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PubMed2005

Anaerobic digestion of kitchen wastes in a single-phased anaerobic sequencing batch reactor (ASBR) with gas-phased absorb of CO2.

The performance of the single-stage anaerobic digestion of kitchen wastes was investigated in an anaerobic sequencing batch reactor(ASBR) with gas-phased absorb of CO2. The ASBR was operated at four chemical oxygen demand(COD) loading rates, 2.8, 5.1, 6.2 and 8.4 g/(L x d) respectively. The COD loading rate was increased with the TS concentration and HRT changing. At maximum COD loading rate of 8.4 g/(L x d), the COD, total solid(TS) removal rate and methane gas yield were 69%, 68% and 2.5 L/(L x d) respectively. The operation of the reactor with gas-phased absorb of CO2 was stable in spite of the low pH (2.6-3.9) and high concentration of TS (142 g/L) of input mixture. The output volatile fatty acid(VFA) concentration was between 2.7-4.7 g/L and had no inhibition on the methanogenic microorganism. The reactor without gas-phased absorb of CO2 became acidified when the total COD loading rate was increased to 5.1 g/(L x d). Stoichiometry of the methanogenesis for kitchen wastes showed a considerable amount of alkaline will be required to keep pH in the appropriate range for the methanogenic microorganism based on theoretical calculation. Gas-phased absorb of CO2 effectively reduced the alkaline consumption, hence avoided excessive cation into the reactor.

Bacteria, Anaerobic↗
PubMed1996

C/EBPbeta is required for the late phases of acute phase genes induction in the liver and for tumour necrosis factor-alpha, but not Interleukin-6, regulation.

C/EBPbeta is a leucine-zipper transcription factor believed to play an important role in the control of liver functions, and in particular in the transcriptional regulation of acute phase genes in response to several inflammatory stimuli and to recombinant cytokines. Moreover, this factor has been proposed as an important activator of several cytokine genes. We recently described the generation of mice in which the C/EBPbeta gene has been inactivated by gene targeting, showing that they are viable, but present specific defects in the myeloid and lymphoid compartments. Here we demonstrate that C/EBPbeta does indeed play a role in the transcriptional induction of some, but not all, liver acute phase genes. Activation is in particular defective in C/EBPbeta-deficient mice in the later phases of induction, suggesting that the early phases may be triggered by factors other than C/EBPs. Moreover, IL-6 activation is normal and TNFalpha activation is defective in the mutant mice, indicating a differential role of C/EBPbeta in the control of these two cytokines' production.

Journal Article↗
PubMed1991

Improvement of phase III psychotropic drug trials by intensive phase II work.

Phase III drug trials are expensive, time-consuming procedures that too often are a disappointment, since the evidence for drug efficacy proves marginal and unconvincing. We believe that this can be remedied by attention to numerous correctable flaws during Phase II. These multiple problems require a structural solution. The development of expert, psychopharmacologic facilities that focus on deficient areas of Phase II studies so as to develop an adequate Phase III design should prove helpful.

Clinical Trials as Topic↗
PubMedDate not supplied

Effects of injection solvent and mobile phase on efficiency in reverse-phase liquid chromatographic determination of aflatoxin M1.

The effects of injection solvent and mobile phase composition on the reverse-phase liquid chromatographic determination of aflatoxin M1 (M1) were examined. M1 was converted to the more highly fluorescent derivative aflatoxin M2a (M2a). Using a C-18 column and a mobile phase of H2O-MeCN-MeOH (60 + 20 + 20) (MP-A), M2a was dissolved in various ratios of MeCN-H2O prior to injection. Chromatographic efficiency for the M2a peak varied from ca 2000 theoretical plates when injected in 30% aqueous MeCN to ca 9000 plates when injected in water alone. However, using the same C-18 column but with a mobile phase of H2O-IPA-MeCN (80 + 12 + 8) (MP-B), the M2a peak exhibited 25,000 plates when injected in 30% aqueous MeCN and 10,000 plates when injected in water alone.

