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Biomedical subjects

A L Jones

Publications and source records attributed to A L Jones.

At least 145 records · Page 8Linked to original sources
PubMed1993

Temperature-induced membrane-lipid adaptation in Acanthamoeba castellanii.

A method has been developed for the separation of the major membrane fractions of Acanthamoeba castellanii after growth at different temperatures. The acyl-lipid compositions of individual membrane fractions, microsomal membranes, plasma membrane and mitochondria were analysed after a shift in culture temperature from 30 degrees C to 15 degrees C. The major change in lipid composition observed was an alteration in the relative proportions of oleate and linoleate. This reciprocal change was seen in all the membrane fractions, but occurred most rapidly in the phosphatidylcholine of the microsomal fraction. Thus, there appears to be a rapid induction of delta 12-desaturase activity in A. castellanii after a downward shift in growth temperature. Changes were also seen in the proportions of the n-6 C20 fatty acids, with a decrease in the proportions of icosadienoate and increases of icosatrienoate and arachidonate. However, unlike the alteration in oleate/linoleate ratios, this change was not seen in all the individual lipids of each membrane fraction.

Acanthamoeba↗
PubMed1993

Pseudomonas exotoxin-based immunotoxins containing the antibody LL2 or LL2-Fab' induce regression of subcutaneous human B-cell lymphoma in mice.

We have produced immunotoxins using LL2, a monoclonal antibody which binds to human B-cell lymphomas and which, in a radioiodinated form, induced responses in lymphoma patients (D.M. Goldberg et al., J. Clin. Oncol., 9: 548-564, 1991). We have coupled LL2 to Lys-PE38KDEL, a derivative of Pseudomonas exotoxin (PE) which does not bind to the PE receptor. LL2-PE38KDEL was cytotoxic toward several Burkitt's lymphoma lines, with 50% inhibitory concentration values ranging from 2 to 6 ng/ml (10-30 pM). Another immunotoxin, LL2-Fab'-PE38KDEL, was produced by chemically coupling the Fab' fragment of LL2 to Lys-PE38KDEL. LL2-Fab'-PE38KDEL also was cytotoxic toward the Burkitt's cells, with a 50% inhibitory concentration of 1-2 ng/ml (13-24 PM). The antibody LL2 alone had no cytotoxicity toward the malignant cells, and excess LL2 prevented the cytotoxicity of LL2-PE38KDEL and LL2-Fab'-PE38KDEL. Control immunotoxins UPC-10-PE38KDEL and Mu-9-Fab'-PE38KDEL were not cytotoxic. LL2-PE38KDEL and LL2-Fab'-PE38KDEL bound to cells with 50% and 17% of the affinity of LL2, respectively. Both immunotoxins, but not UPC-10-PE38KDEL, prevented the development of CA-46 tumors in nude mice. LL2-PE38KDEL and LL2-Fab'-PE38KDEL, but not the control immunotoxins, led to complete regressions of measurable s.c. CA-46 tumors in nude mice, when given at 50% and 35% of the 50% lethal dose, respectively. LL2 alone significantly retarded the growth of CA-46 tumors but did not cause complete tumor regressions. Immunotoxins containing derivatives of Pseudomonas exotoxin can be targeted to human B-cell lymphoma and merit further study as potential therapeutic agents.

ADP Ribose Transferases↗
PubMed1993

Primary medical (neo-adjuvant) chemotherapy for operable breast cancer.

