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Biomedical subjects

M Hensel

Publications and source records attributed to M Hensel.

At least 37 records · Page 2Linked to original sources
PubMed2002

Quality of life and rehabilitation in social and professional life after autologous stem cell transplantation.

BACKGROUND: In this study, we report on quality of life (QOL) in long-term survivors after high-dose chemotherapy and autologous stem cell transplantation (ASCT) with special emphasis on rehabilitation in social and professional life. PATIENTS AND METHODS: The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaire was sent by mail to 391 patients 1 to 12 years (median 31 months) after ASCT. The procedure was performed at our institution alone. Of the questionnaires 78% were returned and evaluated. RESULTS: Of the 238 patients who had an occupation and were employed, 132 (55%) have returned full time (68%) or part time (32%) to their previous occupation. A total of 139 patients (46%) received a 3- to 4-week inpatient rehabilitation treatment in specialised institutions following ASCT. Employment status post-transplantation and QOL were similar in these patients as compared with those who did not participate in rehabilitation programmes. Of the 304 evaluable patients, 39% reported physical problems that reduced their satisfaction with sex and intimacy. The general QOL was significantly reduced in the first year, improved with interval to transplant, and reached the level of the general population after 4 years. CONCLUSIONS: Our retrospective data showed that ASCT has a significant, unfavourable impact on QOL, including reintegration into social and professional life. Most symptoms and scores returned to normal after 3 to 6 years. Employment status and QOL were similar in patients who participated in a rehabilitation programme and those who did not.

Adolescent↗
PubMed2002

Characteristics associated with long-term progression-free survival following high-dose chemotherapy in metastatic breast cancer and influence of chemotherapy dose.

BACKGROUND: The purpose of this study was to characterize long-term progression-free survivors (LTPFS) of metastatic breast cancer (MBC) following high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) and to assess the influence of chemotherapy dose in order to identify patients who derive major benefit from this approach. PATIENTS AND METHODS: We compared patient and tumor characteristics of 16 LTPFS with the characteristics of 118 MBC patients who received HDCT with ASCT at our institution between 1992 and 2000. To estimate the cumulative dose of chemotherapy received, the summation dose intensity product (SDIP) of the different chemotherapy regimens was calculated as recently described by Hryniuk et al. The SDIP of the induction regimens was added to that of the HDCT regimens to yield the total SDIP of the chemotherapy received. Multivariate analysis was performed to describe the influence of the total SDIP and other prognostic factors on progression-free survival (PFS). RESULTS: LTPFS were mostly < or = 50 years of age and had limited, chemotherapy-sensitive, hormone-responsive MBC. Due to an apparent dose-survival relationship, an increase by 10 units (U) in the SDIP increased the PFS time by 3 months. Independent predictors of an improved PFS were positive estrogen receptors (P = 0.001), positive combined hormone receptors (P = 0.020), and a complete remission/no evidence of disease status after HDCT (P < 0.001). In patients who had a disease-free interval (DFI) >24 months after primary surgery, an SDIP of >55 U was independently associated with a longer PFS [hazard ratio (HR) = 2.73; 95% confidence interval 1.29-5.81; P = 0.009]. CONCLUSION: HDCT can achieve long-term PFS in young MBC patients with limited, hormone-responsive and chemotherapy-sensitive disease. After a DFI >24 months, a longer PFS is associated with a higher chemotherapy dose as measured by SDIP. These retrospective analyses suggest SDIP might be a tool for studying cumulative dose as a determinant of outcome of MBC chemotherapy. Thus far, however, we cannot clearly identify any subgroup of MBC patients in whom HDCT with ASCT is of particular benefit.

Adult↗
PubMed2002

Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia.

We studied in 30 patients with progressive or relapsing chronic lymphocytic leukemia (CLL) if hematopoietic stem cell transplantation (HSCT) after conditioning with fludarabine, busulfan and ATG is effective and if treatment related mortality can be reduced compared to myeloablative conditioning regimens. Patients had 15 matched related and 15 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine alone or a combination with "short course" methotrexate or mycophenolate mofetil. The median follow-up is 24 months. At last follow up 11 patients were in complete and 13 in partial remission. Six patients had stable or progressive disease. Late complete remissions occurred up to one year after transplantation and the number of patients with CR is still increasing. Four patients died due to treatment related complications resulting in a probability of treatment-related mortality of 15% (CI 95%, 1% to 29%) at 2 years. The probability of overall survival and progression free survival at two years was 79% and 61%, respectively. In conclusion, HSCT after reduced conditioning may lower the treatment-related toxicity and has the capacity to induce complete remissions.

