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1.
I Laws P G Mantle L Rodrigues R H Penny 《Xenobiotica; the fate of foreign compounds in biological systems》1987,17(8):973-979
1. Verruculogen is eliminated in bile after transformation to TR-2, only a trace of which was excreted as such in faeces of sheep given verruculogen per os. Negligible TR-2 was present free in urine; no glucuronide was found. 2. An isomer of TR-2, a minor component of the bile of sheep given verruculogen, has been defined by 1H-n.m.r. spectroscopy and the isomerism involves the disposition of the two adjacent hydroxyl groups with a concomitant change in the conformation of the ring adjacent to the indole. 3. 14C-TR-2, added to the perfusate of isolated rat liver, was excreted unchanged in the bile, implying no significant loss of any biliary TR-2 subject to enterohepatic recycling in vivo. 4. 14C-TR-2 incubated anaerobically in sheep ileum contents was 95% transformed into more polar metabolites, the majority of the radiolabelled metabolites isolated being water soluble. 5. The principal fate of biliary TR-2 is as a metabolic substrate for the intestinal microflora. 相似文献
2.
R. Alan Aitken Michael C. Bibby John A. Double Andrea L. Laws Robert B. Ritchie David W. J. Wilson 《Archiv der Pharmazie》1997,330(7):215-224
A range of 18 derivatives of flavone-8-acetic acid (FAA) with substituents on the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. There was no clear-cut relationship between in vitro and in vivo activity but the activity in each situation was found to be very sensitive to the precise substitution pattern with closely related isomers giving widely different activities. Some of the compounds, notably 10b,cj , and r , were active in vivo and these require further studies in order to evaluate their potential for development. 相似文献
3.
Ten congenitally athymic "nude" mice and 10 immunocompetent mice underwent intrathecal inoculation with a human glioblastoma cell line (U87MG) via percutaneous lumbar puncture (5 x 10(5) cells/animal). All of the nude mice developed paraplegia with or without incontinence at 2 weeks and routinely died of inanition 3 weeks postimplantation. Histological examination confirmed extensive proliferation of neoplastic cells within the intrathecal space. A second group of animals was inoculated with 5 x 10(4) cells/animal: 20 nude mice, 10 cyclosporine A-immunosuppressed animals, and 10 immunocompetent control mice. The 20 mice were further divided into four subsets. Subset A did not receive chemotherapy, Subset B received 200 mg of carmustine (BCNU) per m2 by intraperitoneal injection, Subset C received a single dose of 4 mg of methotrexate (MTX) per m2 by intrathecal injection 4 hours after tumor inoculation, and Subset D received 12 mg of intrathecal MTX per m2. Decreasing the concentration of cells per animal by 1 log doubled the time interval required for the development of paralysis and incontinence to 4 weeks. Treatment with intrathecal MTX at a dose of 4 mg/m2 extended the symptom-free period by an additional week (to 5 weeks postinoculation), and a dose of 12 mg/m2 allowed an average of 6 weeks before the onset of neurological impairment. The xenografts did not grow in the immunocompetent control mice, the BCNU-treated group, or the cyclosporine A-immunosuppressed animals. An intrathecal xenograft model of central nervous system malignancies allows a novel approach to the evaluation of experimental chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
4.
E G Shaw C Daumas-Duport B W Scheithauer D T Gilbertson J R O'Fallon J D Earle E R Laws H Okazaki 《Journal of neurosurgery》1989,70(6):853-861
The records of 167 patients with grade 1 or 2 supratentorial pilocytic astrocytomas (41 patients), ordinary astrocytomas (91 patients), or mixed oligoastrocytomas (35 patients) diagnosed between 1960 and 1982 are retrospectively reviewed. The extent of surgical tumor removal was gross total or radical subtotal in 33 patients (20%) and subtotal or biopsy only in the remaining 134 patients (80%). Postoperative radiation therapy was given to 139 (83%) of the 167 patients, with a median dose of 5000 cGy (range 600 to 6500 cGy). Multivariate analysis revealed that a pilocytic histology was the most significant prognostic variable associated with a good survival. The 5- and 10-year survival rates were, respectively, 85% and 79% for the 41 patients with pilocytic astrocytomas compared to 51% and 23% for the 126 patients with ordinary astrocytomas or mixed oligoastrocytomas. Postoperative irradiation did not appear to be associated with improved survival times in the patients with pilocytic astrocytomas; however, in the 126 patients with ordinary astrocytomas or mixed oligoastrocytomas, those who received "high-dose" radiation (greater than or equal to 5300 cGy) had significantly better survival times than those who received "low-dose" radiation (less than 5300 cGy) or surgery alone. The 5- and 10-year survival rates were, respectively, 68% and 39% for the 35 patients receiving high-dose radiation, 47% and 21% for the 67 receiving low-dose radiation, and 32% and 11% for the 19 treated with surgery alone. The survival rate was poor for the 23 patients with ordinary astrocytomas and oligoastrocytomas who underwent gross total or radical subtotal tumor removal (14 of whom were also irradiated): 52% at 5 years and 21% at 10 years, with 19 of 23 patients developing tumor progression and dying 1 to 12 years postoperatively. In contrast, all 10 patients with pilocytic astrocytomas who had gross total or radical subtotal tumor removal alone were long-term survivors, with follow-up periods of about 4 to 25 years. 相似文献
5.