84 patients with large operable breast cancer have been treated with primary medical chemotherapy rather than mastectomy in three sequential studies. 86% had tumours greater than 4 cm in diameter; median diameter was 6 cm (range 1-12). Median age was 46 years (range 23-66). In the first two studies 64 patients were treated with either CMF [cyclophosphamide 100 mg orally days 1-14, methotrexate 50 mg intravenously (i.v.) days 1 and 8, and 5-fluorouracil 1 g i.v. days 1 and 8, repeating at 28-day intervals for six courses] or MMM (mitozantrone 8 mg/m2 i.v. once every 3 weeks, methotrexate 50 mg i.v. once every 3 weeks, mitomycin C 8 mg/m2 once every 6 weeks, for 8 courses). 69% achieved an overall response including 17% complete remissions. 27% have had local relapse but only 3% uncontrolled local relapse. Only 14% have required mastectomy. In the third study which is ongoing, 19 patients have been treated with infusional FEC (5-fluorouracil 200 mg/m2 i.v. 24 hourly by continuous infusion via a Hickman line for 6 months, epirubicin 50 mg/m2 i.v. bolus once every 3 weeks for 6 months, cisplatin 60 mg/m2 i.v. once every 3 weeks for 6 months with appropriate intravenous hydration). Overall response rate so far is 84% with 58% complete remissions. There have been no local relapses and no patient has required mastectomy. This study demonstrates that primary medical chemotherapy can be used to avoid mastectomy in the great majority of patients presenting with large operable primary breast cancer. Infusional FEC may be more active than conventional chemotherapy in terms of overall response and complete remission rate, and infusional FEC chemotherapy now needs to be compared with conventional chemotherapy. The concept of primary medical therapy should also be compared with conventional mastectomy followed by adjuvant chemotherapy.

Adult↗
PubMed1993

Evaluation of fluticasone propionate (500 micrograms day-1) administered either as dry powder via a Diskhaler inhaler or pressurized inhaler and compared with beclomethasone dipropionate (1000 micrograms day-1) administered by pressurized inhaler.

Five hundred and eighty-five patients with moderate asthma, currently receiving 400-1000 micrograms day-1 of an inhaled corticosteroid, were treated for 6 weeks in a double-blind, randomized, parallel group study with either 500 micrograms day-1 fluticasone propionate as a dry powder via a Diskhaler inhaler, 500 micrograms day-1 fluticasone propionate via a pressurized inhaler or 1000 micrograms day-1 beclomethasone dipropionate via a pressurized inhaler. For all three treatment groups, mean morning and evening peak expiratory flow rates (PEFRs) increased within 1 week of the start of treatment. There were also improvements in clinic lung function, daytime and night-time asthma symptoms and a reduction in daytime and night-time rescue bronchodilator medication in all three groups. There were no statistically significant differences between the two formulations of fluticasone propionate in any of the efficacy parameters. Fluticasone propionate via the Diskhaler was significantly more effective than beclomethasone dipropionate over the 6 week study period in reducing diurnal variation (mean difference--4 l min-1, 95% CI--8 to 0 l min-1: P = 0.03). Fluticasone propionate via the Diskhaler produced a statistically significant improvement in night-time symptoms when compared to beclomethasone dipropionate whereas, beclomethasone dipropionate 1000 micrograms day-1 was statistically significantly more effective than both formulations of fluticasone propionate in improving daytime symptoms (P < 0.05). However, these statistical differences must be viewed together with the fact that very few patients recorded a score of 2 or more for both daytime or night-time symptoms. There was a similarly low incidence of adverse events with all three treatments with no evidence of hypothalamic pituitary adrenal (HPA)-axis suppression. The results of the 6-week comparative study showed that 500 micrograms day-1 fluticasone propionate whether administered via pressurized inhaler or Diskhaler is as effective and as safe as 1000 micrograms day-1 beclomethasone dipropionate administered via a pressurized inhaler in the treatment of moderate asthma. Over 12 months fluticasone propionate 500 micrograms day-1 via a pressurized inhaler was at least as effective and as well tolerated as beclomethasone dipropionate 1000 micrograms day-1.

Adolescent↗
PubMed1993

Manganese dipyridoxal diphosphate-enhanced magnetic resonance imaging in the evaluation of hepatocyte function.

RATIONALE AND OBJECTIVES: To determine whether contrast-enhanced magnetic resonance imaging can detect ethanol hepatotoxicity in rats. METHODS: Rats were treated with a single high dose of ethanol (acute) intraperitoneally or with a 36% ethanol diet (chronic) for up to 5.5 months. Magnetic resonance imaging was performed before and after intravenous administration of manganese dipyridoxal diphosphate (Mn-DPDP). RESULTS: Enhancement (acute group) was significantly lower in ethanol treated animals on T1-weighted scans (P < .02). Precontrast, a significant difference in intensity was seen on T2-weighted scans (P < .01). Electron microscopy revealed severe hepatocyte damage. In the chronic groups, there was no significant difference in intensity precontrast. Postcontrast, enhancement (ethanol group) was significantly lower on T1-weighted scans only at 2 weeks (P < .05). Electron microscopy demonstrated progressive ethanol hepatotoxicity. CONCLUSIONS: Magnetic resonance imaging can distinguish between normal and certain types of ethanol damaged livers on T1-weighted scans. Enhancement, however, does not correlate with progressive microscopic liver damage.

