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Biomedical subjects

A L Jones

Publications and source records attributed to A L Jones.

At least 19 recordsLinked to original sources
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↗
PubMed1992

The budgetary impact of 5-HT3 receptor antagonists in the management of chemotherapy-induced emesis.

The study examined the budgetary implications of using 5-hydroxytryptamine3 receptor antagonists (5-HT3RA), granisetron or ondansetron, in the management of chemotherapy-induced emesis (CIE). A treatment model was constructed to represent a baseline of efficacy and costs for treating a cohort of patients with conventional antiemetics. Groups of patients who would be expected to receive the most benefit from 5-HT3RA were then identified and the effect upon costs of using these compounds in a consecutively larger proportion of selected patients was calculated. On the basis of illustrative costs from The Cookridge Hospital in the UK, it was concluded that the new antiemetics can be used in acute emesis with substantial clinical benefit for an increase of 3-10% to total treatment costs. However, for delayed emesis these compounds have not yet shown a clinical advantage, and the increase in total costs of 12-34% is not justified.

Antiemetics↗
PubMed1992

Subcellular and molecular mechanisms of bile secretion.

One of the liver's principal functions is the formation of bile, which is requisite for digestion of fat and elimination of detoxified drugs and metabolites. Bile is a complex fluid made up of water, electrolytes, bile acids, pigments, proteins, lipids, and a multitude of chemical breakdown products. In this review, we have summarized the source of various biliary components, the route by which they end up in bile, including the underlying subcellular and molecular mechanisms, and their contribution to bile formation. One of the reasons why bile formation is so complex is that there are many mechanisms with overlapping substrate specificities, i.e., many biochemically unrelated biliary constituents share common transport mechanisms. Additionally, biliary constituents may reach bile by more than one pathway. Some biliary components are critical for bile formation; others are of minor significance for bile formation but play a major physiological role. The major driving force for bile formation is the uptake and transcellular transport of bile salts by hepatocytes. The energy for bile formation comes from the sodium gradient created by the basolateral Na+/K(+)-ATPase, to which bile salt transport is coupled. The secretory pathway for bile salts involves uptake at the basolateral surface of the hepatocyte, vectorial transcellular movement, and transport across the canalicular membrane into the canalicular lumen. Hydrophilic bile salts are taken up via a sodium-dependent, saturable, carrier-mediated process coupled to the Na+/K(+)-ATPase. This uptake mechanism is also shared by other substrates, such as electroneutral lipids, cyclic oligopeptides, and a wide variety of drugs. Hydrophobic bile acids are taken up by a sodium-independent facilitated carrier-mediated mechanism in common with other organic ions, including sulfated bile acids, sulfobromophthalein, bilirubin, glutathione, and glucuronides, or by nonsaturable passive diffusion. Two major carrier proteins have been identified on the hepatocyte basolateral membrane: a 48-kDa protein that appears to be involved with Na(+)-dependent bile salt uptake, and a 54-kDa protein, thought to be associated with Na(+)-independent bile salt uptake. The intracellular transport of bile salts may involve cytosolic carrier proteins, of which several have been identified. Some evidence suggests a vesicular transport mechanism for bile salts. Since bile acids clearly do not enter the cell by endocytosis, formation of transport vesicles must be a more distal event in the transcellular translocation process. Some bile salts appear to be transported within the same unilamellar vesicles that are involved in the secretion of cholesterol and phospholipid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer.

The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13 postmenopausal women with advanced breast cancer. Seven patients received AG 1,000 mg daily plus Hydrocortisone (HC) cover and six received RG as dose escalation of 200 mg bd, 400 mg bd and 800 mg bd. In vivo aromatase inhibition was investigated using the double bolus injection technique with [4-14C] oestrone ([4-14C]E1) and [6,7-3H] androstenedione ([6,7-3H]4A) followed by a 96 h urine collection. The labelled urinary oestrogens were separated and purified by chromatography and HPLC. Plasma oestradiol (E2) was also measured. AG mean aromatase inhibition was 90.6% +/- 1.8 s.e.m. and E2 suppression 75.7% +/- 7.3 s.e.m. RG mean aromatase inhibition was 50.6% +/- 9.8 s.e.m. at 200 mg bd, 63.5% +/- 5.7 s.e.m. at 400 mg bd and 73.8% +/- 5.8 s.e.m. at 800 mg bd. E2 suppression was 30.7% +/- 9.5 s.e.m., 40.2% +/- 10.3 s.e.m. and 57.6% +/- 9.2 s.e.m. respectively. These results confirm the efficacy of AG as an aromatase inhibitor. RG produced dose dependent E2 suppression and aromatase inhibition, but even at the maximum tolerated dose of 800 mg bd had sub-optimal aromatase inhibition and oestradiol suppression compared with AG.

