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PubMed2000

Fractionation of nickel species from airborne aerosols: practical improvements and industrial applications.

Presently recommended methods for fractionation of airborne nickel dusts are laborious and time-consuming. A new method has been developed based on existing procedures of leaching nickel fractions from sample filters, and based on the principles of flow-injection analysis. A special sample filter holder has been constructed to be used in conjunction with the flow-injection system. In this system, soluble nickel compounds are extracted from the filter with ammonium citrate buffer, sulphidic nickel by peroxycitric acid, and metallic nickel by CuCl2/KCl. The final dissolution of the filter by HNO3/HCl results in the oxidic fraction. Endpoint determination of these fractions is performed by use of graphite-furnace atomic absorption spectrometry (GF-AAS). The analytical criteria of this method have been established, and the suitability of the method for application in the practice of industrial hygiene has been demonstrated.

Aerosols↗

PubMed1982

A bactericidal microassay for testing serum sensitivity of Neisseria gonorrhoeae.

A reproducible gonococcal serum bactericidal microassay is described which has easily determined endpoints and lends itself to large scale tests. The microassay may be used to assess sensitivity to normal human serum among strains of gonococci, and to define the antigens conferring this sensitivity. It may be readily adapted to test for bactericidal activity in hyperimmune antisera and to evaluate antigens which inhibit serum bactericidal activity.

Antigens, Bacterial↗

PubMed1986

Diet-induced alterations in theobromine disposition and toxicity in the rat.

To assess the potential influence of diet on theobromine (TBR) disposition and the development of TBR-induced thymic and testicular toxicity, male Sprague-Dawley rats were given the following diets ad libitum for 28 days: (1) semipurified (S); (2) commercial chow (Ch); (3) semipurified + 0.6% TBR (S + TBR); or (4) commercial chow + 0.6% TBR (Ch + TBR). Toxicity endpoints determined in each TBR group indicated that Ch + TBR-treated animals did not exhibit the marked reduction in body weight or testicular atrophy induced by the S + TBR diet, although thymic weight was lower regardless of diet. Metabolic studies performed after the 28-day feeding period using 5 mg/kg TBR + 10 microCi [8-14C]TBR revealed an overall inductive effect of Ch on TBR metabolism as shown by increased urinary excretion (0-24 hr) of the major TBR metabolite, 6-amino-5[N-methylformylamino]-1-methyluracil (6-AMMU), as well as 7-methylxanthine + 3-methylxanthine (7-MX + 3-MX) and 3,7-dimethyluric acid (3,7-DMU). Consumption of 0.6% TBR for 28 days in either S or Ch diets also induced its own metabolism, as shown by decreased urinary excretion of unchanged TBR and increased conversion primarily to 3,7-DMU. Fecal 14C elimination (0-24 hr) was similar between animals fed S and Ch diets, indicating no effect of control diet on TBR bioavailability. Since serum TBR concentrations and overall toxicity were lower in Ch + TBR-treated animals than in S + TBR treated animals, yet TBR bioavailability was similar, this effect was attributed to the inducing potential of the Ch diet on TBR metabolism and clearance. Investigators are cautioned to consider the potential effect of diet on metabolism when performing and evaluating toxicological studies.

Animals↗

PubMed1996

Comparative study of the effects of MCPA, butylate, atrazine, and cyanazine on Selenastrum capricornutum.

The herbicides MCPA, butylate, atrazine and cyanazine are extensively used in Canadian agriculture and information regarding their effects on indigenous biota is scarce. Phytotoxicity assessments were conducted in the laboratory on the common green alga Selenastrum capricornutum using both the active ingredient of the herbicides and their formulated products (for MCPA and butylate). Endpoints determined after the 96 h exposure included algal population growth inhibition (IC50-cell counts), percent lethality (LC50-flow cytometry derived) and photosynthetic electron transport inhibition (EC50-fluorescence induction). Pesticide formulations had greater toxic effects than the active ingredient alone. The 96 h IC50 (50% Inhibition Concentration) and LOEC (Lowest Observable Effects Concentration) using cell counts of S. capricornutum were 18.4 and 8.9 mg l(-1) respectively for MCPA-active ingredient and for MCPA-formulated, these were 0.62 and 0.0062 mg l(-1) respectively. Those for butylateactive ingredient were 61.0 and 8.3 mg l(-1) and for butylate-formulated 1.46 and 0.17 mg l(-1), respectively. The triazines active ingredient, which are photosynthetic inhibitors, had greater effects than either the MCPA or butylate. The IC50 for cyanazine and atrazine were 0.059 and 0.026 mg l(-1), respectively. By comparing the IC50 and LC50 values for the tested active ingredients, it was found that the effects of atrazine were algicidal, whereas those of cyanazine, butylate and MCPA were algistatic.

