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Biomedical subjects

N Murray

Publications and source records attributed to N Murray.

At least 37 records · Page 2Linked to original sources
PubMed1996

Vulnerability of the infant brain stem to ischemia: a possible cause of sudden infant death syndrome.

In infants, extreme extension or rotation of the head can occlude one or both vertebral arteries. We sought to determine whether small communicating arteries or asymmetric vertebral arteries could predispose the brain stem to ischemia should such head movements occur. In 68 infants, the carotid, posterior communicating, precommunicator posterior cerebral, basilar and vertebral arteries were fixed in formalin, embedded in resin, the circumferences measured by image analysis, and the relative conductance of blood in each artery per gram of brain calculated. Conductance in the vertebrobasilar and carotid systems lagged behind increases in brain weight during the postnatal growth spurt. In 81% of infants, conductance through the communicating arteries was less than 25% of basilar artery conductance. Conductance in one vertebral artery was less than half that of the contralateral artery in 41% of infants. In conclusion, the lag in available blood flow and small communicating and asymmetric vertebral arteries may predispose the infant brain stem to ischemia if one or both vertebral arteries are occluded by head rotation or extension. Because these head movements are likely to be accentuated in the prone sleeping position (a risk factor for sudden infant death syndrome), we suggest that vertebral artery occlusion may underlie some cases of sudden unexpected infant death.

Age Factors↗
PubMed1996

Influence of age on the treatment of limited-stage small-cell lung cancer.

PURPOSE: To evaluate the prognostic importance of age on response rate and survival in patients with limited-stage small-cell lung cancer (SCLC), and to determine the effect of age on chemotherapy dose delivery and toxicity. PATIENTS AND METHODS: We undertook a retrospective analysis of data from two multicenter, randomized trials conducted by the National Cancer Institute of Canada (NCIC) in which 608 SCLC patients who presented with limited disease (LD) all received the same chemotherapy. Treatment consisted of cyclophosphamide, doxorubicin, and vincristine (CAV), and etoposide plus cisplatin (EP) administered in an immediate or delayed alternating fashion, plus cranial and thoracic irradiation. RESULTS: There were 520 patients aged less than 70 years, and 88 > or = 70. No significant differences existed between the two age groups in baseline characteristics, including treatment protocol, performance status, and serum lactate dehydrogenase (LDH) level. There were more men in the older group (P = .05). Overall response rates were comparable (78% v 82%, P = .50), and 5-year survival rates were also similar (P = .14), with 11% alive in the younger group and 8% in the older group. Age was a significant predictor of overall survival when analyzed as a continuous variable in a univariate model (P = .01), but it was no longer an independent prognostic factor in our multivariate regression analysis. An analysis of chemotherapy delivery between the two age groups showed that patients aged > or = 70 years received lower total doses of each drug compared with the intended full protocol dose, primarily as a result of dose omissions, rather than dose reductions. The frequency of dose delays was not different between groups. No significant differences were seen in the incidence of either hematologic or most nonhematologic toxicities. CONCLUSION: Age is not a significant adverse prognostic variable in SCLC patients with LD. Moderately aggressive chemotherapy may be delivered safely to elderly patients with a good performance status, although modest attenuation of therapy through either dose reduction or omission may occur more frequently in this population.

Adolescent↗
PubMed1995

Class I major histocompatibility complex-restricted cytotoxic T lymphocytes specific for Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines against which they were raised.