Aflatoxin M1↗
PubMed1990

[Clinical phase I and phase II study on a sustained release formulation of leuprorelin acetate (TAP-144-SR), an LH-RH agonist, in patients with prostatic carcinoma. Collaborative++ Studies on Prostatic Carcinoma by the Study Group for TAP-144-SR].

TAP-144-SR is a sustained release formulation of an LH-RH agonist, leuprorelin acetate (TAP-144), that has been newly developed in Japan. As a phase I study, a single subcutaneous dose of TAP-144-SR was given to 15 patients with prostatic cancer to investigate the safety, endocrinological effects, and serum levels of the drug. The patients were divided into four groups according to the dosage levels of 1.88 mg, 3.75mg, 7.5 mg and 15 mg. No serious side effects were noted in any of the patients treated with any dose. No patients exhibited signs of a local reaction at the site of injection. In two patients transient exacerbation of clinical symptoms owing to "flare up" was observed. Serum testosterone levels decreased to the castration level (less than 1.0 ng/ml) in all of the patients, although the time required to attain the castration level tended to be longer in the patients receiving 1.88 mg. Serum TAP-144 levels increased on the first day and gradually decreased thereafter. In the groups of patients that received 3.75 mg or more of TAP-144-SR, TAP-144 was detected in the serum up to 4 weeks after administration. Based on the results of the phase I study, 3.75 mg and 7.5 mg of TAP-144-SR were selected as the doses for the phase II study. The phase II study was carried out as a multi-center open trial. Patients with stage B-D prostatic cancer received subcutaneously either 3.75 mg (3.75 mg group) or 7.5 mg (7.5 mg group) of TAP-144-SR once every 4 weeks for a total of 3 doses over a period of 12 weeks. TAP-144-SR 3.75 mg was administered to 51 patients and 7.5 mg to 50 patients. Both of these doses were adequate to suppress serum LH and FSH levels. Serum testosterone was decreased to the castration level within 22 days after the first dose, and this suppression was maintained throughout the treatment period. Clinical response rate (CR + PR) was 21% in the 3.75 mg group and 22-24% in the 7.5 mg group according to the Criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria. The response rate by the criteria of Japanese Prostatic Cancer Study Group was 51% in the 3.75 mg group and 62% in the 7.5 mg group. Adverse reactions were noted in 26% of patients in the 3.75 mg group and 34% in the 7.5 mg group.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1989

Different priming on human neutrophil respiratory burst by lipopolysaccharides from phase I and phase II Coxiella burnetii.

Human neutrophils produce small amounts of superoxide anion when stimulated with the chemotactic peptide FMLP; preincubating neutrophils with low concentrations of lipopolysaccharides (LPS) markedly increases this response, an effect referred to as priming. In this work LPS from Coxiella burnetii either phase I (virulent) or phase II (avirulent) were examined for their ability to induce priming. Results clearly show that only LPS from phase II microorganism was able to increase the release from neutrophils upon subsequent stimulation with FMLP. This effect was abolished by preincubation of LPS with polymyxin B. This finding may account for the ability of Coxiella burnetii phase I to escape intracellular phagocyte killing during persistent infections.

Coxiella↗
PubMed1989

Silver ion chromatography using solid-phase extraction columns packed with a bonded-sulfonic acid phase.

Commercial solid-phase extraction columns packed with a stationary phase with bonded benzenesulfonic acid groups are readily converted to the silver ion form and can then be used for silver ion chromatography of lipids. To illustrate the utility of such procedures, methyl ester derivatives of fatty acids with zero to six double bonds were separated from each other by a simple stepwise elution scheme. -Christie, W. W. Silver ion chromatography using solid-phase extraction columns packed with a bonded-sulfonic acid phase.

