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Biomedical subjects

J de Jong

Publications and source records attributed to J de Jong.

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

Degradation of ethinyl estradiol by nitrifying activated sludge.

Degradation of ethinyl estradiol (EE2) by nitrifying activated sludge was studied with micro-organisms grown in a reactor with feedback of sludge fed with only a mineral salts medium containing ammonium as the sole energy source. Ammonium was oxidised by this sludge at a rate of 50 mg NH4+ g(-1) DW h(-1). This activated sludge was also capable of degrading EE2 at a maximum rate of 1 microg g(-1) DW h(-1). Using sludge with an insignificant nitrifying capacity of 1 mg NH4+ g(-1) DW h(-1), no degradation of EE2 was detected. Oxidation of EE2 by nitrifying sludge resulted in the formation of hydrophilic compounds, which were not further identified. Most probably degradation by nitrifying sludge results in a loss of estrogenic activity, as hydroxylated derivatives of EE2 are known to have a substantially lower pharmacological activity than EE2.

Estradiol Congeners↗
PubMed2000

Cell proliferation and apoptosis in stage III inoperable non-small cell lung carcinoma treated by radiotherapy.

PURPOSE: The purpose of this study was to assess the prognostic value of the expression of p53 and bcl-2, the apoptotic index and the expression of topoisomerase II alpha in patients with inoperable non-small cell lung cancer (NSCLC) treated with high dose radiotherapy. PATIENTS AND METHODS: A number of 161 patients with inoperable NSCLC treated with high dose radiotherapy (60 Gy) were included. Immunohistochemical analysis was used to assess the expression of nuclear p53-protein, topoisomerase II alpha and cytoplasmatic expression of bcl-2, while spontaneous apoptosis was assessed using in situ labeling. The minimal follow up period was 2 years. RESULTS: Local control did not only depend on the presence of p53 expression, but also on the proportion of p53 positive cells. The most important prognostic factor was the apoptotic index. A high apoptotic index was associated with worse local control, more distant metastases and a significantly worse overall survival. No association was noted between the expression of bcl-2 and topoisomerase II alpha with any of the endpoints. CONCLUSION: This study indicates that p53 expression and the apoptotic index are prognostic factors with regard to local control in patients with inoperable NSCLC treated with radiotherapy and by combining these 2 factors, a clinically relevant estimation of the local control probability can be made. The apoptotic index turned out to be the only factor significantly related to survival.

Adult↗
PubMed2000

Proposing phase I studies: patients', relatives', nurses' and specialists' perceptions.

PURPOSE: As of now the primary objective of studies on informed consent in phase I trials has been to assess patients' expectations and reasons for participation. We have previously shown that the quantity of information provided through a procedure of subsequent oral interviews with patients was adequate while the attention paid by the physician to the emotional needs and concerns of patients was not. We wanted therefore to assess and compare the perceptions of the information provided about the investigational study of patients, relatives, the research nurse and the investigator responsible for the phase I trial and the impact this information had on the patients' level of anxiety and depression. PATIENTS AND METHODS: The participation to a phase I study was proposed to patients through two subsequent interviews, the latter attended also by patients' relatives, the research nurse and the investigator coordinating the phase I trial. After the second interview, attendees were requested to complete a questionnaire assessing the principal reason for participating in the study and the informative, emotional and interactive dimension of the information. Patients were also requested to complete the Hospital Anxiety and Depression (HAD) scale before and after the second interview. RESULTS: The completed questionnaires of 31 of 42 patients were retrieved and analysed. The possibility to benefit from the study was indicated as the main reason for participating by 59% of the patients while it was judged to be the case in 78% and 86% of the patients by the nurse and the investigator, respectively. The information was judged to be clear and sufficient in almost all cases by all attendees, while the investigator judged that a lower percentage of patients felt at ease and could express their main worries during the interview, had been helped and were less worried after it than it was judged by the nurse and the relatives. Patients' state of anxiety and depression was not adversely affected by the information provided. CONCLUSIONS: Informing patients on the option of receiving an investigational treatment within a phase I study is feasible and can be done in a way felt appropriate by patients and relatives, nursing and medical professionals. Providing information in an appropriate manner does not increase patients' anxiety and depression. Divergence between the aims and interests of the investigators and patients might explain the difference in the evaluation of physician, a problem which could perhaps be partially overcome by the application of innovative phase I designs.