Adult↗
PubMed1992

Haemostatic changes and thromboembolic risk during tamoxifen therapy in normal women.

Tamoxifen has been implicated as a risk factor for venous thrombosis in advanced breast cancer although the evidence for increased arterial or venous thrombosis with tamoxifen in early breast cancer is less clear. The effect of tamoxifen on haemostasis, and thereby possible thromboembolic risk, was investigated in normal women enrolled in a placebo controlled trial of tamoxifen as a chemopreventative agent for breast cancer. There was an initial reduction in fibrinogen levels in all women on tamoxifen over the first year of follow-up and a marginal reduction in antithrombin III and Protein S in postmenopausal women at 6 months. There were no changes in cross linked fibrinogen degradation products or Protein C for pre or post-menopausal women. There was no increase in the incidence of thromboembolic events on tamoxifen. This study demonstrates that tamoxifen has only marginal effects on factors involved in haemostasis reported to affect the incidence of arterial or venous thromboembolic disease. The follow-up time is relatively short (maximum 36 months) and careful long term follow-up is necessary to detect clinically significant morbidity.

Antithrombins↗
PubMed1992

Zygotic induction of plasmid ssb and psiB genes following conjugative transfer of Incl1 plasmid Collb-P9.

The Incl1 conjugative plasmid Collb-P9 carries a psiB gene that prevents induction of the SOS response in host bacteria. This locus is located 2.5 kb downstream of the ssb (single-stranded DNA-binding protein) gene in the leading region. This portion of Collb is strikingly similar to part of the leading region of the otherwise distinct F plasmid. Expression of psiB and ssb is increased when the host cell is exposed to an SOS-inducing treatment or the Collb transfer system is derepressed. Moreover, expression of both genes on a derepressed plasmid is strongly enhanced in conjugatively infected recipient cells. Carriage of the psiB gene by Collb is shown to prevent a low level of SOS induction following conjugation. Plasmid ssb and psiB genes may function to promote installation of the replicon in the new cell.

Amino Acid Sequence↗
PubMed1992

Effects of fine-needle aspiration on the US appearance of the breast.

Fine-needle aspiration (FNA) of normal breast tissue or benign lesions can cause changes that suggest malignancy at ultrasound (US) examination. Serial US studies showed that three of 17 patients developed signs mimicking malignancy following FNA of palpable breast lumps. A second group of 14 patients had US signs of malignancy in palpable lumps following recent FNA. Nine patients with benign lesions were unnecessarily worried, since the appearance was probably due to FNA. Diagnosis of malignancy was delayed in one of five patients because the US appearance was attributed to the FNA in the presence of false-negative cytologic findings. FNA of normal breast tissue or benign masses produced tissue changes in 18% of cases that altered the US appearance from normal or benign to possibly malignant. The changes took up to 4 months to subside. If US is clinically indicated, it should be performed before FNA.

Adolescent↗
PubMed1992

Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years.

PURPOSE: The study purpose was to evaluate aminoglutethimide (AG) as adjuvant therapy in patients with primary node-positive breast cancer in a randomized double-blind placebo-controlled trial. PATIENTS AND METHODS: In a multicenter trial, 354 postmenopausal women with early breast cancer and histologically confirmed positive axillary lymph nodes were randomized after surgery to received aminoplac. Patients were prescribed either AG 250 mg four times per day and hydrocortisone 20 mg twice per day or placebos of identical appearance for 2 years. RESULTS: After a median follow-up of 8.1 years, there has been no overall benefit for AG in terms of either event-free survival or overall survival (OS). However, the results are consistent with interim analyses with a significantly improved event-free survival for patients who received AG for up to 4 years, although this benefit subsequently disappears. Similarly, there is an improved OS for patients who received AG for up to 4 years, but this also subsequently disappears. There was a marginal advantage for estrogen receptor (ER)-positive patients who received AG (n = 74; P = .054). There was no difference in the sites of relapse. There was a significant increase in toxicity for patients who received AG. CONCLUSION: The lack of survival benefit with long-term follow-up for AG may indicate that aromatase inhibitors have less of an impact on early breast cancer than tamoxifen and may imply different biologic mechanisms of action.

Aged↗
PubMed1992

Does aging affect liver microtubules?