Benzenesulfonates↗
PubMed1989

[Phase I study and early phase II of SM-108 (4-carbamoylimidazolium-5-olate) in lung cancer. SM-108 Study Group].

Phase I study with a new oral purine antagonist, SM-108, was conducted in a total of 73 cases in a 5-day consecutive schedule with the dosage ranging from 20-2,500 mg/m2 at II institutes. The incidences of subjective and objective side effects were 20.5% (15/73) and 31.5% (23/73), respectively, however the correlation between these effects and their dosages was unclear. MTD and DLF values were not determined. SM-108 levels in serum reached maximum in 2-4 hours after oral administration of SM-108, and exhibited a dose-response relationship up to the dosage of 2,000 mg/m2/day. Forty to 60% of the administered drug was excreted into urine in 24 hrs; thus, the main excretory pathway was considered to be renal. An early phase II study was undertaken in patients with lung cancer in 5 cancer centers and university hospitals. Each patient had received 400 mg/m2/day (in two divided doses) or 600 mg/m2/day (in three divided doses) for more than 2 weeks. Only one case (adenocarcinoma) showed a minor response out of 27 cases but not reached partial response according to our criteria. In the 400 mg/m2/day group and the 600 m/m2/day group the incidences of subjective side effects (mainly GI tract disturbance) were 33.3% (4/12) and 40.0% (6/15), while objective side effects (hematological changes) were 16.7% (2/12) and 26.7% (4/15) respectively. In conclusion, we could not determine the dose limiting factor and maximum tolerated dose from our phase I clinical study and early phase II study for lung cancer.

Adenocarcinoma↗
PubMed1986

[Stability of high molecular weight anticancer agent SMANCS and its transfer from oil-phase to water-phase. Comparative study with neocarzinostatin].

SMANCS is a conjugate protein of copolymer of styrene-maleic acid [SMA] (molecular weight: 1,500) and an antitumor protein neocarzinostatin [NCS] (molecular weight: 11,700). It has an approximate molecular weight of 15,000. We report here stability of SMANCS in oil and in water, and NCS in water, under various physical conditions such as exposure to heat, UV, pH, and ultrasonic treatment. Then, we carried out an experiment of transfer of SMANCS in lipid contrast medium [lipiodol] (oil phase) to water phase (blood and physiological saline) in vitro. Results are summarized as follows: In aqueous condition, SMANCS is far more stable than NCS against the exposure to heat and UV, though it is inactivated by excessive exposures. SMANCS in an oily medium was found much more stable even at higher temperatures than in the aqueous phase. Both SMANCS and NCS are the most stable at pH 4.9-6.0. SMANCS dissolved in oil transferred to water phase slowly, having T1/10 of 24 hours (in case of lipiodol). This helps maintaining the anticancer effect of the drug in vivo for a long period of time. SMANCS in lipiodol was found to exert its action against cultured tumor cells as in an aqueous solution.

Antibiotics, Antineoplastic↗
PubMed1986

Phase II study of rDNA alpha-2 interferon (INTRON A) in patients with multiple myeloma utilizing an escalating induction phase.

Twenty previously treated patients with multiple myeloma were treated with rDNA human alpha-2 interferon (INTRON A) in a phase II trial. Patients received an induction phase of therapy consisting of 3-100 X 10(6) IU/m2 iv given every other day pending myelosuppression. Patients then received 10 X 10(6) IU/m2 three times a week sc. In patients not responding to the iv and sc protocol, prednisone (20 mg orally) was given with each dose of INTRON A to determine whether additional responses could be produced and whether toxicity could be reduced. During the sc phases of therapy, INTRON A was escalated pending hematologic and nonhematologic toxicity. Three partial remissions were achieved in patients receiving the initial iv/sc therapy, and one additional patient responded when prednisone was added (durations of remission, 5, 6, 8, and 9 months). Myelosuppression was the dose-limiting toxic effect in both the iv and sc phases of therapy. Constitutional symptoms (flu-like) were seen in the majority of patients, but were tolerable. With the utilization of prednisone, flu-like symptoms were reduced in frequency and degree. Escalation of the dose of INTRON A was possible in the majority of patients when prednisone was added; however, only one patient (of seven) responded to combination therapy. INTRON A can produce remissions in 20% of patients with previously treated multiple myeloma. No improvement in the response rate was achieved utilizing a high-dose induction program. Although the dose of INTRON A could be escalated when prednisone was added, the response rate was not enhanced.