Animals↗
PubMed1993

Interaction of insulin with Pseudomonas pseudomallei.

Pseudomonas pseudomallei is the causative agent of melioidosis, a disease being increasingly recognized as an important cause of morbidity and mortality in many regions of the world. An intriguing observation regarding melioidosis is that a significant percentage of patients who develop the disease have preexisting diabetes mellitus. In this regard, we have tested the hypothesis that insulin may modulate the growth of P. pseudomallei. We have demonstrated that insulin markedly inhibits the growth of P. pseudomallei in vitro and in vivo. The growth rate of P. pseudomallei in minimal medium containing human recombinant insulin was significantly lower than that of control cultures containing no insulin. P. pseudomallei grew at an increased rate in serum samples obtained from diabetic rats compared with that in serum samples obtained from control animals. When the insulin level was restored by the addition of human recombinant insulin, the growth rate was reduced to a level similar to that seen in control serum. P. pseudomallei also grew significantly better in insulin-depleted human serum than control human serum. 125I-insulin binding studies demonstrated that P. pseudomallei possesses a specific, high-affinity binding site for human insulin. In in vivo studies, rats made diabetic by streptozotocin injection (80 mg/kg of body weight, intraperitoneally) were significantly more susceptible to P. pseudomallei septicemia than control rats. Thus, it appears that serum insulin levels may play a significant role in modulating the pathogenesis of P. pseudomallei septicemic infections.

Animals↗
PubMed1993

Nucleotide sequence analysis of a transposon (Tn5393) carrying streptomycin resistance genes in Erwinia amylovora and other gram-negative bacteria.

A class II Tn3-type transposable element, designated Tn5393 and located on plasmid pEa34 from streptomycin-resistant strain CA11 of Erwinia amylovora, was identified by its ability to move from pEa34 to different sites in plasmids pGEM3Zf(+) and pUCD800. Nucleotide sequence analysis reveals that Tn5393 consists of 6,705 bp with 81-bp terminal inverted repeats and generates 5-bp duplications of the target DNA following insertion. Tn5393 contains open reading frames that encode a putative transposase (tnpA) and resolvase (tnpR) of 961 and 181 amino acids, respectively. The two open reading frames are separated by a putative recombination site (res) consisting of 194 bp. Two streptomycin resistance genes, strA and strB, were identified on the basis of their DNA sequence homology to streptomycin resistance genes in plasmid RSF1010. StrA is separated from tnpR by a 1.2-kb insertion element designated IS1133. The tnpA-res-tnpR region of Tn5393 was detected in Pseudomonas syringae pv. papulans Psp36 and in many other gram-negative bacteria harboring strA and strB. Except for some strains of Erwinia herbicola, these other gram-negative bacteria lacked insertion sequence IS1133. The prevalence of strA and strB could be accounted for by transposition of Tn5393 to conjugative plasmids that are then disseminated widely among gram-negative bacteria.

Amino Acid Sequence↗
PubMed1993

CVM versus ACE in the treatment of small cell lung cancer.

In an attempt to achieve adequate palliation in patients with small cell lung cancer (SCLC) while keeping toxicity to a minimum, we compared CVM (carboplatin/vinblastine/methotrexate) and standard therapy with ACE (doxorubicin/cyclophosphamide/etoposide). None of the 104 SCLC patients with limited or extensive disease who participated had received previous treatment. After stratification according to disease extent, patients were randomized to receive either CVM or ACE. The maximum number of chemotherapy courses was six. When response rates were compared, ACE was found to be somewhat superior to CVM in terms of objective response [CVM 67%, 95% confidence interval (CI) 54-79%; ACE 88%, 95% CI 80-97%; p = 0.06]; however, a significant difference was evident only among extensive-disease patients. Median response durations (CVM 6 months, 95% CI 5-8; ACE 5 months, 95% CI 3-6) and median survival times (CVM 8 months, 95% CI 7-10; ACE 7 months, 95% CI 4-9) were comparable. CVM met the goal of producing significantly less hematologic toxicity than occurred with ACE. Leukopenia affected 92% of ACE-treated patients and 48% of CVM-treated patients (p = 0.005), and was severe in 80% of the ACE group and 20% of the CVM group. Alopecia occurred much more frequently among those treated with ACE (91 vs. 24%; p < 0.001), as did infection (59 vs. 24%; p < 0.001). The selection of a specific chemotherapy regimen must be individualized. CVM may be appropriate for patients in whom intensive chemotherapy is contraindicated due to performance status, age, concomitant medical disease, or patient refusal.

