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Biomedical subjects

J Nicholls

Publications and source records attributed to J Nicholls.

At least 91 records · Page 5Linked to original sources
PubMed1992

The activity of single-agent carboplatin in advanced seminoma.

Between 1982 and 1990, 70 patients with advanced metastatic seminoma were treated with 4-6 courses of single-agent carboplatin (SAC) administered at 400 mg/m2 every 3-4 weeks. Treatment was of low toxicity and no patients suffered neurotoxicity, ototoxicity or significant renal damage. There was only one episode of neutropenic sepsis and no thrombocytopenic bleeding. The median follow-up of surviving patients was 3 years. 16 patients have relapsed and 4 of these 16 have died, thus the actuarial 3-year relapse-free survival was 77% (95% CI 65-86%), cause-specific survival was 94% (95% CI 82-99%) and overall survival was 91% (95% CI 80-96%). The risk of relapse was reduced by post-chemotherapy irradiation (PCRT) to involved nodes, occurring in 1/20 patients treated with PCRT compared with 11/31 who could have been treated but were not (P = 0.04). Of the 16 patients who relapsed, 12(75%) have been salvaged with combination chemotherapy and remain free from further relapse with a median follow-up of 18 months. Though this level of survival is equivalent to that obtained with initial cisplatin-based combination chemotherapy, the recurrence rate indicates that SAC remains an investigative treatment, except for unfit patients.

Adult↗
PubMed1992

Oestradiol synthesis from oestrone in malignant breast epithelial cells: studies on a high affinity, 80 kDa form of oestradiol dehydrogenase.

Previous studies have shown that in the breast there are multiple forms of the enzyme oestradiol dehydrogenase (E2DH), responsible for the interconversion of oestrone (E1) to oestradiol (E2). We have now re-examined oestrogen metabolism in the breast cancer cell lines (T47D and MCF-7) and have shown that steroids previously shown to inhibit the conversion of E1 to E2 in normal breast tissue failed to do so when added to growing monolayers of these malignant cells. In contrast to earlier estimates in normal breast tissues, the apparent Km for this conversion in monolayers of these malignant cells is shown here to be considerably lower, at around 50 nM. Cell free studies on these cell lines have revealed the presence of a high affinity (for E1) form of this enzyme of Mw approximately 80 kDa. The ability to detect this enzyme in soluble cell fractions appears to be critically dependent on buffer composition. Normal breast epithelial cells and adipose tissue appear to be devoid of this form of E2DH. As this form of E2DH has the highest affinity for the substrate E1 of all the forms in the breast, it is probable that this 80 kDa enzyme is responsible for the conversion of E1 to E2 in cell monolayers. If the observation holds that the 80 kDa enzyme is absent in the normal tissues, then the possibility arises that this E2DH may be linked with the neoplastic process in some breast tumours containing malignant epithelial cells of a similar type as studied here.

Adipose Tissue↗
PubMed1992

Surveillance following orchidectomy for stage I testicular seminoma.

An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% (95% confidence intervals, 74%-88%). No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol.

Adult↗
PubMed1992

Immunodeficiency in methylmalonic acidaemia.

Three Chinese infants with methylmalonic acidaemia were described. They presented in the neonatal period with recurrent episodes of poor feeding, lethargy, apnoea and severe acidosis. The diagnosis was established by increased methylmalonic acid concentration in the plasma and/or urine. Pancytopenia was a prominent feature in all three patients. Only patient three had assessment of lymphocyte subsets and it showed diminished population of B-lymphocytes and a reversed CD4/CD8 ratio. All three patients were unresponsive to vitamin B12. They experienced severe infections including Gram-negative septicaemia, candidiasis and Pneumocystis carinii pneumonia which caused their deaths. Patients with this disease should be regarded as having severe immunodeficiency, and in addition to optimal metabolic control, they should be treated aggressively for any suspected infective episodes.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Characterization of P1-purinoceptors on rat duodenum and urinary bladder.