Adult↗
PubMed2000

Simvastatin. A new therapeutic approach for Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome (SLOS) is caused by deficient Delta(7)-dehydrocholesterol reductase, which catalyzes the final step of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursors 7-dehydrocholesterol (7DHC) and 8DHC. We hypothesized that i) 7DHC and 8DHC accumulation contributes to the poor outcome of SLOS patients and ii) blood exchange transfusions with hydroxymethylglutaryl (HMG)-CoA reductase inhibition would improve the precursor-to-cholesterol ratio and may improve the clinical outcome of SLO patients. First, an in vitro study was performed to study sterol exchange between plasma and erythrocyte membranes. Second, several exchange transfusions were carried out in vivo in two SLOS patients. Third, simvastatin was given for 23 and 14 months to two patients. The in vitro results illustrated rapid sterol exchange between plasma and erythrocyte membranes. The effect of exchange transfusion was impressive and prompt but the effect on plasma sterol levels lasted only for 3 days. In contrast, simvastatin treatment for several months demonstrated a lasting improvement of the precursor-to-cholesterol ratio in plasma, erythrocyte membranes, and cerebrospinal fluid (CSF). Plasma precursor concentrations decreased to 28 and 33% of the initial level, respectively, whereas the cholesterol concentration normalized by a more than twofold increase. During the follow-up period all morphometric parameters improved. The therapy was well tolerated and no unwanted clinical side effects occurred. This is the first study in which the blood cholesterol level in SLOS patients is normalized with a simultaneous significant decrease in precursor levels. There was a lasting biochemical improvement with encouraging clinical improvement. Statin therapy is a promising novel approach in SLOS that deserves further studies in larger series of patients.

Cholestadienols↗
PubMed2000

Effect of viscosity on digestion of nutrients in conventional and germ-free chicks.

A study was conducted with conventional and germ-free broiler chicks to obtain more information on the role of the intestinal microflora in the anti-nutritive effects of NSP in broiler chicks. As the NSP source, highly methylated citrus pectin (HMC) was used at a dose level of 30 g/kg in a maize-based diet. The diets fed to the germ-free chicks were gamma-irradiated, whereas those fed to the conventional chicks were not. Feeding the HMC diet to conventional birds depressed weight gain and food utilization (P < 0.05), whereas in germ-free birds only weight gain was reduced (P < 0.05). Feeding the HMC diet to conventional birds reduced digestibilities of energy and starch at the end of the jejunum. Ileal digestibilities of starch and energy were not strongly affected when birds were fed on the HMC-containing diet. Faecal digestibilities of organic matter, crude fat, starch and amino acids, N retention and metabolizable energy were reduced when conventional chicks were fed on the HMC diet. Feeding the HMC diet to germ-free birds hardly affected faecal digestibility of nutrients and N retention, whereas metabolizable energy was increased. Feeding the HMC diet to conventional or germ-free birds increased the viscosity of the digesta in the small intestine. This increase in digesta viscosity was more pronounced in conventional than in germ-free birds. The pH of ileal digesta was reduced when HMC was added to the diet of conventional chicks, but not in germ-free chicks. Feeding the HMC diet to conventional birds markedly affected morphology of the gut wall, whereas in germ-free chicks very little effect was found on gut morphology. Based on the results of the present study, it is concluded that the gastrointestinal microflora mediates the magnitude of the anti-nutritive effects of HMC in broiler chicks. However, the exact role of the microflora in chicks in the magnitude of the anti-nutritional effects of HMC could not be derived from the present study, since the results might have been influenced by gamma-irradiation of the diets fed to the germ-free chicks.

Animals↗
PubMed1999

Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein.

The antiapoptotic protein cellular FLICE (Fas-associated death domain-like IL-1beta-converting enzyme) inhibitory protein (cFLIP) protects cells from CD95(APO-1/Fas)-induced apoptosis in vitro and was found to be overexpressed in human melanomas. However, cytotoxic T cell-induced apoptosis, which is critically involved in tumor control in vivo, is not inhibited by cFLIP in vitro, as only CD95- and not perforin-dependent lysis is affected. This calls into question whether cFLIP is sufficient to allow escape from T cell-dependent immunity. Using two murine tumors, we directly demonstrate that cFLIP does result in escape from T cell immunity in vivo. Moreover, tumor cells are selected in vivo for elevated cFLIP expression. Therefore, our data indicate that CD95-dependent apoptosis constitutes a more prominent mechanism for tumor clearance than has so far been anticipated and that blockade of this pathway can result in tumor escape even when the perforin pathway is operational.

Animals↗
PubMed1999

Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243).