We have raised CD8+ cytotoxic T lymphocytes (CTL) from three Epstein-Barr virus-seropositive donors by incubating peripheral blood lymphocytes with irradiated autologous B95.8-strain EBV-transformed B lymphoblastoid cells (LCL). However, to detect lysis in a standard 51Cr release assay of the LCL against which these CTL were raised, superinfection with recombinant vaccinia expressing the appropriate EBV protein or incubation with the peptide epitope was necessary. The untreated LCL were not lysed, even though Western blotting demonstrated that they expressed the EBV antigens containing the CTL epitopes. We have found CTL of this phenotype that are restricted by human leukocyte antigen-A2, -A3, -B7, or -B39, and which recognize the EBV latent proteins, EBV nuclear antigen (EBNA)-3A, EBNA-3C, or terminal protein. During these experiments, we identified a new human leukocyte antigen-A3-restricted EBNA-3A epitope, residues 603-611, RLRAEAGVK. We raised a spontaneous LCL, transformed by endogenous EBV, from one donor, but this was also not lysed. For at least one of the epitopes, CTL from another donor lysed the LCL without superinfection or addition of peptides. We conclude that the CTL were unable to achieve a high enough avidity of interaction with untreated LCL to trigger effector function, although the LCL were able to stimulate them to grow in vitro for up to 4 mo. To assess whether a small percentage of the LCL might possess a higher antigen density, we used an assay of tumor necrosis factor release from a CTL clone, which was able to detect antigen-bearing cells representing only 1% of a stimulating LCL population. Nevertheless, the untreated autologous LCL line failed to stimulate tumor necrosis factor release.

Amino Acid Sequence↗
PubMed1995

Epitope mapping and functional properties of anti-intercellular adhesion molecule-3 (CD50) monoclonal antibodies.

Intercellular adhesion molecule-3 (ICAM-3, CD50), a member of the immunoglobulin gene superfamily, is a major ligand for the lymphocyte function-associated antigen 1 (LFA-1, CD18/CD11a) in the resting immune system and plays a role as a signaling and costimulatory molecule on T lymphocytes. In this study we have generated a large panel of anti-ICAM-3 monoclonal antibodies (mAb) and show that the biological effects of these antibodies are critically dependent on the epitope recognized. By using an adhesion assay employing COS cells expressing LFA-1 binding to recombinant chimeric ICAM-3-Fc proteins (which overcomes the confounding effects of interleukocyte LFA-1/ICAM binding events), we have been able to examine the effects of these antibodies in blocking LFA-1/ICAM-3 adhesion. Our data suggests that only a small minority of ICAM-3 mAb, recognizing a distinct epitope, are able to mimic the effects of LFA-1 binding to ICAM-3. Moreover these antibodies are functionally distinct as defined by their costimulatory activity and ability to elicit interleukin-2 production and cell proliferation in T lymphocytes.

Animals↗
PubMed1995

A single site on the epsilon subunit is responsible for the change in ACh receptor channel conductance during skeletal muscle development.

Four critically positioned amino acids on each of the alpha, beta, delta, and gamma subunits of the Torpedo nicotinic acetylcholine receptor are determinants of channel conductance. Our results show that the gamma and epsilon subunits of Xenopus muscle receptors are identical at all four positions, despite the fact that alpha 2 beta delta epsilon receptors have a 50% greater conductance than alpha 2 beta delta gamma receptors. Instead, the functional difference is conferred by a single charged residue that lies extracellular to all four positions, corresponding to a location in the Torpedo receptor previously shown to have no influence on conductance. Substitution of a positively charged lysine residue in gamma by the neutral methionine in epsilon at this extra-cellular position is responsible for the increased conductance during maturation of the amphibian neuromuscular junction.

Amino Acid Sequence↗
PubMed1995

Brain stem nuclei in sudden infant death syndrome (SIDS): volumes, neuronal numbers and positions.

It has been suggested that the defect underlying the sudden infant death syndrome (SIDS) lies in brain stem nuclei involved in cardiac and respiratory function. However, most studies have not used rigorous quantitative techniques to assess brain stem nuclear volumes and neuronal numbers. We have measured the volume, neuronal numbers and position of brain stem nuclei in 11 SIDS and 11 aged-matched control infants. Using serial sagittal sections, nuclei involved in maintaining airway patency (hypoglossal, ambiguus and retroambiguus), heart rate (dorsal vagal) and generation of respiratory rhythm (ambiguus and dorsal vagal) were studied. No significant differences were found in nuclear volume increase with age, total neuronal number or nuclear position between SIDS and control cases. These findings support the hypothesis that the nervous system in SIDS may be normal until the final event that kills these infants.