1. The P1-purinoceptors mediating relaxation of the rat duodenum and inhibition of contraction of the rat urinary bladder were characterized by use of adenosine and its analogues 5'-N-ethylcarboxamidoadenosine (NECA), N6-cyclopentyladenosine (CPA) and 2-p-((carboxyethyl)phenethylamino)-5'- carboxamidoadenosine (CGS 21680), as well as the A1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The stable analogue of adenosine 5'-triphosphate (ATP), adenylyl 5'-(beta,gamma-methylene)diphosphonate (AMPPCP), was also used as previous work had indicated that it has a direct action on some P1 receptors in addition to its P2-purinoceptor activity. 2. In the rat duodenum, the order of potency of the adenosine agonists was NECA greater than or equal to CPA greater than AMPPCP = adenosine greater than CGS 21680, and DPCPX antagonized CPA and AMPPCP at a concentration of 1 nM whereas equivalent antagonism of NECA and adenosine required a concentration of 1 microM. This suggests the presence of a mixture of A1 and A2 receptors in this tissue, with CPA and AMPPCP acting on the A1 and NECA and adenosine acting on the A2 receptors. 3. In the rat bladder, the order of potency of the adenosine agonists for inhibition of carbachol-induced contractions was NECA much greater than adenosine greater than CPA = CGS 21680, and a concentration of DPCPX of 1 microM was required to antagonize responses to NECA and adenosine. This suggests the presence of A2 receptors in this tissue. ATP and AMPPCP each caused contractions which were not enhanced by DPCPX (1 microM) which suggests that in this tissue AMPPCP was acting only via P2 receptors and had no P1 agonist activity. That AMPPCP was active on the A1 receptors in the duodenum but inactive on the A2 receptors in the bladder implies that it has selectivity for the A1 subtype.4. That CGS 21680, which has been reported to bind selectively to the high affinity A2a subclass of A2 receptors, had a very low potency on the A2 receptors in the duodenum and in the bladder suggests that these receptors are of the low affinity A2b subclass.

Adenosine↗
PubMed1992

Is there a calcium paradox in isolated bovine aortic endothelial cells?

When bovine aortic endothelial (BAE) cells are superfused with a solution containing low calcium (approximately 10 nM) and subsequently exposed to a solution containing normal Ca2+ (2 mM) a large transient increase in intracellular calcium is seen. This elevation in [Ca2+]i is similar to that described as the calcium paradox in cardiac cells. If the cells are exposed to the agonist, ATP, during the period in low-Ca2+ solution the paradoxical rise in [Ca2+]i is increased. Removal of external Na+ from the low-Ca2+ solution reduces the rise in [Ca2+]i on returning to 2mM-Ca2+ solution. These data are consistent with the presence of a calcium paradox in these cells and with the hypothesis that the underlying mechanism involves the loading of the cell with Na+ during the period in low Ca2+. This process may occur as a result of the altered selectivity of the ATP-activated Ca2+ influx mechanism.

Adenosine Triphosphate↗
PubMed1992

Influence of substrate on retraction of neurites following electrical activity of leech Retzius cells in culture.

1. The aim of these experiments was to determine how electrical stimulation of identified neurones in culture influences their growth on defined substrates. Single Retzius cells isolated from the central nervous system (CNS) of the leech were plated in culture dishes coated with the plant lectin Concanavalin A or with extracellular matrix extract containing leech laminin to promote neurite outgrowth. Stimuli were applied by a fine tungsten microelectrode placed close to the cell surface. The efficacy of electrical stimulation was checked occasionally by recording intracellularly with a microelectrode. 2. After the period of stimulation had ended, there was a short delay before neurones plated on leech laminin retracted their neurites. Of 112 neurones, only 11 failed to respond to stimulation. Neurite retraction in each cell was non-uniform, some processes retracting while others did not. After having retracted, most neurites subsequently showed clear regrowth. The degree of retraction depended on the duration of the stimulus train: whereas a few minutes was sufficient to produce observable effects, prolonged periods of stimulation caused more extensive retraction. Trains of impulses at 4 s-1 were equally effective when they were delivered in intermittent bursts or continuously. 3. The time in relation to growth at which stimuli were applied was of critical importance. Neurones stimulated during the phase of rapid outgrowth on leech laminin did not retract their neurites, which continued to elongate during and after stimulation. Neurones that had not retracted during the early phase were stimulated again later, when extension and outgrowth of neurites had ceased or slowed. At this stage stimulation was followed by retraction and subsequent regrowth. 4. Retzius cells plated on a substrate of Concanavalin A instead of leech laminin failed to show any retraction after stimulation. 5. To investigate the possible role of Ca2+, cells were grown with raised concentrations of Mg2+ in the bathing fluid. Raised [Mg2+] did not influence the rate or the extent of neurite outgrowth. It reduced, but did not block, the effects of electrical stimulation. Earlier experiments have shown that growth on Concanavalin A occurs without obvious Ca2+ entry following stimulation. Together with the present experiments, the results suggest that Ca2+ entry following impulses in cells grown on laminin is responsible for the massive retraction.