Reddy MV Storer RD Laws GM Armstrong MJ Barnum JE Gara JP McKnight CG Skopek TR Sina JF DeLuca JG Galloway SM 《Environmental and molecular mutagenesis》2002,40(1):1-17
3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, DNA strand breaks, chromosomal aberrations (Abs), inhibition of DNA synthesis, and mutations. All compounds produced DNA adducts in calf thymus DNA in the presence of rat liver S9. In cultured rat hepatocytes, all produced DNA adducts but none induced DNA strand breaks. In Chinese hamster ovary cells, 3MI and Mel produced DNA adducts, Abs, and inhibition of DNA synthesis with and without S9, except that Mel without S9 did not form adducts. Ser formed DNA adducts, was an equivocal Abs inducer, and suppressed DNA synthesis. Tryp induced neither adducts nor Abs, but did suppress DNA synthesis with S9. Ser and Tryp were less cytotoxic than 3MI and Mel. Mel, Ser, and Tryp failed to induce mutations in Salmonella and E. coli strains with or without S9. 3MI and Mel produced DNA adducts but not mutations in Salmonella TA100 with S9. 3MI and its metabolite indole 3-carbinol also did not induce mutations in a shuttle vector system in human cells. The lack of correlation between DNA adducts and other genotoxicity endpoints for these indole compounds may be due to the higher sensitivity of the (32)P-postlabeling adduct assay or it may indicate that the indole-DNA adducts per se are not mutagenic and are not able to induce strand breaks or alkali-labile lesions. The indole-induced Abs may result from cytotoxicity and suppression of DNA synthesis with minimal if any contribution from DNA adducts. 相似文献
6.
Alyce C. Russell Agnieszka Kepka Irena Trbojević-Akmačić Ivo Ugrina Manshu Song Jennie Hui Michael Hunter Simon M. Laws Gordan Lauc Wei Wang 《Immunobiology》2019,224(1):110-115
Background
Increased body fat may be associated with an increased risk of developing an underlying pro-inflammatory state, thus leading to greater risk of developing certain chronic conditions. Immunoglobulin G has the ability to exert both anti- and pro-inflammatory effects, and the N-glycosylation of the fragment crystallisable portion is involved in mediating this process. Body mass index, a rudimentary yet gold standard indication for body fat, has been shown to be associated with agalactosylated immunoglobulin G N-glycans.Aim
We aimed to determine the association between increased body fat and the immunoglobulin G glycosylation features, comparing body mass index to other measures of body fat distribution.Methods
We investigated a sample of 637 community-based 45–69?year olds, with mixed phenotypes, residing in Busselton, Western Australia. Body mass index and the waist-to-hip and waist-to-height ratios were calculated using anthropometry, while dual-energy x-ray absorptiometry was performed to gain an accurate measure of total and area specific body fat. Serum immunoglobulin GN-glycans were analysed by ultra-performance liquid chromatography.Results
Twenty-two N-glycan peaks were found to be associated with at least one of the fat measures. While the previous association of body mass index to agalactosylated immunoglobulin G was replicated, measures of central adiposity explained the most variation in the immunoglobulin G glycome.Conclusion
Central adiposity is associated with an increased pro-inflammatory fraction of immunoglobulin G, suggesting that the android/gynoid ratio or waist-to-height ratio instead be considered when controlling for adiposity in immunoglobulin G glycome biomarker studies. 相似文献7.
Laws KR 《Cognitive neuropsychiatry》1999,4(1):1-30; discussion 31-5
A majority of studies show that schizophrenics perform poorly on so-called tests of executive or frontal lobe function--the paradigmatic case being the Wisconsin Card Sort Test (WCST). Nevertheless, the specific character of this deficit in schizophrenia remains underspecified. In particular, it seems premature to assume that schizophrenia is characterised by an executive dysfunction and/or a disorder of frontal lobe function before determining whether any deficit is: selective; disproportionate to the general level of intellectual functioning; or qualitatively comparable with that of frontal lobe patients. A meta-analysis was conducted on 29 studies comparing the performance of schizophrenics and normal controls on the WCST. This showed that the mean weighted effect size was large for categories achieved (d = 0.91), medium for absolute level of perseveration (d = 0.53), but only small for the proportion of perseverative errors (d = 0.18). By contrast, the effect size for Wechsler Adult Intelligence Scale Intelligence Quotient (WAIS IQ) in a subset of these studies (d = 1.23) was significantly larger than for any WCST measures. This pattern of findings challenges notions that schizophrenia is characterised by an executive dysfunction that is: selective; disproportionate to IQ level; and analogous to that found in frontal lobe patients. Rather, the poor WCST performance of schizophrenics appears to reflect a generalised intellectual deficit. 相似文献
8.