Microtubules are essential for many cell processes, e.g., ligand-receptor endocytosis and the vectorial movement of endosomes. The cytoskeleton, particularly microtubules, may undergo age-related changes that are reflected in cell dysfunctions. For example, the translocation of 125I-IgA-containing vesicles from the sinusoidal surface to the pericanalicular cytoplasm is reduced (greater than 40%) in old versus young rats. Electron microscopic analysis demonstrated that the concentration of microtubule profiles in young animals is within 10-20% of that in old rats. The relative concentration of polymerized tubulin declines greater than 70% by 12 months of age, but the total tubulin content remains unchanged until later, i.e., declining 50% by 24 months. Concomitant increases occur in the free fractions of microtubule-associated proteins (MAP), i.e., MAP1 and heat-stable MAPS. These fractions are not associated with polymerized tubulin. The declines in total and polymerized tubulin, together with the increases in the MAPS' free fractions, may be indicative of fewer and/or shorter microtubules. These data lend credence to the supposition that aging is accompanied by perturbations of microtubule functions that ultimately are expressed as biomarkers characteristic of aging.

Aging↗
PubMed1991

Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy.

A multicentre, randomised, double-blind, cross-over trial was done to compare the efficacy and safety of a serotonin receptor antagonist--ondansetron--and dexamethasone in the prophylaxis of acute and delayed emesis and nausea induced by moderately emetogenic non-platinum-containing chemotherapy regimens. Patients were treated as outpatients and received intravenous ondansetron 4 mg or dexamethasone 8 mg before chemotherapy and oral maintenance (ondansetron 4 mg every 6 h and dexamethasone reducing from 4 mg to 1 mg 6-hourly between days 1 and 5) for 5 days. 112 patients were treated (38 men, 73 women, 1 with no gender recorded; age range 30-73 years) and 100 were evaluable for cross-over analysis. Patients taking ondansetron or dexamethasone reported no significant difference in complete and major control of acute (83% vs 79%, p = 0.46) or delayed (82% vs 88%, p = 0.214) emesis (vomiting plus retches). Significantly more patients on dexamethasone (87%) than on ondansetron (72%) reported control of delayed nausea (days 2-5) (p = 0.003). Both drugs were well tolerated with no significant difference in the number of adverse events, and this is reflected by similar patient preference for ondansetron (40%) and dexamethasone (30%) (p = 0.244). Both drugs offer adequate out-patient control of chemotherapy-induced emesis; however, dexamethasone has an advantage in the control of delayed nausea, and also in terms of cost and resource allocation.

Acute Disease↗
PubMed1991

A clinical study of nafazatrom in advanced human breast cancer.

Prostaglandins (PGs) have been shown to inhibit tumour metastases in experimental animal systems. Nafazatrom is a pyrazolinone derivative that increases endogenous prostacyclin (PGI2) and has experimental anti-cancer activity. In the present study, nafazatrom was given to 47 women with advanced breast cancer; objective remission of metastases was seen in 2 patients and stabilisation of disease in 1 case. Nafazatrom was safe and well tolerated.

Aged↗
PubMed1991

Effective new low toxicity chemotherapy with carboplatin, vinblastine and methotrexate for small cell lung cancer: a randomised trial against doxorubicin, cyclophosphamide and etoposide.

Carboplatin has been incorporated into a new low toxicity combination chemotherapy regimen with methotrexate and vinblastine (CVM) against small cell lung cancer (SCLC). We have compared CVM (carboplatin 300 mg/m2, vinblastine 6 mg/m2, methotrexate 30 mg/m2, all intravenously every 4 weeks) with ACE (doxorubicin 40 mg/m2, cyclophosphamide 600 mg/m2, etoposide 100 mg/m2 all intravenously day 1-3, every 3 weeks) in a randomised trial. 36/54 evaluable patients treated with CVM achieved an objective response (67%) (95% confidence limits [CL] 54-79%) compared with 44/50 treated with ACE (88%) (95% CL 80-97%, P = 0.06). For patients with limited disease treated with CVM, 14/17 (83%) (95% CL 64-100%) had an objective response compared with 14/15 (93%) (95% CL 81-100%) treated with ACE (not significant). Overall median survival was 8 months for CVM and 7 months for ACE. Haematological toxicity was significantly lower for CVM than ACE and consequently dose reduction/delay and infection were less with CVM. Subjective toxicity was low and alopecia was significantly less for CVM than ACE. CVM is an active, well tolerated new chemotherapy regimen for SCLC.

Adult↗