Action Potentials↗
PubMed1991

Combination chemotherapy with bleomycin, etoposide and cisplatin (BEP) for metastatic testicular teratoma: long-term follow-up.

127 men with previously untreated non-seminomatous germ cell tumours (NSGCT) of the testis were given BEP chemotherapy (bleomycin, etoposide and cisplatin) between 1979-1986. Long-term follow-up (median 65 months) has shown an overall 5 year survival of 87.2% (95% confidence limits 81.1%-93.3%). Outcome was related to both tumour volume and serum marker levels of alpha-fetoprotein (alpha FP) and beta human chorionic gonadotropin (HCG), with 5 year actuarial survivals of 97.8%, 72.2% and 26.7% respectively for small, large and very large volume disease defined by Medical Research Council criteria, and 91.2% and 60.8%, respectively, for men with low (alpha FP less than or equal to 500 kU/l and HCG less than or equal to 1000 iU/l) or high serum marker levels. 79 men (62%) had a complete radiological and serum marker response to chemotherapy alone; residual masses postchemotheraphy were resected in 39 patients (31%), showing undifferentiated tumour in only 6 (15%). 23 of the 127 patients (18%) failed to respond or developed recurrent disease after BEP; only 5 were successfully salvaged. Myelotoxicity of treatment was mild with grade 4 toxicity in 2% of chemotherapy courses and 3 episodes of neutropenic sepsis. Mean glomerular filtration rates fell by 15.6% between courses 1 and 4 of BEP. Bleomycin pneumonitis developed in 13% of cases with 1 fatality. So far 21 men have had children following chemotherapy, but semen analysis 12 months or more (median 36 months) after treatment showed azoospermia in 11 out of 54 (20%) men tested. BEP chemotherapy can be regarded as standard treatment for patients with metastatic NSGCT in low-risk categories, but more intensive therapy is required for advanced presentations. Strategies to develop "risk related" treatment are under investigation.

Adolescent↗
PubMed1991

Assessing quality of life in patients treated for advanced head and neck cancer.

A pilot study was undertaken to determine which measures of Quality of Life (QL) would be of most use in the follow-up of patients participating in clinical trials of treatments for head and neck cancer. A total of 96 non-randomized patients who had been treated for head and neck cancer either by surgery (three patients), radiotherapy (54 patients), or combined modality therapy (39 patients) completed a detailed questionnaire assessing a wide range of QL parameters. All participating patients were clinically disease-free. It was found that questions relating to quality of speech, ability to eat, levels of energy and activity, and aspects of psychological wellbeing detected the largest effects on QL. The level of QL impairment was consistently greater in those patients treated by surgery plus radiotherapy as compared to those treated by radiotherapy alone. Eleven patients were interviewed in their own homes and the findings generally supported the conclusions drawn from the questionnaire responses. The interviews also demonstrated that impairment of arm movement amongst some surgically treated patients detracted from QL by causing difficulties in performing everyday selfcare and domestic tasks. This study has provided the basis for a QL assessment to be incorporated into a randomized trial of radiotherapy alone versus surgery plus radiotherapy in the treatment of advanced head and neck cancer. The findings suggest that QL impairment is greater for patients who have surgery in addition to radiotherapy as primary treatment but this may be acceptable if a clear survival advantage is demonstrated.

Combined Modality Therapy↗
PubMed1991

The effect of carboplatin on renal function in patients with metastatic germ cell tumours.

Renal function was determined before and at varying times after chemotherapy in 62 patients with metastatic germ cell tumours treated with carboplatin. Eighteen patients were excluded because of urinary tract obstruction, leaving 44 evaluable patients treated with carboplatin either as a single agent (13 patients) or in combination with other agents (31 patients). No significant differences were observed in mean 51Cr-labelled Ethylenediamine tetraacetic acid (EDTA) clearances before and after carboplatin in either the group as a whole (P = 0.58), or when assessment at 1 month or less (P = 0.4), 3 months or less (P = 0.91), or later than 3 months (P = 0.38) were analysed. Carboplatin does not have significant renal toxicity when used at conventional dosage in patients with germ cell tumours.

