Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates

Resistance-modifying agents (RMAs) such as Verapamil have been proved to be effective in reversing multi-drug resistance (MDR) in many in vitro assays. In this study we have investigated the efficacy of Dex-Verapamil, the R-isomer of Verapamil, as a chemosensitizer in a murine leukemia cell line (P388) and in its resistant counterpart (P388/Dx) expressing a typical MDR phenotype. We have examined in vivo the effect of the co-administration of Dex-Verapamil and Doxorubicin in mice transplanted with P388 or P388/Dx cells. Mice treated with the combination of Doxorubicin plus RMA had a significant increase in survival rate as compared to controls; however, the effect was modest. On the contrary, in vitro Dex-Verapamil can enhance Doxorubicin cytotoxicity in P388/Dx cells with a much greater effect depending on the treatment scheme used, by increasing the intracellular content of drug. Taken together our data indicate that Dex-Verapamil can indeed increase the sensitivity to Doxorubicin in resistant cells, but the limited efficacy shown in vivo demonstrates that this phenomenon is strongly dependent on the treatment scheme used and on the maintenance of constantly elevated serum levels.     

Epididymo-orchitis and Reiter''s disease. Two infrequent complications after intravesical bacillus Calmette-Guérin therapy

Two cases of adverse reactions to intravesical treatment with bacillus Calmette-Guérin are reported. The first patient presented with a severe suppurating epididymo-orchitis three months after his last treatment. The second patient developed Reiter's disease with arthritis of one knee and conjunctivitis 1 week after the fourth instillation.     

Direct administration of insulin-like growth factor to fetal rhesus monkeys (Macaca mulatta)

A potential treatment for the amelioration of fetal growth failure is insulin-like growth factor-I (IGF-I). To address concerns of safety and efficacy, IGF-I (80 microg/kg; GroPep Pty.) was administered i.p. to healthy rhesus monkey fetuses via ultrasound guidance every other day between gestational days (GD) 110-120 and 130-140 (third trimester; term = approximately GD 165 +/- 10; n = 6). Pregnancies were monitored sonographically, and fetal/maternal blood samples were collected for complete blood counts, immunophenotyping, and biochemical analyses. Blood samples, external measures of the fetus and newborn, and tissue and organ weights were collected at fetal necropsy (GD 150; n = 2) or at term delivery of neonates (GD 160; n = 4). The results of these investigations have shown no evidence of hypoglycemia in the fetus or dam during the course of treatment. Circulating concentrations of fetal, but not maternal, IGF-I increased with treatment (approximately 80 to approximately 1015 ng/ml), and there was no evidence of a change in serum IGF-II or an increase in IGF binding protein-3 compared with historical control values. Fetal lymphocytes and select red cell parameters increased, and a significant elevation in circulating B cells and CD4/CD8 ratios in fetal lymph nodes was shown. Although no changes were detected in body weights, increases in thymic, splenic, and kidney weights and small intestine lengths occurred. Thus, administration of IGF-I to the fetal monkey is safe and results in 1) transient increases in circulating IGF-I, 2) a significant effect on fetal hematopoietic and lymphoid tissues, and 3) an increase in select fetal organ weights and measures. These data suggest that IGF-I may represent a potential candidate for therapeutic treatment of growth-compromised human fetuses in utero.     

An intelligent visualisation and decision support system for decentralised wastewater treatment plants.

Current sanitation concepts of decentralised wastewater treatment and reuse raise the issue of monitoring and maintenance of such systems. To guarantee high quality of the recycled water, systems with high requirements concerning process technology are essential. With increasing numbers of decentralised treatment systems spread over far distances it will become more and more impossible and uneconomic to have expert personnel on site. Therefore, new visualisation and intelligent information systems are necessary. The paper describes the structure and 3D-demonstrations as a base for information visualisation. Up-to-date visualisation techniques, facilitating the cognition of context-adapted information, make it possible to maximise the amount of information presented to the user without overwhelming her or him. Concerning diagnosis and decision support systems in the domain of wastewater treatment, several interesting approaches are presented, estimating their applicability for decentralised wastewater treatment systems. The intelligent decision support system presented here consists of a combined ontology- and case-based reasoning system in addition to a process monitoring system. It is responsible for plausibility checks, error diagnosis, solution proposals, and optimisation suggestions.     

Combined-Stage Sintering Model

By focusing on the similarities between the three stages of sintering, a single equation is derived that quantifies sintering as a continuous process from beginning to end. The microstructure is characterized by two separate parameters representing geometry and scale. The dimensionless geometry parameter, denoted T, comprises five scaling factors that relate specific microstructural featuers (e.g., surface curvature) to the scale (grain diameter). Calculations of T from experimental data show (a) agreement with computer simulations of initial-stage sintering, (b) the effect of surface diffusion on T, and (c) changes in T with microstructural evolution during sintering. Application of the model to the design of firing schedules and the study of microstructural geometry effects on sintering is discussed.     