Adult↗
PubMed1983

Rat alpha 1-cysteine proteinase inhibitor. An acute phase reactant identical with alpha 1 acute phase globulin.

alpha 1-Cysteine proteinase inhibitor was isolated from normal and acute phase rat serum. The procedure, which includes successive fractionations on AcA 34, Cibacron blue Sepharose, DEAE-Sephacel, and hydroxyapatite, but avoids the use of an affinity chromatography step on a cysteine proteinase gel, led to the preparation of two electrophoretically distinct components. These resolved to a single band of apparent Mr = 68,000 when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A slightly higher Mr was estimated from gel filtration studies, possibly related to the rather high carbohydrate content (15.25% of the dry weight). The purified protein exhibited strong inhibiting capacity towards papain with a Ki of 5 X 10(-11) M. As shown by immunochemical quantitation as well as functional activity, a 6-10-fold increase in the alpha 1-cysteine cysteine proteinase inhibitor content was recorded in inflammatory serum, thus demonstrating the protein to be a typical acute phase reactant. Its partial physicochemical characterization (Mr, isoelectric point, extinction coefficient, amino acid and carbohydrate compositions) shows large similarities with alpha 1 acute phase globulin whose biological function remains unknown, and which is present at the same concentration (about 0.5 g/liter) in normal serum. Identity between the two molecules has been further demonstrated by double immunodiffusion analysis since a continuous precipitating line was observed when purified alpha 1-cysteine proteinase inhibitor was reacted against anti-alpha 1 acute phase globulin and anti-alpha 1-cysteine cysteine proteinase inhibitor antibodies.

Amino Acids↗
PubMed1984

The acute phase response of mouse liver. Genetic analysis of the major acute phase reactants.

We have examined changes in translatable liver mRNAs during the acute phase response in several inbred mouse strains. Induction of mRNAs for the known acute phase reactants serum amyloid A, hemopexin, haptoglobin, and alpha 1-acid glycoprotein was observed. Two alpha 1-acid glycoproteins, termed AGP-1 and AGP-2, differing in size and charge, were found in all mice and appear to derive from distinct yet closely related mRNAs. Polymorphism in the structure of AGP-1 among strains was used to map the structural gene, Agp-1, to chromosome 4 near the b locus. Structural variation for serum amyloid A enabled mapping its structural gene, S alpha alpha, to chromosome 7, near Gpi-1. A wild-derived population of mice, Mus spretus, contains several variations of interest, including structural variations in many acute phase proteins and a putative regulatory variation specific to AGP-1. Further analysis of these genetic variants should provide novel insights into the acute phase response and the factors that mediate it.

Animals↗
PubMed1981

[Exponential growth status of the cell number. I. The independence of the portion of proliferating cells found in different phases of the mitotic cycle from the variability in phase durations].

A mathematical model of the cell tumour kinetics has been analysed for a population being characterized with the exponential growth of the cell number, the absence of cell losses, and the proliferative pool Pc less than or equal to 1. It is shown that the values of part of proliferative cells, being in one phase of the mitotic cycle, do not depend on the kind of cell distribution function in respect to the phase duration. A graphic method is proposed for the estimation of the proliferative pool, the mean mitotic duration and the doubling time of the cell number, provided we know the mitotic, index, the index of the phase S, and the mean durations of mitotic cycle, of mitosis and of phase S.