PURPOSE: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non-cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. METHODS: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 microg/m(2). Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, was required beginning with the dose of 118 microg/m(2). The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. RESULTS: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 microg/m(2), with neutropenia grade 3-4 in two of three patients. Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 microg/m(2), with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a <70% colony growth inhibition with no correlation between the growth inhibition effect and the degree of myelotoxicity in the same patient. Plasma concentrations of PNU 152243 were 1000 times lower than the concentration inhibiting the growth of 70% of colonies. No objective tumor responses were seen. CONCLUSIONS: Owing to the occurrence of severe and prolonged nausea and vomiting, the clinical development of oral PNU 152243 was discontinued. The higher-than-expected neutropenia and its lack of relationship with plasma levels of PNU 152243 and its 13-dihydroderivative PNU 155051 might be related to the formation of potent cytotoxic metabolites present in human plasma at undetectable concentrations and with prolonged half-life, as suggested by hematotoxicity tests performed with plasma from patients in GM-CFC assays.

Administration, Oral↗
PubMed1999

Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer.

A significant myeloprotective effect of melatonin in mice treated with etoposide, cyclophosphamide or carboplatin has been reported. The present study was designed to evaluate if the same effect could be observed in patients receiving chemotherapy. Twenty previously untreated patients with inoperable lung cancer received two cycles of carboplatin (given at area under the curve 5 by the Calvert formula) on day 1 and etoposide (150 mg m(-2) i.v.) on days 1-3 every 4 weeks. Melatonin 40 mg or placebo (double-blind) was given orally in the evening for 21 consecutive days, starting 2 days before chemotherapy. Patients were randomized to receive melatonin either with the first or the second cycle. Complete blood cell count with differential was done three times per week for 3 weeks. The median age of the cohort was 60 years (range 42-69), 16 patients had non-small cell and four patients small-cell lung cancer, 12 stage III and eight stage IV disease. In a multivariate analysis including age, sex, diagnosis, stage, performance status, doses of carboplatin and etoposide, and concomitant treatment with melatonin or placebo, the haematological parameters--depth and duration of toxicity for haemoglobin, platelets and neutrophils (ANC)--were not significantly different between cycles with/without melatonin. The mean ANC nadir and the mean number of days with ANC < 0.5 x 10(9) l(-1) were 0.5 x 10(9) l(-1) and 2.5 days, respectively, with/without melatonin. We concluded that, in patients with lung cancer, melatonin given orally at a dose of 40 mg per day for 21 days in the evening, does not protect against the myelotoxic effect of carboplatin and etoposide.

Adult↗
PubMed1999

Valproic acid toxicokinetics: serial hemodialysis and hemoperfusion.

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission, the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 micromol/ L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics.

Adult↗
PubMed1999

Development and evaluation of a rapid dipstick assay for serodiagnosis of acute human brucellosis.

A dipstick assay for the detection of brucella-specific immunoglobulin M antibodies was evaluated with 707 sera from 247 laboratory-confirmed brucellosis patients and 342 control sera from brucellosis-free individuals. These sera were collected from six different countries. The assay was found to be highly sensitive and specific. In addition, the test is easy to use and does not require specialized training or equipment, and the components are stable without a requirement for refrigeration. All of these factors make the test ideal for developing countries and rural settings.

Acute Disease↗
PubMed1999

Kainate-elicited seizures induce mRNA encoding a CaMK-related peptide: a putative modulator of kinase activity in rat hippocampus.

By means of differential display techniques, we have previously identified an mRNA transcript whose expression is highly induced in the rat hippocampus by kainate-elicited seizures. Here, we report the cloning of a corresponding cDNA encoding a 55-amino-acid, serine-rich peptide which contains four predicted phosphorylation sites. The peptide was designated CaMK-related peptide (CARP) as it shares significant amino acid sequence identity with part of a novel putative calcium/calmodulin-dependent kinase (CaMK-VI) that was also cloned in this study. It appears that CARP and CaMK-VI are derived from the same gene through differential splicing. Intriguingly, CARP also exhibits 64% amino acid sequence identity with the C-terminal part of human doublecortin, encoded by a recently identified gene which is mutated in patients with X-linked lissencephaly and the double-cortex syndrome. In addition, the structure of CARP resembles the autoinhibitory, serine-rich N-terminal domain of CaMK-IV, suggesting a possible modulatory role of CARP with respect to CaMK activity. Northern blot analysis and in situ hybridization experiments showed that CARP mRNA is specifically induced by kainate-elicited seizures in the dentate gyrus and in the pyramidal layers CA1 and CA2, but not in CA3. In contrast, kainate-induced seizures did not change the level of expression of the CaMK-VI gene. We propose that CARP induction leads to the modulation of kinase activity in specific subregions of the rat hippocampus, providing a negative feedback mechanism for seizure-induced kinases.

Amino Acid Sequence↗
PubMed1998

Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone.