Adult↗
PubMed1993

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.

Animals↗
PubMed1993

A patient with neurosyphilis presenting as chorea.

Despite the marked decline in frequency of neurosyphilis over the past three decades in the United Kingdom, new cases continue to appear both sporadically and as a complication of HIV infection. There is clinical evidence that neurosyphilis is becoming less typical. We describe a case of neurosyphilis presenting predominantly with choreoathetosis and associated hemiparesis in an otherwise healthy, immunocompetent patient. Only six cases of neurosyphilis presenting with features of basal ganglia damage have been reported in the recent literature, five of whom had HIV infection.

Athetosis↗
PubMed1993

The pharmacokinetics of five pre-mixed combinations of 'short-' and 'intermediate-acting' (NPH) insulins in healthy subjects following subcutaneous administration.

The pharmacokinetics of five pre-mixed insulin preparations in the ratio of soluble to NPH insulin of 10:90, 20:80, 30:70, 40:60 and 50:50, were examined in a two part study in fasting healthy subjects. Each received by bolus subcutaneous injection into the anterior abdominal wall, on separate occasions one to two weeks apart, 20U of each of three pre-mixed insulin preparations in random order. In Part 1, nine subjects received Penmix 10:90, Penmix 20:80 and Penmix 30:70 and were observed over a period of 24 hours. In Part 2, eight subjects received Penmix 30:70, Penmix 40:60 and Penmix 50:50 and were observed over an 8 hr post-injection period. Three subjects were common to both parts of the study. Plasma glucose, C-peptide and insulin levels were measured frequently throughout both study periods. Increasing soluble insulin content in the pre-mixtures was reflected in increasing peak plasma insulin concentrations and a greater hypoglycaemic response. There were highly significant differences between the five premixtures and preparations in the 0-4 and 0-8 hours area under the curve (AUC) values for plasma glucose, C-peptide and immunoreactive insulin concentration (p < 0.01). Whereas a gradual difference between the premixtures was seen no two adjacent ones were significantly different, however an overall highly significant difference between the five preparations tested was observed.

Adolescent↗
PubMed1992

Ontogeny of the secretory immune system: maturation of a functional polymeric immunoglobulin receptor regulated by gene expression.

In the rat, secretion of polymeric IgA from serum into bile is dependent upon the presence of a functional polymeric immunoglobulin receptor (pIgR) that acts as a hepatocyte plasma membrane receptor for ligand binding and as a transcellular transport molecule. The objective of this study was to document the developmental maturation and regulation of functionally intact rat liver pIgR. An adult pattern of IgA secretion was not detected until after day 23 postpartum (dPP), by using intravenously injected 125I-labeled dimeric IgA. Radioactive dimeric IgA was not detectable in hepatocyte transport vesicles until 21 dPP by electron microscopy autoradiographic analysis. By using a rabbit polyclonal antibody against the rat secretory component domain of the pIgR, Western blot analysis demonstrated that the plasma-membrane-bound pIgR levels in hepatocytes from rats aged 19-22 dPP increased 10-fold during this period. To determine whether or not this increase in membrane-bound pIgR reflected increased pIgR gene expression, we probed Northern blots of total cellular RNA extracted from neonatal rat liver with pIgR cDNA [GORF-1; Banting, G., Brake, B., Braghetta, P., Luzio, J.P. & Stanley, K. K. (1989) FEBS Lett. 254, 177-183]. The pIgR RNA levels between 19 and 22 dPP rose more than 20-fold and paralleled the increased membrane-bound pIgR protein during this same interval. These data demonstrate a developmentally regulated process that controls the ontogeny of biliary dimeric IgA secretion at the termination of the third week postpartum. The process appears to depend on the up-regulation of pIgR gene expression.