Busulfan↗
PubMed2001

Infectious complications in chronic lymphoid malignancy.

Taking steps to minimize, prevent, and treat infection in patients with chronic lymphoid malignancies, especially chronic lymphocytic leukemia, has always been a challenge. As more patients with these diseases live longer and lead productive lives upon successful initial treatment, strategies for preventing infections have become more important. Distinguishing patients at low risk for infection from those at high risk is a crucial but challenging issue. Unfortunately, there are hardly any data on the use of prophylactic antibiotics for patients with chronic lymphoid malignancy (CLL). If patients cannot be enrolled in a clinical trial, antibiotics with co-trimoxazole should be administered when steroids are warranted. They should also be administered in patients who have had a documented infection early in the treatment course and during neutropenia. Viral infections remain another controversial issue in patients with CLL receiving treatment, especially a purine analogue. Very low CD4 counts (less than 50 cells/mL) might predict for reactivation for herpes zoster. Outside of depleted CD4 counts, there are no other means of identifying a high-risk group. Based on limited data, it would be reasonable to administer herpes zoster prophylaxis to patients with CD4 counts that are severely depleted or to patients with a prior episode of zoster. Controversial issues still remain regarding immunoglobulin treatment, specifically cost, scarcity of the product, and adequate dose, which has not yet been established. We would consider intravenous immunoglobulin (Ig) replacement in patients with marked hypogammaglobulinemia (IgG less than 400 mg/dL) with more than two recent severe infections [1]. Lower Ig doses (240 mg/kg) have been shown to be equivalent to higher ones in this trial [1].

Anti-Infective Agents↗
PubMed2001

Salmonella pathogenicity islands encoding type III secretion systems.

Salmonella enterica harbours two Salmonella pathogenicity islands (SPIs) each encoding a type III secretion system for virulence proteins. SPI1 is required for invasion, while systemic infections and intracellular accumulation of Salmonella are dependent on SPI2 function. This review will describe and compare the genetic organisation, evolution, regulation and molecular functions of SPI1 and SPI2.

Animals↗
PubMed2001

SseBCD proteins are secreted by the type III secretion system of Salmonella pathogenicity island 2 and function as a translocon.

The type III secretion system encoded by Salmonella pathogenicity island 2 (SPI2) is required for systemic infections and intracellular accumulation of Salmonella enterica. This system is induced by intracellular Salmonella and subsequently transfers effector proteins into the host cell. Growth conditions either inducing expression of the type III secretion system or the secretion of substrate proteins were defined. Here we report the identification of a set of substrate proteins consisting of SseB, SseC, and SseD that are secreted by the SPI2 system in vitro. Secretion was observed if bacterial cells were exposed to acidic pH after growth in minimal medium with limitation of Mg(2+) or phosphate. SseB, -C, and -D were isolated in a fraction detached from the bacterial cell surface by mechanical shearing, indicating that these proteins are predominantly assembled into complexes on the bacterial cell surface. The three proteins were required for the translocation of SPI2 effector proteins SspH1 and SspH2 into infected host cells. Thus, SseB, SseC, and SseD function as the translocon for effector proteins by intracellular Salmonella.

Animals↗
PubMed2001

Comparison of double and triple high-dose chemotherapy with autologous blood stem cell transplantation in patients with metastatic breast cancer.

In patients with metastatic breast cancer (MBC), early dose intensification with multiple cycles of peripheral blood stem cell-supported high-dose chemotherapy (HDCT) seems superior to a late dose-intensification strategy. We compared the progression-free survival (PFS) and overall survival (OS) of 20 patients treated with a double (D)-HDCT regimen to 20 patients who received a triple (T)-HDCT, matched by age, estrogen receptor (ER) status, adjuvant chemotherapy, initial disease-free interval, predominant metastatic site, and number of metastatic sites. At a median follow-up of 41.5 months (range, 14-88 months) an intent-to-treat analysis showed no difference in PFS (p = 0.72) and OS (p = 0.93) between the matched patients. For all 76 patients treated within the D- or T-HDCT trial, median PFS and OS was 13 months (range, 2-78 months) and 24.5 months (range, 7-78 months), respectively. In multivariate analysis independent predictors of shorter OS included negative ER (relative risk [RR] = 3.0 [95% confidence interval (CI) 1.5-5.9]; p = 0.002), more than two metastatic sites (RR = 2.4 [95% CI 1.0-5.7]; p = 0.049) and failure to achieve complete remission/no evidence of disease (CR/NED) after HDCT (RR = 4.5 [95% CI 2.0-10.1]; p < 0.0001). These data show that early dose intensification with T-HDCT is not superior to a D-HDCT regimen in patients with MBC. ER-negative tumors, more than two metastatic sites and no CR/NED after HDCT, are associated with inferior outcome.