Previously, we showed that corticosterone regulates BDNF mRNA levels in the hippocampus. In the present study, we have investigated the time course and dose-dependency of this effect at both the mRNA and the protein level. Corticosterone was administered in doses of 30 and 1000 microgram/kg b.w. subcutaneously to adrenalectomized animals. At 3, 6, 12 and 24 h after administration BDNF and trkB mRNA levels in hippocampal subfields were measured by in situ hybridization. Our results show a dose-dependent decrease in BDNF mRNA in dentate gyrus and CA1 at 3 h. After the high dose, this decrease was 70% and 40% respectively. In addition, ELISA was performed to study if this downregulation is also detectable at the protein level. Hippocampal tissue was used from adrenalectomized animals which had received 1000 microgram/kg b.w. corticosterone 4 and 6 h before decapitation. At both time points, a decrease in BDNF protein was observed; 17% at 4 h and 14% at 6 h after corticosterone, as compared to the vehicle injected controls. TrkB mRNA levels were not affected by corticosterone. However, between 6 and 24 h after treatment, increases in trkB mRNA were observed. In conclusion, we have found a transient, dose-dependent decrease in BDNF mRNA and protein in the hippocampus, which may underly changes in neuronal plasticity in the hippocampus after short-term changes in corticosterone concentrations.

Animals↗
PubMed1998

Expression of the alpha 1, alpha 2, and beta 1 T3-receptor mRNAs in the fasted rat measured using competitive PCR.

Fasting is associated with a decrease in the maximal binding capacity of the T3-receptor in different tissues and the responsiveness of some genes to exogenous T3 is not as pronounced as normal. One possible explanation for these observations is a change in the expression of one or all of the isoform mRNAs. We set out to measure the levels of the alpha 1, alpha 2, and beta 1 isoform mRNAs in liver and heart of fasted rats using a competitive PCR method. We constructed competitors based on the isoforms themselves so the amplification efficiencies of the target and the competitor are similar. Using this method we found that during fasting levels of alpha 2 mRNA in the liver of rats increased threefold (P < 0.002) over a 48-h period, whereas alpha 1 and beta 1 did not show any change. In the heart, no change in any of the TR isoform mRNAs was found.

Animals↗
PubMed1998

Validation of an LC-MS assay for the quantification of the enantiomers of Org 4428 in human plasma.

A sensitive and selective liquid chromatographic mass spectrometric assay has been validated for the quantification of Org 4428 enantiomers in human plasma. The assay employs n-hexane extraction from alkalinized plasma, separation on a narrow-bore enantioselective normal phase Chiralpak AD column and APCI MS-MS detection. The lower limit of quantification is 0.5 ng ml-1 plasma for the individual enantiomers.

Adrenergic Uptake Inhibitors↗
PubMed1998

Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days.

BACKGROUND: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients. PATIENTS AND METHODS: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS). RESULTS: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d x 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities. CONCLUSIONS: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.

Administration, Oral↗
PubMed1998

Thyroid status affects the rat cardiac beta-adrenoceptor system transiently and time-dependently.

1. The aim of this study was to investigate the time-dependency of the influence of dysthyroid states on the beta-adrenoceptor system in rat heart left ventricle. Therefore, the influence of acute and chronic hyper- and hypothyroidism on beta-adrenoceptor-induced left ventricular responses, beta-adrenoceptor density, cardiac noradrenaline tissue concentrations, Gs alpha-proteins, and basal and stimulated adenylate cyclase activities was determined. 2. Hyperthyroid rats were obtained by feeding with thyroxine (T4)-containing rat-chow for 1, 4 and 8 weeks. Hypothyroidism was induced by adding 0.05% propylthiouracil (PTU) to the drinking water. Rats of varying ages were used in order to compensate for the differences in the duration of the treatments. Rats were aged 3 and 5 months at the end of the experiments. 3. Thyroxine treatment for 4 and 8 weeks increased the cardiac sensitivity to isoprenaline, but maximal induced inotropic responses were decreased. Cardiac ventricular beta-adrenoceptor density was increased only in rats treated with T4 for 1 week. This transient effect of hyperthyroidism on cardiac beta-adrenoceptor density was not observed in older rats. The PTU treatment resulted in a stable decrease of cardiac beta-adrenoceptor density. 4. Left ventricular tissue noradrenaline concentrations were unaffected by hyperthyroidism, where a decrease was observed in hypothyroid rats. Density of Gs alpha proteins was increased in hearts from chronic hyperthyroid rats. 5. These results indicate that the increased sensitivity to beta-adrenoceptor-mediated stimulation in chronic hyperthyroidism cannot be attributed to changes in cardiac beta-adrenoceptor density, but is probably caused by an enhanced content of Gs alpha. Accordingly, in hyperthyroidism, the beta-adrenoceptor system is influenced time-dependently, whereas hypothyroidism affects the beta-adrenoceptor system independent of time.

Adenylyl Cyclases↗