Journal Article↗

PubMed1988

Comparison of chemosensitivity of transplantable non-small cell bronchial tumours of rats in syngeneic hosts and in nude rodents.

Four transplantable poorly to well differentiated bronchial carcinomas, originally induced in the lungs of WAG/Rij and BN rats, were used to study their responsiveness to cytostatic drugs when growing in syngeneic hosts or in nude mice or rats. Growth delay was the endpoint determined. The responsiveness to drugs was specific for each tumour line and between tumours it was heterogeneous. In general, the same tumour specific pattern of response was observed regardless whether tumours grew in syngeneic hosts or in nude mice or nude rats. These results indicate that the stroma of the host does not contribute significantly to the response of the tumour, but that the intrinsic sensitivity of the malignant cells is the prevailing factor.

Animals↗

PubMed1979

A refractory period after brief activation of mammalian skeletal muscle fibres.

A two pulse technique was used to study the decay of mechanical activation in TTX poisoned mouse extensor digitorum longus (EDL) and soleus muscle fibres. A two microelectrode point voltage clamp technique was used with visual endpoint determination of the threshold potential for activation. The excitatory effect of a brief (0.5-2.0 msec) depolarizing pulse decayed quickly and became inhibitory. In EDL fibres the peak inhibition was 0.5-1.0 msec after the termination of the conditioning pulse and decayed within 3.0 msec. Inhibition was less pronounced in soleus fibres and decayed more slowly. It is suggested that inhibition may be responsible for a refractory period in excitation-contraction coupling.

Animals↗

PubMed1994

Cyto- and genotoxic potential of the photosensitizer Photosan 3 in the absence of light.

In the present investigation, cultures of rat hepatocytes were treated with Photosan 3 (PS 3) and examined for possible mutagenic effects in the absence of light. Hepatocytes are particularly useful in genotoxicity studies because of their capacity to metabolize a large variety of promutagenic/procarcinogenic compounds. The cytogenetic endpoints determined were chromosomal aberrations and the induction of micronuclei. Three hours of incubation with PS 3 (at concentrations of 0.1, 1, 10, and 100 micrograms ml-1) induced significantly elevated levels of chromosomal aberrations and micronuclei already at the lowest concentration of 0.1 micrograms ml-1 compared with the controls. A concentration of 100 micrograms ml-1 PS 3 appeared to be cytotoxic: no mitotic figures could be detected.

Animals↗

PubMed1996

Does delta-aminolaevulinic acid induce genotoxic effects?

5-Aminolaevulinic acid (ALA) is a precursor of protoporphyrin IX (PpIX) in the biosynthetic pathway of haem. The presence of exogenous ALA bypasses the feedback control and may induce the accumulation of PpIX. Since haem-containing enzymes are essential for energy metabolism, every nucleated cell in the body must have at least a minimal capacity to synthesize PpIX. Photodynamic therapy (PDT), which is the treatment of malignant lesions with light following the administration of a tumour-localizing photosensitizer, leads to oxidative damage, including the formation of genotoxic membrane degradation products via lipid peroxidation. In addition, it has been demonstrated that ALA itself can form the reactive oxygen species Ox.-, H2O2 and OH. by auto-oxidation, suggesting that it could potentially induce DNA damage. Therefore cultures of rat hepatocytes, which have been demonstrated to be very sensitive indicators for genotoxic effects induced by the lipid peroxidation product 4-hydroxynonenal and analogous aldehydes, were examined for possible mutagenic effects after treatment with ALA in the absence of light. The cytogenetic endpoints determined were chromosomal aberrations and the induction of micronuclei. Compared with the controls, significantly elevated levels of chromosomal aberrations and micronuclei were observed at concentrations of 1 microgram ml-1 or greater. Chromosomal aberrations and micronuclei were found to increase up to a concentration of 100 micrograms ml-1 ALA. While micronuclei decrease at higher concentrations, chromosomal aberrations remain at the same level. The kinetics of PpIX formation after induction with 100 and 1000 micrograms ml-1 ALA appear to be the same for both concentrations, suggesting that the induction of chromosomal aberrations may be due to PpIX.