Adult↗
PubMed2000

Detection and substrate selectivity of new microbial D-amino acid oxidases.

In order to screen for new microbial D-amino acid oxidase activities a selective and sensitive peroxidase/o-dianisidine assay, detecting the formation of hydrogen peroxide was developed. Catalase, which coexists with oxidases in the peroxisomes or the microsomes and, which competes with peroxidase for hydrogen peroxide, was completely inhibited by o-dianisidine up to a catalase activity of 500 nkat ml(-)(1). Thus, using the peroxidase/o-dianisidine assay and employing crude extracts of microorganisms in a microplate reader, a detection sensitivity for oxidase activity of 0.6 nkat ml(-)(1) was obtained.Wild type colonies which were grown on a selective medium containing D-alanine as carbon, energy and nitrogen source were examined for D-amino acid oxidase activity by the peroxidase/o-dianisidine assay. The oxidase positive colonies possessing an apparent oxidase activity > 2 nkat g dry biomass(-)(1) were isolated. Among them three new D-amino acid oxidase-producers were found and identified as Fusarium oxysporum, Verticilium lutealbum and Candida parapsilosis. The best new D-amino oxidase producer was the fungus F. oxysporum with a D-amino acid oxidase activity of about 900 nkat g dry biomass(-)(1) or 21 nkat mg protein(-)(1). With regard to the use as a biocatalytic tool in biotechnology the substrate specificities of the three new D-amino acid oxidases were compared with those of the known D-amino acid oxidases from Trigonopsis variabilis, Rhodotorula gracilis and pig kidney under the same conditions. All six D-amino acid oxidases accepted the D-enantiomers of alanine, valine, leucine, proline, phenylalanine, serine and glutamine as substrates and, except for the D-amino acid oxidase from V. luteoalbum, D-tryptophane, D-tyrosine, D-arginine and D-histidine were accepted as well. The relative highest activities (>95%) were measured versus D-alanine (C. parapsilosis, F. oxysporum, T. variabilis), D-methionine (V. luteoalbum, R. gracilis), D-valine (T. variabilis, R. gracilis) and D-proline (pig kidney). The D-amino oxidases from F. oxysporum and V. luteoalbum were able to react with the industrially important substrate cephalosporin C although the D-amino acid oxidase from T. variabilis was at least about 20-fold more active with this substrate.As the results of our studies, a reliable oxidase assay was developed, allowing high throughput screening in a microplate reader. Furthermore, three new microbial D-amino acid oxidase-producers with interesting broad substrate specificities were introduced in the field of biotechnology.

Journal Article↗
PubMed2000

Secretion of MCP-1 and IL-6 by cytokine stimulated production of reactive oxygen species in endothelial cells.

Endothelial cells are known to produce reactive oxygen species by several mechanisms. Functional consequences of increased production of reactive oxygen species were investigated in vitro after stimulation with several proinflammatory cytokines. Time dependent increases in DCF-fluorescence as a measure of reactive oxygen load were quantified in single cells after incubation with TNF-alpha, IL-1 and IFN-gamma. The increased DCF-fluorescence was inhibited by cell permeant antioxidative substances Tiron and Tempol. NMMA, an inhibitor of nitric oxide synthase reduced endothelial DCF-fluorescence only marginally, indicating a minor participation of nitric oxide production in this detection system. Cytokine induced endothelial DCF-fluorescence increased in the presence of NADH, whereas coincubation with NADPH or xanthine was without effect. Flavoenzyme inhibitor diphenyliodonium abolished stimulated DCF-fluorescence. Cytokine induced release of MCP-1 and IL-6 by endothelial cells was completely inhibited in the presence of Tiron and Tempol, whereas NMMA was less effective. Collectively these data indicate that cytokine stimulated endothelial cells increase their reactive oxygen species production probably via NADH oxidase and this production may critically be involved in the secretion of MCP-1 and IL-6.

