European surveillance of infections and risk factors in cancer patients.
Explore the source record for details and available documents.
Europe↗
Biomedical subjects
M Wilhelm
Publications and source records attributed to M Wilhelm.
Tachykinin receptors are involved in the "local efferent" motor response to capsaicin in the guinea-pig small intestine and oesophagus.
The sensory neuron stimulant drug capsaicin stimulates primary afferent nerve endings in the guinea-pig small intestine, which in turn activate myenteric cholinergic neurons by an unknown mechanism. The tachykinins substance P and neurokinin A are present in primary afferent neurons. This study was performed to assess the possible involvement of endogenous tachykinins acting via neurokinin-1, neurokinin-2 and neurokinin-3 receptors in the contractile effect of capsaicin in the isolated guinea-pig ileum and oesophagus by using the receptor-specific antagonists GR 82334 (3 microM) for neurokinin-1 receptors, MEN 10627 (3 microM; ileum) or MEN 11420 (1 microM; oesophagus) for neurokinin-2 receptors and SR 142801 (0.1 microM) for neurokinin-3 receptors. In the ileum, the peak contraction evoked by capsaicin (2 microM) was not reduced when tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors were blocked separately, whereas an inhibition of neurokinin-3 receptors diminished the area under the curve of the capsaicin response. A combined blockade of neurokinin-1 and neurokinin-3 receptors significantly depressed the effect of capsaicin; the amplitude of the contractile response was 53.3+/-3.7% of the maximal longitudinal spasm in control preparations, whereas in the presence of GR 82334 plus SR 142801 it reached only 27.6+/-5% (P<0.001, Kruskal-Wallis test; n=9 and 10, respectively). Also, the area under the curve of the contractile response to capsaicin was more than 85% lower in the group of preparations treated with GR 82334 plus SR 142801 than in the control group (P<0.001). Including a neurokinin-2 blocker in the combination did not produce any further inhibition. A concomitant tachyphylaxis to substance P (natural neurokinin-1 receptor stimulant) and the neurokinin-3 receptor agonist senktide (5 and 1 microM, respectively) also reduced the contractile effect of capsaicin. In the oesophagus, capsaicin (1 microM) induced biphasic contractions which were strongly inhibited by atropine (1 microM) or capsaicin pretreatment (1 microM for 10 min). Here again, a blockade of tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors separately failed to inhibit the response to capsaicin, whereas a combined blockade of any two tachykinin receptors caused a partial inhibition. The reduction of the contractile effect of capsaicin was strongest when all three tachykinin receptors were blocked. In seven control preparations, peaks for the first and second phases of contraction reached 35.3+/-3.7% and 20+/-3.2% of maximal longitudinal spasm; the corresponding values in the presence of a combination of GR 82334, MEN 11420 and SR 142801 were 7.5+/-0.8% and 9.1+/-2.2%, respectively (n=6, P<0.001 and 0.05, respectively). Tetrodotoxin (0.5 microM) practically abolished the contractile effect of capsaicin in both tissues studied. It is concluded that an interplay of neuronal tachykinin neurokinin-1 and neurokinin-3 receptors (ileum) and neurokinin-1, neurokinin-2 and neurokinin-3 receptors (oesophagus) is involved in the contractile action of capsaicin, probably in mediating excitation of myenteric neurons by tachykinins released from primary afferents. In both tissues, there also seems to be a non-tachykininergic component of the capsaicin-induced contraction.
Animals↗
Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?
BACKGROUND: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. RESULTS: High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. CONCLUSIONS: The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.
Aspartic Acid Endopeptidases↗
Redefining the therapeutic goals in chronic lymphocytic leukemia: towards an evidence-based, risk-adapted therapy.
Explore the source record for details and available documents.
Bacterial Infections↗
Inhibition of T cell/B cell interaction by B-CLL cells.
The course of disease in patients suffering from chronic lymphocytic leukemia (CLL) is determined by a profound dysregulation of the immune system. The resulting immune suppression is the main cause of death in those patients. In the present study we addressed the question of whether leukemic B cells (B-CLL) are able to suppress regular T cell/B cell interaction. Activated CD4+ T cell clones induce expression of the early activation antigen CD23 on B lymphocytes in vitro. Under conditions used, this B cell activation event was dependent upon direct T cell contact. Addition of certain bystander B-CLL cells or normal B lymphocytes resulted in a cell number-dependent inhibition of B cell induction. This seems to reflect the competition of B-CLL cells for a cell contact-mediated T cell helper signal. By using CD40 ligand transfected fibroblasts as a substitute for T cell help, we show that the same B-CLL cells also suppress CD40 ligand-mediated B cell activation. B-CLL cells differ in their ability to inhibit CD40 ligand-mediated B cell activation. Some B-CLL cases (eight out of 14) are unable to compete for the T cell or CD40 ligand-mediated signal, even though they can functionally interact with CD40 ligand and thereby get activated themselves. In addition, these results indicate that the observed inhibition is not a result of cell crowding by merely reducing the chance of specific B cell/T cell interactions. Collectively, these data indicate that B-CLL cells are able to inhibit the interaction of activated T lymphocytes with normal B lymphocytes in vitro. Perturbed T cell/B cell interaction may represent an important mechanism underlying the various defects of the specific immune system observed in patients suffering from B-CLL.