Adolescent↗
PubMed1991

Direct effects of adenylyl 5'-(beta,gamma-methylene)diphosphonate, a stable ATP analogue, on relaxant P1-purinoceptors in smooth muscle.

1. Previous results obtained with the rat colon muscularis mucosae, which contracts in response to adenosine and adenosine 5'-triphosphate (ATP), had suggested that adenylyl 5'-(beta,gamma-methylene)diphosphonate (AMPPCP), a stable ATP analogue, acted on P1-purinoceptors rather than, as expected, on P2-purinoceptors. This possibility has been examined in two tissues in which adenosine and ATP both cause relaxation, the guinea-pig taenia caeci and the rat duodenum. 2. ATP, 2-methylthio-ATP (2-MeSATP), AMPPCP, adenosine 5'-(alpha,beta-methylene)triphosphonate (AMPCPP) and adenosine each relaxed the taenia caeci and the duodenum, and the order of potency of the nucleotides in each tissue was 2-MeSATP greater than ATP greater than AMPCPP greater than AMPPCP, indicating that these effects were mediated by P2Y-purinoceptors. 3. The P1 antagonist 8-(p-sulphophenyl)theophylline (8-SPT) (100 microM) did not affect the responses to ATP, 2-MeSATP or AMPCPP in either tissue, but inhibited the responses of adenosine and of AMPPCP in both tissues. In the duodenum a lower concentration of 8-SPT caused a parallel shift to the right of the concentration-response curve to adenosine and to AMPPCP but to different extents, with AMPPCP being inhibited more powerfully than adenosine. A dose-ratio of around 5 was observed for adenosine and AMPPCP at concentrations of 8-SPT of 20 microM and 2 microM respectively, but Schild analysis resulted in plots with slopes greater than unity. In the taenia caeci, however, 8-SPT inhibited adenosine more powerfully than AMPPCP, and a range of concentrations (10-20 microM) only caused a two fold shift in the concentration-response curve for AMPPCP, although the concentration-response curve to adenosine was shifted in a concentration-dependent manner and Schild analysis gave a pA2 value of 5.13 with a slope of 0.90.4. As has been shown in other tissues, including the guinea-pig taenia caeci, ATP (100 microM) was rapidly dephosphorylated by enzymes present in the rat duodenum, with less than 10% remaining after 20min incubation, whereas AMPPCP (100 microM) was resistant to degradation, with greater than 90% remaining at the same time point.5. AMPPCP therefore has pronounced but variable agonist actions on P,-purinoceptors, and appears to act entirely via these receptors on the rat duodenum although in the guinea-pig taenia caeci this action is less important and it acts largely via P2y-purinoceptors. These Pl-purinoceptor effects of AMPPCP are direct and are not due to its degradation to adenosine.

Adenosine↗
PubMed1991

Effectiveness of carboplatin, etoposide, and bleomycin combination chemotherapy in good-prognosis metastatic testicular nonseminomatous germ cell tumors.

The combination of carboplatin, etoposide, and bleomycin (CEB) was evaluated as initial chemotherapy in 76 patients with good-prognosis metastatic nonseminomatous germ cell tumors (NSGCT) between 1984 and 1988. The classification of eligible patients included Royal Marsden Hospital (RMH) stages IM, IIA, IIB, IIC, IIIA, IIIB, IV0ABCL1, and IV0ABL2. Four courses of combination chemotherapy were administered in a 21-day cycle, and surgical excision of residual mass was performed in 27 cases (23 laparotomies and four thoracotomies). At the time of analysis, median follow-up was 24 months from start of chemotherapy (range, 6 to 54 months). The 2-year cause-specific survival probability was 98.5%, the single cause-related mortality being caused by bleomycin pneumonitis. Five patients failed CEB chemotherapy, but all have been successfully salvaged with a combination of surgery and intensive chemotherapy, follow-up from completion of all treatment being 35 to 44 months. The toxicity of CEB included bone marrow suppression and alopecia in all patients but no significant neurotoxicity or ototoxicity, and minimal renal toxicity. Only four (5%) patients had a decrease in the glomerular filtration rate greater than 15%. In 51% of patients, the hemoglobin fell below 10 g/dL. The WBC count nadir was less than 1,500/microL in 11% of treatment cycles and in 16% the platelet nadir fell below 50,000/microL. Decreases in the WBC and platelet counts were of very brief duration. Only one of 310 CEB cycles was complicated by neutropenic sepsis, and there were no episodes of thrombocytopenic purpura or bleeding. We conclude that the CEB combination represents an effective alternative to cisplatin-based chemotherapy in good-prognosis NSGCT and that the replacement of cisplatin by carboplatin leads to reduced toxicity.