1. In the first experiment sheep taken from pasture were given a low-protein diet for six weeks in individual pens. Then, for 1 week, groups were given a supplement of lucerne chaff, safflower meal or lucerne chaff plus safflower meal. In the second experiment eighteen sheep maintained on lucerne chaff rather than pasture were then depleted of protein to a greater extent by feeding on a restricted low-protein diet. Six of the sheep received a supplement of molasses throughout the period of protein depletion while six of the sheep on the basal ration received a supplement of safflower meal after 6 weeks on the low-protein diet. 2. The urea tolerance of the sheep, is indicated by blood ammonia levels after oral dosing with aqueous solutions of urea, was determined after the period of supplementation. "Arginine synthetase" activity (combined activities of argininosuccinate synthetase (EC 6.3.4.5) and argininosuccinate lyase (EC 4.3.2.1) was determined in liver samples obtained by biopsy at various intervals during the experiment. 3. Supplementation for 7 d with 73 g crude protein (nitrogen X 6-25)/d increased the tolerance to urea as indicated by reduced blood NH3 levels, and also increased "arginine synthetase" activity. 4. Giving supplements of molasses delayed the onset of urea toxicity but not the extent of toxicity. 5. It is suggested that short-term feeding of protein concentrates to sheep before giving urea supplements can increase their tolerance to urea. 相似文献
9.
BACKGROUND: Cushing's disease causes significant pathological changes throughout the body as a result of elevated cortisol levels. Very few systematic investigations have focused on the morphologic effects of hypercortisolism on the central nervous system. The validity of using premature cerebral atrophy as a diagnostic tool for Cushing's disease remains unknown. METHODS: This study includes 63 patients with Cushing's disease who were evaluated and treated at the University of Virginia Medical Center. Radiologists randomly compared these individuals with age- and sex-matched controls in a blinded protocol, assessing the degree of cerebral atrophy on computed tomography and magnetic resonance scans. RESULTS: Patients with Cushing's disease showed significant premature atrophy when compared with controls. This trend continued after subdividing the groups based on age and duration of symptoms except in the following groups: age greater than 60, duration of symptoms less than 1 year, and symptoms lasting between 4-5 years. CONCLUSIONS: Excluding the three aforementioned groups, the hypercortisolemic state manifested in patients with Cushing's disease promotes the premature development of cerebral atrophy, which can be identified on routine radiologic imaging and may assist in the clinical diagnosis of the condition. 相似文献
10.
Adjuvant radiation therapy after surgical resection of solitary brain metastasis: association with pattern of failure and survival 总被引:6,自引:0,他引:6
S R Smalley M F Schray E R Laws J R O'Fallon 《International journal of radiation oncology, biology, physics》1987,13(11):1611-1616
We reviewed patients treated by resection of solitary cerebral metastasis at the Mayo Clinic from January 1, 1972, to December 1, 1982. Eighty-five patients rendered clinically disease-free and who received intramural follow-up after craniotomy were studied. Adjuvant whole-brain radiation therapy (WBRT) was delivered to 34, and 51 were observed after craniotomy. Pattern-of-failure analysis showed a much smaller incidence of subsequent brain relapse in the adjuvant WBRT group than in the observation group (21% versus 85%, respectively). Multivariate analysis utilizing 17 patient, tumor, and treatment characteristics showed adjuvant WBRT to have the strongest association with brain control (p less than 0.0001). The only other variable which was significant (p less than 0.01) was multilobe involvement of the metastatic lesion, which was associated with a greater likelihood of brain failure. Systemic failures were more frequent (61% versus 37%), and the proportion of patients remaining disease-free (29% versus 4%) was higher in the adjuvant group. Those patients who received adjuvant WBRT to a dose of 39 Gy or greater manifested an 11% rate of subsequent brain failure versus a 31% rate when less than 39 Gy was delivered. The median survival was longer for the adjuvant WBRT group (21 months versus 11.5 months). Multivariate analysis indicated that adjuvant WBRT was one of several variables (including female gender, long disease-free survival, and good neurologic function prior to craniotomy) significantly associated with improved survival. This study suggests that adjuvant cranial irradiation may help prevent clinical recurrence of resected metastatic intracranial disease and that improved control of intracranial disease may be associated with an improved survival in patients without clinical evidence of systemic disease at the time of craniotomy. 相似文献