Antioxidants↗
PubMed2000

Safety, efficacy, and long-term results of a modified version of rapid opiate detoxification under general anaesthesia: a prospective study in methadone, heroin, codeine and morphine addicts.

BACKGROUND: In the present study a method of rapid opiate detoxification under general anaesthesia has been evaluated regarding the safety, the efficacy in preventing withdrawal symptoms, and the long-term results. In addition, it was investigated whether the profile and severity of withdrawal symptoms depend on the type of opiate abused (methadone, heroin, codeine, morphine). METHODS: Seventy-two opiate addicts were detoxified in an intensive care unit (ICU). Anaesthesia was induced and maintained using propofol infusion. Patients were endotracheally intubated. The opiate receptor antagonist naltrexon was administered into the stomach via a nasogastric tube. Withdrawal symptoms before and after the detoxification treatment were assessed using an objective and a subjective opiate withdrawal scale (OOWS, SOWS). After detoxification patients entered a long-term naltrexone maintenance programme as well as a supportive psychotherapy programme. Vital organ function was monitored using haemodynamic and respiratory parameters as well as body temperature. RESULTS: Organ function parameters were stable during the whole treatment in all patients and no anaesthetic complications were registered. Minor side effects such as bradycardia or hypotension were observed in 20 patients. Compared to patients with pre-existing heroin, codeine, or morphine abuse respectively, patients from the methadone maintenance programme had significantly higher (P<0.01) OOWS as well as SOWS values after the treatment. Twelve months after the detoxification 49 patients (68%) were abstinent from opiates whereas 17 patients had relapsed during the period of follow-up. Six patients were lost during follow-up. CONCLUSIONS: Rapid opiate detoxification under general anaesthesia is a safe and efficient method to suppress withdrawal symptoms. This treatment may be of benefit in patients who particularly suffer from severe withdrawal symptoms during detoxification and who have failed repeatedly to complete conventional withdrawal. Methadone patients have more withdrawal symptoms than other opiate addicts.

Adult↗
PubMed2000

Salmonella pathogenicity island 2.

Systemic infections by Salmonella enterica, such as typhoid fever, are a significant threat to human health. Recent studies indicate that the function of a type III secretion system encoded by Salmonella Pathogenicity Island 2 (SPI2) is central for the ability of S. enterica to cause systemic infections and for intracellular pathogenesis. This review summarizes approaches leading to the identification of SPI2, the molecular genetics and evolution of SPI2, and the current understanding of the regulation of gene expression. Recent studies have indicated that SPI2 is used by intracellular Salmonella to actively modify functions of the host cells. The role of SPI2 during pathogenesis of salmonellosis and current models regarding function will be discussed.

Animals↗
PubMed2000

EEG controlled rapid opioid withdrawal under general anaesthesia.

We performed rapid opioid detoxification under propofol anaesthesia in 30 opioid addicts, using the opioid receptor antagonist naltrexone. Two strategies to obtain a sufficient depth of anaesthesia and to avoid anaesthetic overdose were evaluated. Patients were allocated randomly to one of two groups. In group 1, the effects of propofol were monitored by observing clinical signs, and in group 2, depth of anaesthesia was controlled using an EEG threshold method. Withdrawal symptoms and post-anaesthetic recovery time were assessed. All patients remained stable and no anaesthetic complications were noted. There were significant differences in the total dose of propofol given (group 1, mean 72 (SD 9) mg kg-1; group 2, 63 (8) mg kg-1; P < 0.01), duration of anaesthesia (318 (53) min vs 309 (42) min; P < 0.05), duration of recovery time (49 (13) min vs 40 (12) min; P < 0.01) and frequency of withdrawal symptoms between groups. In addition, the incidence of side effects was different between groups (62 vs 29 points on a withdrawal symptom scale; P < 0.01). To obtain a sufficient depth of anaesthesia but to avoid inappropriately large doses of anaesthetic, we consider that EEG monitoring is valuable during rapid opioid detoxification.

Anesthesia, General↗
PubMed1999

Molecular and functional analysis indicates a mosaic structure of Salmonella pathogenicity island 2.