Adolescent↗
PubMed1990

Orchidectomy alone for stage I seminoma of the testis.

Between 1983 and 1988, 113 patients with Stage I seminoma were managed after orchidectomy by surveillance rather than adjuvant radiotherapy. The actuarial risk of relapse at 3 years was 15.8% (95% confidence interval, 7.8% to 23.8%). All 13 patients who experienced a relapse are currently in remission (4 to 45 months after salvage therapy), although 5 suffered second relapses requiring further treatment. Close surveillance is a safe alternative to adjuvant radiotherapy in Stage I seminoma. However, the policy requires prolonged observation of patients with intensive use of resources. Therefore, adjuvant radiotherapy should be considered the treatment of choice.

Adult↗
PubMed1990

Pharmacokinetics of the long-acting somatostatin analogue octreotide (SMS 201-995) in acromegaly.

A single-dose study was performed to examine the pharmacokinetics of subcutaneous octreotide in acromegalic patients and to investigate the relationship between growth hormone and the elimination half-life of the drug. Fourteen acromegalic patients (six men and eight women; age range 35-59 years) who had previously received conventional treatment were studied. Two subjects were on long-term octreotide which had been discontinued 72 h before the study. Octreotide 100 micrograms was administered subcutaneously and plasma samples taken every 10 min for 1 h and then hourly for up to 8 h. Growth hormone was measured at 0, 2 and 8 h. Octreotide was rapidly absorbed with a mean (+/- SEM) t1/2abs of 5.4 min (+/- 0.8) peaking at a mean plasma concentration of 3.4 nmol/l (+/- 0.2) in 27.4 min (+/- 3.7). The monoexponential elimination phase had a mean half-life of 110 min (+/- 9.6). The apparent volume of distribution was 29.4 1 (+/- 1.9) and total clearance was 172 ml/min (+/- 10.4). These results were similar to those obtained in normal volunteers. There was no simple relationship between the level of growth hormone and the half-life of octreotide. Growth hormone levels ranged from 2.5 to 34.0 mIU/l but were only greater than 10 mIU/l in three subjects. Further studies of octreotide pharmacokinetics are needed in untreated patients with acromegaly with raised growth hormone levels.

Acromegaly↗
PubMed1990

The ontogeny of purinoceptors in rat urinary bladder and duodenum.

1. The ontogeny of responses to purines and analogues of smooth muscle preparations was studied in rat duodenum and rat urinary bladder. 2. Responses to adenosine and to adenosine 5'-triphosphate (ATP) mediated by P1- and P2-purinoceptors respectively were present as early as postnatal day 2, the earliest day studied. 3. In rat bladder, adenosine was inhibitory and ATP and adenosine 5'-(beta, gamma-methylene) triphosphonate (AMP-PCP) were excitatory, acting on the P2X subtype of P2-purinoceptors. Adenosine was more potent in the neonate than in the adult, while the potency of the nucleotides initially increased with age but then declined, being highest between postnatal days 10 and 25. 4. In rat duodenum also, adenosine was inhibitory, its potency being less than the adult before day 15. 5. ATP at low concentrations was inhibitory in rat duodenum at every age studied and its potency increased with age, but higher concentrations of ATP (3 microM and above) were excitatory until day 15. Both relaxations and contractions were mediated by the P2Y subtype of P2-purinoceptors. These ATP-induced contractions were not inhibited by indomethacin (25 microM) or by tetrodotoxin (1 microM) and are therefore not due to prostaglandin synthesis or to ATP-induced release of transmitter substances from nerves. 6. These results show that responses to adenosine and to adenine nucleotides are present from birth and vary with age, and that the changes seen indicate a differential development for P1-, P2X- and P2Y-purinoceptors.

Aging↗