Antigens, CD↗
Molecular epidemiology of Candida albicans isolates from AIDS and cancer patients using a novel standardized CARE-2 DNA fingerprinting technique.
A total of 277 Candida isolates from various body sites of 149 AIDS and cancer patients treated in four different university clinics in Würzburg, Germany were collected over a period of 27 months and phenotypically and genotypically characterized. The fingerprinting patterns of 194 Candida albicans isolates obtained with the moderately repetitive, C. albicans-specific DNA fragment CARE-2 were digitized and retrospectively compared with a highly accurate computer-assisted standardization method. A total of 168 different genotypic patterns (< 100% identity) could be differentiated using this technique. Although comparative analysis of C. albicans subsets revealed a pronounced tendency of C. albicans isolates from HIV patients to form clusters, the mean genetic variability in HIV and cancer patient isolates was virtually identical. Patients with a specific disease condition or in a certain age group were not found to harbour C. albicans isolates displaying a characteristic "signature genotype". Micro-evolutionary changes were detected by CARE-2 fingerprinting in temporal successive isolates of one patient, but nosocomial transmission of identical isolates between unrelated patients was never seen. Genotyping showed that patient isolates can replace one another; occasionally also species switches were observed. Secreted aspartic protease (SAP) production was not correlated with a specific C. albicans banding pattern; isolates obtained from HIV patients and from an internal control group secreted comparable amounts of SAP. Candida dubliniensis isolates in this study showed an elevated level of SAP production. When used under standardized conditions, CARE-2 fingerprinting is an efficient, reproducible and sensitive technique to characterize C. albicans isolates.
Acquired Immunodeficiency Syndrome↗
Use of an intraaortic balloon pump in patients with impaired left ventricular function.
Prophylactic use of an intraaortic balloon pump (IABP) prior to open-heart surgery in patients with impaired left ventricular function is still under debate. Patients with left ventricular ejection fraction (LVEF) < 40% were therefore compared according to time of IABP placement, viz. preoperative (n = 56), intraoperative (n = 40) or postoperative (n = 17), and also with patients who did not receive mechanical support despite LVEF < 40% (n = 78). The main indication for preoperative IABP insertion was severely impaired left ventricular function (80%), while patients with intraoperative or postoperative IABP placement mainly presented with low cardiac-output syndrome (70%/53%). Preoperative IABP was associated with a low mortality rate (8.9%), whereas patients with intraoperative or postoperative IABP placement had a high mortality risk and an increased catecholamine requirement. Of the patients scheduled for surgery without prophylactic IABP, 19% required intra- or postoperative insertion. Prophylactic placement of IABP thus reduced the mortality rate as well as the postoperative need for mechanical and catecholamine support. Need for intraoperative IABP insertion was associated with high mortality, whereas the outcome after postoperative IABP placement depended on the indication for the measure.
Aged↗
Four years of experience with silver-copper ionization for control of legionella in a german university hospital hot water plumbing system.
Silver-copper ionization was used for controlling Legionella distribution in a German university hospital hot water plumbing system for 4 years. In the beginning, silver concentrations were not allowed to exceed 10 microg/L because of drinking water regulation limits in Germany. Water samples were monitored for Legionella counts, temperature, and silver and copper concentrations. A significant (P<.001) 3.8-log reduction of Legionella counts, from 40, 000 cfu/L to 7 cfu/L, was found during the first year with silver-copper ionization. Nevertheless, the long-term efficacy of silver concentrations <10 ,++microg/L was not sufficient. Legionella counts increased to 10,000 cfu/L during the third year. During the fourth year, we studied the influence of higher silver concentrations on Legionella distribution. With an average silver level of 30 microg/L, only a 1.3-log reduction in Legionella, to 500 cfu/L, was achieved. The effect was not significant (P=.071); therefore, it must be considered that Legionella developed a tolerance to silver ions.
Chlorine↗
Vgamma9/Vdelta2 T cell activation induced by bacterial low molecular mass compounds depends on the 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid biosynthesis.