Aging↗
PubMed1992

A randomised phase II study of carmustine alone or in combination with tumour necrosis factor in patients with advanced melanoma.

Laboratory data suggest a synergistic interaction between carmustine (BCNU) and tumour necrosis factor (TNF) in melanoma. We therefore studied the activity of 200 mg/m2 BCNU given alone or in combination with 88 micrograms/m2 recombinant human TNF-alpha (rhTNF alpha) as a daily i.v. infusion for 5 days at 48-day intervals to patients with metastatic melanoma. In this randomised phase II trial, the rate of response to BCNU alone was 20% [95% confidence interval (CI), 2%-38%], and this was not improved by the addition of TNF (response rate, 10.5%; 95% CI, 1.3%-33%). Toxicity was higher in the combination arm, and there was no difference in survival.

Adolescent↗
PubMed1992

Influence of an endogenous lectin substrate on cultured dorsal root ganglion cells.

Dorsal root ganglion neurons normally contain a 14,500 molecular weight lactose-binding lectin, designated L-14. Although this lectin is developmentally regulated, and is localized to specific neurons as well as to specific areas of the rat spinal cord, its function in the nervous system is not known. In an effort to study the possible role of this lectin on peripheral neurons, they were dissociated and grown on substrates consisting of either L-14 or laminin, a molecule known to support neurite outgrowth. In contrast to the random distribution and fine neurites displayed by neurons on laminin, those growing on L-14 formed large aggregates with highly fasciculated neurite bundles. Experiments using plant lectins with sugar-binding specificity similar to that of L-14, as well as another endogenous rat lectin not present in neurons, resulted in essentially no neuronal attachment or neurite outgrowth. In addition, the effects induced by L-14 were not blocked by high concentrations of competing sugars, suggesting that it interacts with neurons by a domain distinct from its carbohydrate-binding site.

Animals↗
PubMed1992

Estrogen and phenol sulfotransferase activities in human fetal lung.

The sulfation of steroid hormones and xenobiotics by human fetal lung cytosol was examined. 1-Naphthol and estrone were extensively sulfated, whereas paracetamol and dehydroepiandrosterone were not good substrates for the pulmonary enzyme. Investigation of the thermostability and inhibition by 2,6-dichloro-4-nitrophenol (DCNP) of the 1-naphthol and estrone sulfotransferase (ST) activities revealed that the estrone ST activity was more thermolabile and more readily inhibited by DCNP than was the 1-naphthol ST activity. Anion exchange chromatography by FPLC resulted in the resolution of two 1-naphthol ST activities, with the estrone ST activity co-eluting with the more basic 1-naphthol ST activity. When human fetal lung cytosol was subjected to gel filtration FPLC, both the 1-naphthol and estrone ST activities had the same native molecular weight of 63,000 Da. this is the first demonstration of estrogen ST activity in human fetal lung. These results suggest that there are at least two forms of sulfotransferase in human fetal lung and that this tissue is capable of sulfating both xenobiotics and endogenous compounds.

Arylsulfotransferase↗
PubMed1992

The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients.

The influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA) given intramuscularly on the peripheral aromatisation of androstenedione into oestrone was investigated in postmenopausal women with breast cancer and compared with the suppression of plasma oestradiol (E2). 7 patients were investigated before and during treatment on day 7, i.e. midway between two weekly injections. After an intravenous injection of [3H] androstenedione and [14C] oestrone, urine was collected for 96 h and the isotope ratio determined in the urinary oestrogen metabolites after isolation with high performance liquid chromatography. At 250 mg, 4OHA inhibited aromatisation to [mean (S.D.)] 15.2 (5)% of baseline (P < 0.002). There was significantly greater inhibition to 8.1 (2.7)% at 4OHA 500 mg (P < 0.01). Plasma E2 was reduced to 41.2 (14.1)% of baseline at 4OHA 250 mg with a further reduction to 32.7 (19.8)% at 500 mg (P < 0.05). These results confirm the dose-response relation previously established with plasma oestrogen measurements alone.

Aged↗