Aminolevulinic Acid↗

PubMed2005

Assessment of anthracene toxicity toward environmental eukaryotic microorganisms: Tetrahymena pyriformis and selected micromycetes.

The toxicity of anthracene, a nonmutagenic, noncarcinogenic, low-molecular-weight polycyclic aromatic hydrocarbon present in the environment, was assessed using a ciliated protozoan, Tetrahymena pyriformis, and a selection of 10 micromycetes from different taxonomic groups living in two environmental compartments, namely aquatic and soil ecosystems. With T. pyriformis, a concentration-dependent inhibitory effect was shown on the cell proliferation rate, IC(50) = 33.40+/-4.84 mg/L (kinetic method). Phagocytosis of nonsoluble anthracene was confirmed by the presence of digestive vacuoles with photon microscopy. In fungi, anthracene did not exhibit a fungicide effect but showed a fungistatic action. Except for Absidia fusca and Cladosporium herbarum, the micromycetes showed a concentration-dependent decrease in growth. From IC(50) values determined by endpoint or kinetic methods, Rhodotorula glutinis and all of the Ascomycotina (except for Penicillium chrysogenum) were the most sensitive species, while Phanerochaete chrysosporium, P. chrysogenum, and the two Deuteromycotina were more resistant to anthracene. Our discussion focuses on the evaluation of toxicity by the two methods used for the calculation of the IC(50) values (endpoint and kinetic), the advantages of studying growth by a kinetic method (the dynamic aspect), and a comparison of toxicity to T. pyriformis and the different micromycetes.

Animals↗

PubMed2005

Intravenous opioid testing in patients with chronic non-cancer pain.

The clinical use of an intravenous opioid testing can help to predict whether opioids will be beneficial. The determination of individual opioid responsiveness justifies subsequent long-term opioid treatment and is generally recommended. An overview over current testing procedures is given with particular regard to choice of opioid, maximum dose, determination of endpoints and duration of testing and recovery. Remifentanil testing is a new approch and is studied in a randomized placebo-controlled cross-over study in 24 patients suffering from severe non-cancer pain. An ascending infusion of remifentanil and placebo respectively was titrated against endpoints. The testing allowed a disctinction between 11 opioid-responders and 13 non-responders. Complete recovery after end of infusion was rapid with a reach of baseline conditions after 25 min in all patients. Thus the complete remifentanil testing procedure required at utmost 1 h. In conclusion, remifentanil testing offers a more rapid procedure allowing the routine use in an ambulatory setting.

Analgesics, Opioid↗

PubMed2005

Statistical considerations for vaccine immunogenicity trials. Part 1: Introduction and bioassay design and analysis.

The foundation for any vaccine immunogenicity trial is the identification of appropriate correlates for protection and the measurement of these quantities with well-designed bioassays. An important requirement for developing bioassay protocols is the standardization of each procedure, so it is performed in a uniform manner within a facility and, in the case of multicenter trials, across laboratories. It is also crucial to recognize that the selection and use of techniques used to quantify assay endpoints (e.g., antibody concentration) will affect their accuracy and precision and these methods must also be defined and uniformly applied within and across laboratories. This paper discusses a number of methodological issues related to bioassay design and analysis that would ultimately lead to highly accurate assay endpoint determinations with minimum variance that would be comparable across laboratories. Guidelines are presented for the development of bioassay and data analysis protocols. Strengthening vaccine immunogenicity trial protocols will ensure that these quantities are estimated with the greatest degree of reliability and facilitate the subsequent evaluation of new vaccine formulations. Following these guidelines will give other researchers as well as regulatory authorities more confidence in evaluating and comparing the differences in immunogenicity levels elicited by new and developing vaccines.

Animals↗

PubMed1975

Improved method for euglobulin clot lysis time.

1. The use of Evans Blue dye to facilitate endpoint determination the elimination of 4 degrees, assay conditions are technical improvements in the euglobulin clot lysis test. 2. Plasma samples have limited stability at 30 degrees or 4 degrees, but are stable for prolonged periods at minus 20 degrees. Samples with accelerated clot lysis are much less stable than normal samples at 30 degrees. 3. The normal range is determined as greater than 70 minutes for citrated plasma and greater than 50 minutes for oxalated plasma. There is no sex difference in the normal range.