Isopentenyl diphosphate (IPP), an important precursor of isoprenoid biosynthesis in prokaryotic and eukaryotic organisms, has been shown to activate Vgamma9/Vdelta2 T cells, the major subset of human gammadelta T cells. The biosynthesis of IPP has been first described as the acetate/mevalonate pathway. Recently, 1-deoxy-D-xylulose 5-phosphate (DOXP) and 2-C-methyl-D-erythritol 4-phosphate have been shown to be key metabolites in the DOXP pathway also leading to the formation of IPP in some eubacteria such as Escherichia coli. Here we report that the low molecular mass fraction of extracts from bacteria using the DOXP pathway induces Vgamma9/Vdelta2 T cell activation, while analogous preparations from bacteria using the classical mevalonate pathway fail to do so. Addition of 1-deoxy-D-xylulose potentiates the ability of E. coli extracts to activate Vgamma9/Vdelta2 T cells. As the amounts of IPP present in the bacterial preparations are not sufficient to induce significant Vgamma9/Vdelta2 T cell activation, our data suggest that compounds other than IPP associated with the DOXP pathway are responsible for Vgamma9/Vdelta2 T cell activation.
Chemical Fractionation↗
Phase I study of arabinosyl-5-azacytidine (fazarabine) in adult acute leukemia and chronic myelogenous leukemia in blastic phase.
Fazarabine has demonstrated a broad spectrum of antitumor activity in experimental models including P388 and L1210 cell lines. Previous phase I clinical trials using a 3-day continuous infusion schedule of Fazarabine have shown myelosuppression to be the dose limiting toxicity in solid tumors. Based on this clinical and preclinical experience we designed a phase I study to determine the toxicity, maximum tolerated dose (MTD), and antileukemic efficacy of Fazarabine using a 3-day continuous infusion schedule in patients with refractory or relapsed acute leukemia or chronic myelogenous (CML) in blastic phase. Adults with a diagnosis of acute leukemia or blastic phase CML who were refractory or had relapsed on salvage chemotherapy were entered on study. Fazarabine was administered as a continuous infusion over 3 days every 3 to 4 weeks. The initial dose was 2 mg/m2/hour x 72 hours. Results showed that the MTD was 425 mg/m2/hour infused over 72 hours every 3 to 4 weeks. At this dose level neurotoxicity and fluid overload were the dose limiting toxicities. Among 71 patients treated, we observed one complete remission, one partial remission and one hematologic improvement. No obvious dose response relationship could be determined. In conclusion, Fazarabine has not shown a beneficial effect in the therapy of acute leukemia. Since 71 patients and 20 dose levels were required to determine the MTD of Fazarabine, a reassessment of our phase I study designs should be considered to provide patients with better potential toxic: therapeutic benefits in such trials.
Adolescent↗
[What can a hospital offer?].
Explore the source record for details and available documents.
Ancillary Services, Hospital↗
[Statistically evaluated 95% prediction ranges as alternative to reference ranges exemplified by polychlorinated dibenzo-p-dioxins/dibenzofurans and lead].
Using the 95% prediction limits of an age-related multiplicative regression model describing the datasets of blood examinations carried out on subjects suspected of having been exposed to lead and to polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/F), it was shown that the relevant curves can be used as an alternative to reference ranges describing the actual background exposure to these pollutants. The upper limit of the actual German background exposure can be estimated by the following equations: PCDD/F as International Toxicity Equivalents in the age range of 10-70 years [pg/g lipid basis] = 1.64.age0.871 and lead in the age range of 15-80 years [microgram/l] = 18.15.age0.3638.
Adolescent↗
Potency Testing of Swine Erysipelas Vaccines by Serology Results of a Pre-validation Study.
The European Pharmacopoeia (Ph. Eur.) monograph on Swine Erysipelas Vaccine (inactivated) (Ph. Eur., 1997) requires the potency of each batch to be demonstrated in a mouse protection test. In this parallel-line bioassay, mice are challenged with a virulent strain of Erysipelothrix (E.) rhusiopathiae after immunisation with different doses of either the standard preparation or of the test vaccine. More than one hundred animals are necessary for the routine testing of a single batch. In previous studies (Beckmann und Cubetaler, 1994; Rosskopf-Streicher et al., 1998), we have shown that an indirect enzyme-linked immunosorbent assay (ELISA) may be used to quantify the humoral response of mice. This method can replace the challenge model for the purposes of potency testing in the following manner: Ten mice are immunised subcutaneously with 1/10 of the vaccine dose required for pig vaccination. After three weeks, the mice are bled under anaesthesia. Serum samples are pooled and the antibody content is compared to that of a reference serum. In view of animal welfare the advantages of the alternative model are obvious: A highly reduced number of animals and the replacement of challenge exposure. This includes the discontinuation of the control group with a mortality rate of 100%. A pre-validation study was initiated to evaluate the performance of the serological method. Eight laboratories used the test kits to evaluate pooled serum samples from vaccinated mice. Both the reagents and the test protocol were shown to be satisfactory. The intra- and inter-laboratory reproducibility that was achieved indicates that the method is a strong candidate for validation.