Two large virulence loci encoding type III secretion systems are present on the chromosome of Salmonella typhimurium. Salmonella pathogenicity island 2 (SPI2) is important for the survival of S. typhimurium in host organs and forms an insertion of about 40 kb at the tRNA(Val) gene. However, several indications suggested that SPI2 was not the result of a single event of horizontal gene transfer. We characterized the portion of SPI2 towards the 30 cs boundary and performed mutational analysis to investigate the contribution of this region to S. enterica virulence. This analysis indicates that SPI2 may be composed of at least two different genetic elements. About 15 kb of the 40 kb of SPI2 contain genes without a significant contribution to systemic infections in the model of murine salmonellosis. Our study allowed us to define genes in SPI2 important for virulence further and indicated that this locus has a complex mosaic structure.

Base Sequence↗
PubMed1999

Environmental regulation of Salmonella pathogenicity island 2 gene expression.

The enteric pathogen Salmonella typhimurium co-ordinates the expression of virulence determinants in response to environmental cues from the host organism. S. typhimurium possesses Salmonella pathogenicity island 2 (SPI2), a large virulence locus encoding a type III secretion system for virulence determinants required for systemic infections and accumulation inside host cells. We have generated transcriptional fusions to SPI2 genes to analyse expression and used antibodies against recombinant SPI2 proteins to monitor levels of SPI2 proteins under various conditions. Here, we demonstrate that SPI2 gene expression is induced by Mg2+ deprivation and phosphate starvation. These conditions are likely to represent the environmental cues encountered by S. typhimurium inside the phagosome of infected host cells. The induction of SPI2 gene expression is modulated by the global regulatory system PhoPQ and is dependent on SsrAB, a two-component regulatory system encoded by SPI2.

Amino Acid Sequence↗
PubMed1999

The genetic basis of tetrathionate respiration in Salmonella typhimurium.

A range of bacteria are able to use tetrathionate as a terminal respiratory electron acceptor. Here we report the identification and characterization of the ttrRSBCA locus required for tetrathionate respiration in Salmonella typhimurium LT2a. The ttr genes are located within Salmonella pathogenicity island 2 at centisome 30.5. ttrA, ttrB and ttrC are the tetrathionate reductase structural genes. Sequence analysis suggests that TtrA contains a molybdopterin guanine dinucleotide cofactor and a [4Fe-4S] cluster, that TtrB binds four [4Fe-4S] clusters, and that TtrC is an integral membrane protein containing a quinol oxidation site. TtrA and TtrB are predicted to be anchored by TtrC to the periplasmic face of the cytoplasmic membrane implying a periplasmic site for tetrathionate reduction. It is inferred that the tetrathionate reductase, together with thiosulphate and polysulphide reductases, make up a previously unrecognized class of molybdopterin-dependent enzymes that carry out the reductive cleavage of sulphur-sulphur bonds. Cys-256 in TtrA is proposed to be the amino acid ligand to the molybdopterin cofactor. TtrS and TtrR are the sensor and response regulator components of a two-component regulatory system that is absolutely required for transcription of the ttrBCA operon. Expression of an active tetrathionate reduction system also requires the anoxia-responsive global transcriptional regulator Fnr. The ttrRSBCA gene cluster confers on Escherichia coli the ability to respire with tetrathionate as electron acceptor.

Amino Acid Sequence↗
PubMed1999

pH-dependent secretion of SseB, a product of the SPI-2 type III secretion system of Salmonella typhimurium.

The type III secretion system of Salmonella pathogenicity island 2 (SPI-2) is required for bacterial replication inside macrophages. SseB has been considered a putative target of the secretion system on the basis of its similarity with EspA, a protein secreted by the type III secretion system of enteropathogenic Escherichia coli (EPEC). EspA forms a filamentous structure on the bacterial cell surface and is involved in translocation of proteins into the eukaryotic cytosol. In this paper, we show that SseB is a secreted protein that associates with the surface of the bacterial cell and might, therefore, also be required for delivery of SPI-2 effector proteins to the eukaryotic cell cytosol. SseB begins to accumulate inside the bacterial cell when the culture enters early stationary phase. However, SseB is only secreted if the bacteria are grown at low pH or if the pH is shifted after growth from 7.0 to below pH 5.0. The secretion occurs within minutes of acidification and is totally dependent on a functional SPI-2 type III secretion system. As the pH of the Salmonella-containing vacuole inside host cells has been shown to acidify to between pH 4.0 and 5.0, and as SPI-2 gene expression occurs inside host cells, low pH might be a physiological stimulus for SPI-2-mediated secretion in vivo.

Agglutination Tests↗