Blood Coagulation Tests↗

PubMed1997

Cytotoxic and genotoxic effects of 4-hydroxynonenal in cerebral endothelial cells.

Oxygen free radicals are produced in the central nervous system (CNS) as a consequence of normal physiological metabolic reactions of neuronal cells, but there is evidence accumulating that they are also implicated in the processes leading to a number of pathological changes in the brain. A general mechanism whereby oxygen free radicals induce tissue damage is lipid peroxidation (LPO), which generates a large variety of water-soluble carbonyl compounds. Due to their high reactivity, we focused our investigations on 4-hydroxyalkenals, in particular on 4-hydroxynonenal (HNE), the major 4-hydroxyalkenal. Two phenotypes of cerebral endothelial cells (cECs) were treated with various concentrations of 4-hydroxynonenal and the cyto- and genotoxic effects studied. The cytogenetic endpoints determined were chromosomal aberrations and the induction of micronuclei. Three hours of incubation with HNE induced significantly elevated levels of chromosomal aberrations at concentrations > or = 1 microM and micronuclei at concentrations > or = 10 microM in both cEC phenotypes, compared to the controls. Cytotoxicity was observed at a concentration of 50 microM HNE and was significantly higher in the elongated and spindle-shaped cEC phenotype (type II) than in the epithelial cEC phenotype (type I). The results indicate that cECs are affected by HNE even at low concentrations with minor differences between the two cEC phenotypes.

Aldehydes↗

PubMedDate not supplied

Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial.

BACKGROUND: Development of an effective malaria vaccine could greatly contribute to disease control. RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on Plasmodium falciparum circumsporozoite surface antigen. We aimed to assess vaccine efficacy, immunogenicity, and safety in young African children. METHODS: We did a double-blind, phase IIb, randomised controlled trial in Mozambique in 2022 children aged 1-4 years. The study included two cohorts of children living in two separate areas which underwent different follow-up schemes. Participants were randomly allocated three doses of either RTS,S/AS02A candidate malaria vaccine or control vaccines. The primary endpoint, determined in cohort 1 (n=1605), was time to first clinical episode of P falciparum malaria (axillary temperature > or =37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) over a 6-month surveillance period. Efficacy for prevention of new infections was determined in cohort 2 (n=417). Analysis was per protocol. FINDINGS: 115 children in cohort 1 and 50 in cohort 2 did not receive all three doses and were excluded from the per-protocol analysis. Vaccine efficacy for the first clinical episodes was 29.9% (95% CI 11.0-44.8; p=0.004). At the end of the 6-month observation period, prevalence of P falciparum infection was 37% lower in the RTS,S/AS02A group compared with the control group (11.9% vs 18.9%; p=0.0003). Vaccine efficacy for severe malaria was 57.7% (95% CI 16.2-80.6; p=0.019). In cohort 2, vaccine efficacy for extending time to first infection was 45.0% (31.4-55.9; p<0.0001). INTERPRETATION: The RTS,S/AS02A vaccine was safe, well tolerated, and immunogenic. Our results show development of an effective vaccine against malaria is feasible.

Animals↗

PubMed2001

Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate.

PURPOSE: To evaluate the outcome of adjuvant and salvage radiotherapy (RT) after radical prostatectomy (RP) for clinically localized prostate cancer using conventional clinical end-points, and the biochemical relapse-free rate (bRFR). METHODS: Between 1987 and 1994, 113 node negative, hormonally naïve men received RT 1 month to 12 years after RP. Adjuvant RT was given for positive resection margins and/or pT3 disease. Salvage RT was given for a persistently elevated prostatic specific antigen (PSA), a rising PSA, or palpable recurrence post RP. Clinical and biochemical endpoints determined outcome. Log-rank testing and the Cox proportional hazards model identified factors predictive for biochemical relapse free rate. RESULTS: Median follow-up after RT was 3.7 years (range 0.2-9 years). Five-year clinical local control was 95% for patients with no palpable evidence of disease and 59% for those with palpable recurrence (P < 0.0001). 5-year bRFR was 81% for adjuvant RT, 19% for salvage of biochemical recurrence, 0% for patients with palpable disease (P < 0.0001). Improved bRFR for adjuvant and salvage RT was predicted by a Gleason score < 7 vs. 7 vs. > 7 (hazard ratio 1.53; 95% CI 0.99-2.35) and an undetectable pre-RT PSA vs. PSA < 2.0 ng/ml vs. PSA > 2.0 ng/ml (hazard ratio 3.81; 95% CI 2.47-5.87). Seminal vesicle involvement was not a statistically significant independent predictor of bRFR. CONCLUSIONS: The most favourable bRFR was observed for adjuvant therapy. Salvage was most successful with a pre-RT PSA < 2.0 ng/ml, or Gleason score < 7. Few patients with a pre-RT PSA > 2.0 ng/ml were salvaged, and none with palpable recurrence. These patients require investigation of alternative salvage strategies.