Neutrophil attractant protein-1 and monocyte chemoattractant protein-1 in human serum. Effects of intravenous lipopolysaccharide on free attractants, specific IgG autoantibodies and immune complexes

We recently found that normal human sera contain IgG antibodies against two chemoattractants, neutrophil attractant protein-1 (NAP-1/IL-8) and monocyte chemoattractant protein-1 (MCP-1), as well as immune complexes of these proteins. Intravenously administered LPS was reported to cause a sharp rise in serum NAP-1 concentration. Our study was designed to determine if LPS also caused an increase in MCP-1 and to measure associated changes in concentrations of antibody and immune complex. LPS caused a rise to peak within 2 to 3 h in serum concentrations of free NAP-1 and MCP-1, followed by an almost equally rapid fall toward base-line levels by about 5 h postinjection. MCP-1 concentration in sera from the 11 subjects rose to a peak of 330 +/- 52 pM. The peak value for NAP-1 was 80 +/- 11 pM. In 10 of the 11 subjects, free IgG autoantibody to MCP-1 decreased from a mean pre-LPS value of 1820 +/- 660 pM to a mean low of 53% of the respective initial values. Corresponding data for IgG anti-NAP-1 were a pre-LPS concentration of 216 +/- 7 pM, which decreased to a mean low of 44% of the respective initial values. The finding in some subjects of a rapid rise in free antibody after the nadir suggests the possibility of acute regulation of autoantibody secretion rates. Although the results suggested that LPS-induced chemoattractant combined with free antibody, serum concentrations of MCP-1-IgG or NAP-1-IgG did not increase, which points to an as yet unknown mechanism for trapping and elimination of the immune complexes.     

Temporary results only in electroconvulsive therapy in therapy-resistant depression; retrospective study

OBJECTIVE: To evaluate the use and efficacy of electroconvulsive therapy (ECT) in refractory major depression according to DSM-III-R criteria, and to look for factors predicting response in the acute phase and the occurrence of relapse or recurrence after recovery. DESIGN: Retrospective. SETTING: University Hospital Rotterdam, The Netherlands. METHODS: Of all patients who received ECT between January 1988 and July 1993 data were collected by study of clinical records and of information by treating physicians after discharge. Every patient was visited once, or received an outpatient department appointment, to obtain informed consent, take a follow-up history and evaluate social functioning by scoring Global Assessment of Functioning and Sickness Impact Profile rating scales. RESULTS: 35 patients received ECT. In clinical practice, the guidelines of the Netherlands Psychiatric Association were not violated; most patients had received adequate pharmacological pretreatment before the decision to start ECT was made. Two patients died in hospital (not from ECT). In the acute phase 25 of the 33 patients still alive upon discharge showed good recovery. Seven of these suffered relapse within six months. The number of patients with a return of depressive symptoms rose to 12 by the end of the first year of follow-up. Sociodemographic variables and treatment characteristics did not appear to influence the result of treatment in the acute phase, nor the occurrence of relapse or recurrence. With less intensive pre- and post-ECT drug treatment the chances of relapse were increased. CONCLUSIONS: ECT is an effective treatment in the acute phase of a depression. Results after a longer period of follow-up are less satisfactory.     

Diminished levels of insulin-like growth factor-I in lungs in streptozotocin-induced diabetes: relation to nutritional status and growth

It is yet unknown whether the impaired nutritional status of streptozotocin-induced diabetic rats influences changes in levels of insulin-like growth factor-I (IGF-I) in this experimental model of diabetes. To explore this possibility, simultaneous studies were undertaken of rats made diabetic by streptozotocin (75 mg/kg body wt, intraperitoneally) and undernourished control rats with similar somatic growth rate (determined by body weight gain), in comparison with normal controls. Serum IGF-I levels were diminished in the untreated diabetic and undernourished control animals, but more so in the diabetic group. Lung IGF-I levels (per lung and per lung DNA) and DNA contents were diminished to similar degrees in the untreated diabetic animals and the undernourished control group. Lung dry weights of the diabetic rats were greater than those of the undernourished control group, such that lung IGF-I/100 mg tissue dry wt in the former was significantly lower than in the latter group. Insulin treatment of the diabetic rats restored their body weights, serum and lung IGF-I levels, and DNA contents to normal control values. Lung IGF-I levels in the diabetic rats correlated strongly with serum glucose (r = .75) and body weight (r = .79), and moderately with lung weight (r = .43) and lung DNA (r = .58). These findings suggest that the diminished lung IGF-I levels in streptozotocin-induced diabetes may be related to the impaired nutritional status and/or somatic growth of the experimental animals, and that this relationship may be responsible, at least in part, for the diminished lung cellular proliferation observed in experimental diabetic animals.     

Varying Electron Cyclotron Resonance Heating on the Levitated Dipole Experiment

Plasmas in the Levitated Dipole Experiment (LDX) are formed and sustained currently via two electron cyclotron resonance heating (ECRH) sources: 2.5 kW at 2.45 GHz and 2.5 kW at 6.4 GHz. An important topic being investigated is how varying the ECRH affects the confinement and stability of the plasma. We report the results of using different operational combinations of our RF sources, such as varying the power composition, changing the power levels, and sequencing of the onset time.