Cell Count↗
PubMed1999

BCR/ABL- CD34(+)HLA-DR- progenitor cells in early chronic phase, but not in more advanced phases, of chronic myelogenous leukemia are polyclonal.

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia (Ph) translocation and BCR/ABL gene rearrangement which occur in a pluripotent hematopoietic progenitor cell. Ph-negative (Ph-) hematopoiesis can be restored in vivo after treatment with -interferon or intensive chemotherapy, suggesting that normal stem and progenitor cells coexist with the Ph+ clone. We have previously shown that Ph- progenitors are highly enriched in the CD34(+)HLA-DR- fraction from early chronic phase (ECP) CML patients. Previous studies have suggested that the Ph-translocation represents a secondary clonal hit occurring in an already clonally mutated Ph- progenitor or stem cells, leaving the unanswered question whether Ph- CD34(+)HLA-DR- progenitors are normal. To show the clonal nature of Ph- CD34(+)HLA-DR- CML progenitors, we have compared the expression of BCR/ABL mRNA with X-chromosome inactivation patterns (HUMARA) in mononuclear cells and in CD34(+)HLA-DR+ and CD34(+)HLA-DR- progenitors in marrow and blood obtained from 11 female CML patients (8 in chronic phase and 3 in accelerated phase [AP] disease). Steady-state marrow-derived BCR/ABL mRNA-, CD34(+)HLA-DR- progenitors had polyclonal X-chromosome inactivation patterns in 2 of 2 patients. The same polyclonal pattern was found in the progeny of CD34(+)HLA-DR- derived long-term culture-initiating cells. Mobilization with intensive chemotherapy induced a Ph-, BCR/ABL mRNA- and polyclonal state in the CD34(+)HLA-DR- and CD34(+)HLA-DR+ progenitors from 2 ECP patients. In a third ECP patient, polyclonal CD34(+) cells could only be found in the first peripheral blood collection. In contrast to ECP CML, steady-state marrow progenitors in late chronic phase and AP disease were mostly Ph+, BCR/ABL mRNA+, and clonal. Further, in the majority of these patients, a Ph-, polyclonal state could not be restored despite mobilization with intensive chemotherapy. We conclude from these studies that CD34(+)HLA-DR- cells that are Ph- and BCR/ABL mRNA- are polyclonal and therefore benign. This population is suitable for autografting in CML.

Adult↗
PubMed2006

Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study.

BACKGROUND: It has been proposed that objective cognitive testing provides additional information to that collected via adverse event (AE) recordings. However, in clinical trials of compounds with potentially negative effects on cognition, the results of cognitive testing may overlap with AE recordings. AIMS: To examine cognitive function in subjects who do and do not report sedation-related AEs in a Phase I clinical trial. METHODS: Five computerized cognitive tasks were administered to 28 healthy male volunteers enrolled in a simulated Phase I study using midazolam to induce sedation-related AEs and cognitive dysfunction. For each subject, the magnitude of cognitive change between pre-dose and 1 hr post-dose assessments was calculated. Group and individual level cognitive outcome was compared between subjects who did and did not report sedation-related AEs following administration of 1.75 and 5.25 mg midazolam. RESULTS: At both doses of midazolam, cognitive dysfunction was observed in both subject groups (i.e., those who did and did not report AEs). Analysis of individual outcomes identified consistent cognitive dysfunction among subjects who reported sedation-related AEs. Further, in the 5.25 mg condition a subset of individuals (66.7%) who did not report sedation-related AEs nevertheless displayed substantial cognitive dysfunction. CONCLUSIONS: Following administration of oral midazolam, there is a dissociation between sedation-related AE recordings and performance on computerized cognitive tests of motor function, attention, strategy use and problem solving, learning and delayed recall. Inclusion of computerized cognitive tests in early phase trials may allow identification of subtle cognitive change, beyond that which is possible by self-report and clinical observation.