Adenocarcinoma↗

PubMed2000

The synthesis of metoprolol monitored using Raman spectroscopy and chemometrics.

The synthesis of Metoprolol base was studied using Raman spectroscopy with a 785-nm laser, optical fibres, a holographic transmission grating, confocal optics and a charge-coupled device (CCD) detector. The reaction mixture was heated according to a temperature gradient and spectra of the reaction mixture were obtained by focusing the laser beam through ordinary reaction flasks. Because of overlapping bands, multivariate techniques such as principal components analysis (PCA) and partial least-squares projections to latent structures (PLS) were used in the evaluation of the obtained spectra. The use of PCA or PLS against time does not require any calibration samples and a quantitative calibration is not necessary in order to monitor the reaction. A method for reaction endpoint determination, based on euclidean distances in the score space, is presented. The use of multivariate batch control charts have been demonstrated and a number of problems and solutions regarding the sample presentation have been discussed. The effect of spectral pretreatment on the multivariate results is shown and discussed. The monitoring results show that the time to produce Metoprolol base could be reduced.

Antihypertensive Agents↗

PubMed2003

Dissection of the EntF condensation domain boundary and active site residues in nonribosomal peptide synthesis.

Nonribosomal peptide synthetases (NRPSs) make many natural products of clinical importance, but a deeper understanding of the protein domains that compose NRPS assembly lines is required before these megasynthetases can be effectively engineered to produce novel drugs. The N-terminal amide bond-forming condensation (C) domain of the enterobactin NRPS EntF was excised from the multidomain synthetase using endpoints determined from sequence alignments and secondary structure predictions. The isolated domain was well-folded when compared by circular dichroism to the vibriobactin NRPS VibH, a naturally free-standing C domain. The EntF domain was also fully functional in an assay based on a synthetic small-molecule substrate, seryl N-acetylcysteamine. Active site mutants of the EntF C domain were surprisingly inactive in vitro as compared to their VibH counterparts, yet maintained the overall domain structure. An in vivo assay was developed in the context of the full-length EntF protein to more sensitively probe the activity level of the C domain mutants, and this supported strong effects for the active site mutations. The crucial role of histidine-138 was confirmed by assay of the full-length protein in vitro. These results suggest a strong resemblance of catalysis by the EntF C domain to chloramphenicol acetyltransferase, including an active site organized by an arginine-aspartate salt bridge, a key histidine acting as a general base, and an asparagine instead of a serine stabilizing the proposed tetrahedral intermediate by hydrogen bonding. The precise definition of a functional C domain excised from a NRPS should aid efforts at swapping NRPS domains between assembly lines.

Alanine↗

PubMedDate not supplied

Halogenated aliphatic toxicity QSARs employing metabolite descriptors.

The toxic effects from exposure to halogenated hydrocarbons (HAs), which are produced in large amounts and used in a variety of applications, are well-known. Previously, QSARs for the toxicity of a series of HAs in vitro have been studied extensively. In this work, using a composite toxicity metric calculated from a set of five in vitro hepatotoxicity endpoints determined for 20 HAs, we find that QSARs derived using quantum descriptors calculated from the neutral HA species are statistically similar to QSARs calculated from HA metabolites. In most cases, QSARs derived using descriptors calculated from both neutral HAs and metabolites are statistically superior to those derived using either neutral-HA descriptors or metabolite descriptors. However, to properly utilize metabolite descriptors, multiple QSARs, each of which utilizes a set of HAs that form unique metabolites, must be derived and toxicity values calculated therefrom must be averaged. These average toxicity values agree better with experiment than those calculated from the neutral-HA QSARs.

Cells, Cultured↗