Journal Article↗
Interlesion dependence of the risk for restenosis in patients with coronary stent placement in in multiple lesions.
BACKGROUND: Little is known about the behavior with regard to restenosis of multiple lesions within the same patient treated with intracoronary stenting. Our objective was to test the hypothesis that there is an intrapatient dependence of restenosis between lesions. METHODS AND RESULTS: Quantitative analysis was carried out on angiograms obtained before, immediately after, and at 6 months after coronary stent placement in 1734 lesions in 1244 patients. We used a specialized logistic regression that not only accounts for intraclass correlation but also quantifies it in the form of odds ratio (OR) as the change in risk of a lesion to develop restenosis if another companion lesion had restenosis. The model was based on 23 patient- and lesion-related variables with binary restenosis (diameter stenosis > or =50%) as end point. The overall restenosis rate was 27.5%: 24.4% for single-lesion, 28.6% for double-lesion, and 33.8% for > or =3-lesion interventions. After adjustment for the influence of significant factors (hypercholesterolemia, systemic arterial hypertension, diabetes mellitus, previous PTCA, ostial lesion, location in left anterior descending coronary artery, number of stents placed, vessel size, stenosis severity, balloon-to-vessel ratio, and final result), the analysis found a significant intrapatient correlation, OR 2.5 (1.8 to 3.6). This means that in patients with multilesion interventions, the risk of a lesion to develop restenosis is 2.5 times higher if a companion lesion has restenosis, independently of the presence or absence of analyzed patient risk factors (eg, diabetes). CONCLUSIONS: This study demonstrates that there is a dependence of restenosis between coronary lesions in patients who undergo a multilesion intervention. The likelihood of restenosis for a lesion is higher when another companion lesion has also developed restenosis. Other, as yet unidentified patient factors may be the source of this intrapatient correlation of restenosis.
Aged↗
2D CP/MAS 13C isotropic chemical shift correlation established by 1H spin diffusion.
A new 2D solid-state CP/MAS 13C NMR exchange experiment for through-space isotropic chemical shift correlation is proposed and demonstrated. Through-space correlation is established via a second cross polarization from 13C to 1H and subsequent 1H spin diffusion. A third cross polarization results in the final 13C-13C isotropic chemical shift correlation. The 1H spin diffusion time is a variable parameter allowing different mean square magnetization displacements to be probed. Experimental results on mixtures of differently 13C-labeled alanine and polyethylene indicate that this site-selective 2D technique can be used to characterize domain sizes and proximities over a wide range of length scales (1-200 nm) in solids such as polymers or biological materials.
Alanine↗
[Is subjective health status a good predictor of work resumption?].
The aim of the study is to investigate how persons with long term work-disability due to low back pain assess their health status and how the subjective health measurement influence work resumption (n = 663). Information on their subjective health status at 42 days after start of work-disability is set in relation to the outcomes "Continued work disability after 84 days" versus "work resumption". Bi- and multivariate analysis show that information on the subjective health status and the subjective work prognosis differs between both groups already after 42 days. The results show that the subjective health status in connection with the subjective work prognosis is a good predictor for "Non-resumption of work", but not a sufficiently good predictor for "Resumption to work".
Adolescent↗
Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney.
Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.
Animals↗
Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients.
Infections remain the major cause of morbidity and mortality among neutropenic cancer patients. The current study addresses the question whether monotherapy with the new broad-spectrum carbapenem meropenem exhibits efficacy comparable to that of the standard combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Seventy-one patients with hematological malignancies (55%) or solid tumors (45%), neutropenia < 500/microliter, and fever > 38.5 degrees C were randomly assigned to either meropenem (1 g every 8 h) or ceftazidime (2 g every 8 h) and amikacin (15 mg/kg/day) intravenously. Meropenem (n = 34) and ceftazidime/amikacin (n = 37) were equivalent with respect to the clinical response at 72 h (62% versus 68%) (p > 0.05) and at the end of unmodified therapy (59% versus 62%). Gram-positive bacteremia responded poorly in the meropenem and ceftazidime/amikacin group (29% versus 25%), whereas all gram-negative bacteremias responded except for one in the meropenem group caused by Pseudomonas aeruginosa. All patients survived to 72 h. One patient in each group died of gram-positive sepsis resistant to study medication. No significant side effects occurred in any regimen. This study suggests that meropenem monotherapy might be as effective as combination therapy with ceftazidime and amikacin for the empirical treatment of febrile neutropenic patients.
Adolescent↗