Adolescent↗
PubMed1996

P21waf-1/cip-1/sdi-1 is expressed at G1 phase in primary culture of hepatocytes from old rats, presumably preventing the cells from entering the S phase of the cell cycle.

To elucidate whether p21waf-1/cip-1/sdi-1 expression is associated with loss of growth potential of hepatocytes of old rats, we determined p21waf-1/cip-1/sdi-1 expression of hepatocytes from old (30 months) rats during the cell cycle in primary culture. A high level of expression of p21waf-1/cip-1/sdi-1 was detected at the G1 phase in old-rat hepatocytes, but after the S phase in young-rat hepatocytes. Consistently, the incidence of the cells positive for p21waf-1/cip-1/sdi-1 in nuclei before entering the S phase was significantly higher in old-rat hepatocytes than in young-rat hepatocytes. These results account for the loss of growth potential of old-rat hepatocytes in vitro and the marked retardation of regeneration of liver in old rats in vivo.

Animals↗
PubMed1990

Acute phase reaction in rats: independent change of acute phase protein plasma concentration and macroscopic inflammation in primary rat adjuvant inflammation.

Experiments in rats suffering from primary acute adjuvant inflammation showed independent changes in serum acute phase protein concentration and macroscopic paw inflammation during antiinflammatory treatment: soybean trypsin inhibitor and horse-radish peroxidase caused antiinflammatory effects but simultaneously produced increased alpha 2 macroglobulin levels. On the other hand, cycloheximide significantly inhibited the increase of alpha 2 macroglobulin concentration in adjuvant inflammation, however, it had no antiinflammatory effect. All forms of treatment caused even some change in protein plasma levels of healthy rats which probably relates to an activation of cells producing interleukin-1, interleukin-6, and/or hepatocyte stimulating factor which trigger the synthesis of acute phase proteins in the liver. In inflamed rats, the snake venom batroxobin caused a significant decrease in the fibrinogen level whereas the paw swelling remained completely unaffected. Therefore, it seems to be doubtful whether acute phase proteins essentially contribute to the modulation of acute inflammatory reaction in primary rat adjuvant inflammation.

Acute-Phase Proteins↗
PubMed2001

Differential sensitivity to etoposide (VP-16)-induced S phase delay in a panel of small-cell lung carcinoma cell lines with G1/S phase checkpoint dysfunction.

PURPOSE: The highly schedule-dependent cytotoxic agent etoposide (VP-16) is initially effective in the treatment of small-cell lung cancer (SCLC), particularly in multidrug combination chemotherapy. Heterogeneity in cellular sensitivity to cell cycle arrest may underpin the inadequacy of low-dose extended-cycle single-agent regimes in tumours with partially dysfunctional apoptotic signalling pathways. We have studied the longevity and dose dependency of cell cycle and to a limited extent the apoptotic responses of a panel of seven unselected SCLC cell lines, screened for TP53 status. METHODS: Cells were analysed using flow cytometry for the cell cycle responses and field inversion gel electrophoresis for apoptotic patterns. The mitotic inhibitor nocodazole was used to assess and correct cell line response data for differences in cell cycle traverse per se. RESULTS: An overall lack of G1/S arrest and muted DNA fragmentation were consistent with the presence of TP53 gene abnormalities. Maximal G2 arrest but with clear recovery potential occurred at an exposure dose (ED, concentration of drug x time) value of approximately 24 microM h. Higher doses (ED values >48 microM h) revealed a wide variation in S phase delay that was independent of population doubling time and could not be compensated for by drug concentration changes alone. CONCLUSION: The results suggest that heterogeneity in the in vitro sensitivity of unselected SCLC cell lines to S phase arrest is demonstrable at ED values projected to be critical for clinical activity. Such variation in S phase responsiveness may reflect differences in checkpoint activation and offer a functional target for the design of more-effective combination therapy.

Antineoplastic Agents, Phytogenic↗