].

The laparoscopic cholecystectomy has become the gold standard in the therapy of gall bladder stones in the last few years. The most contraindications of the first period of the laparoscopic era had been eliminated by the development of laparoscopic technique and growing experience. Since September 1995 the laparoscopic cholecystectomy has been established as routine procedure also for acute cholecystitis. From September 1995 to Dezember 1996 177 laparoscopic cholecystectomies were performed, 132 for symptomatic cholecystolithiasis and 45 for acute cholecystitis. Postoperative complications occurred in 8.3% in the elective group and in 8.8% in the acute cholecystitis group. There was no death in both groups. Patients left the hospital on day 3 (range 2-21) in the elective group, on day 4 (1-13) in the acute colecystitis group. There are no statistically significant differences. According to our results acute cholecystitis does not increase postoperative morbidity and mortality after laparoscopic cholecystectomy and has to be a contraindication for this method no longer.

Acute Disease↗