Age Factors↗
PubMed1994

Patterns of failure following loco-regional radiotherapy in the treatment of limited stage small cell lung cancer.

PURPOSE: The probability of treatment resistant cells developing in a tumor, such as small cell lung cancer (SCLC) which has a rapid cell cycle time, is a function of the number of tumor cells present and of time. Theoretically, the development of resistance to chemotherapy and radiotherapy should be minimized by using all treatment modalities early in the treatment program. METHODS AND MATERIALS: The importance of the timing of loco-regional radiotherapy was assessed in a multi-institution randomized study. Three hundred and eight patients with limited small cell lung cancer (LSCLC) were given three cycles of cyclophosphamide, doxorubicin and vincristine alternating with three cycles of etoposide and cisplatin. In addition, patients were randomized to receive locoregional radiotherapy: 40 Gy in 15 fractions in 3 weeks with treatment planning techniques to limit the spinal cord dose to be < or = 35 Gy either with the first cycle (early) or with the sixth cycle of chemotherapy (late). Responding patients received prophylactic brain irradiation (25 Gy in 10 fractions in 2 weeks) after completion of locoregional radiotherapy and chemotherapy. RESULTS: 96% of the 155 eligible patients allocated to the "early" arm and 87% of the 153 allocated to the "late" arm received locoregional radiotherapy; 26 patients did not receive locoregional radiotherapy. The mean field sizes were similar in both arms. The mean radiation doses were significantly less in the "early" arm (p = 0.0319 Wilcoxon rank sum test). Any differences in the frequency of toxicities were minor. All patients have been followed for at least 2 years and the median follow up is 4 years. 64% had a complete response in the "early" arm compared with 56% in the "late" arm (p = 0.137). Survival was measured from the start of chemotherapy. There was a significant improvement in survival in the "early" arm; median survival was 21.2 months compared with 16.0 months in the "late" arm (p = .008 log rank test). Survival at 2, 3, and 4 years was 40%, 32%, and 25%, respectively, for the "early" arm and 33%, 22%, and 15% for the "late" arm. There were 232 (75%) recurrences among those patients whose disease recurred. The proportion who had local recurrence within the radiation field was 41% and 39% for "early" and "late" treatment arms respectively. The proportion of brain metastases in the "late" arm (28%) was significantly higher than in the "early" arm (18%) p = .0425 Fishers' exact test. CONCLUSION: We conclude that early administration of locoregional radiotherapy in a combined modality treatment is superior to late consolidative locoregional radiotherapy in limited small cell lung cancer.

Brain Neoplasms↗
PubMed1994

LCB 2183 inhibits the inflammation associated with oxazolone-induced contact sensitivity.

LCB 2183, an anti-allergic and potential anti-asthma compound, has been investigated for its ability to inhibit contact sensitivity in the mouse. The delayed response to epicutaneous hapten challenge in this model is a classical T-cell-mediated inflammatory reaction which is dependent on an early initiation phase. Both the early and late components of oxazolone-induced contact sensitivity were inhibited by oral administration of LCB 2183 in a dose-dependent manner. The drug appears to act on the efferent limb of the response since administration before hapten challenge was effective, while administration before the initial sensitization was not. LCB 2183 acts early in the cascade of events leading to inflammation, since the initiation phase of the response was inhibited; nonetheless, an effect of the drug on the late acting inflammatory cells cannot be ruled out. In comparison with oral prednisolone, which was also able to inhibit both the early and late components of the response, LCB 2183 was less active. Sodium cromoglycate and nedocromil sodium, which are poorly absorbed from the gastrointestinal tract, were tested by intraperitoneal administration. Neither of these agents significantly altered the delayed response and only nedocromil sodium had a limited inhibitory effect on the early initiation phase. Thus, in this model, LCB 2183 demonstrated more anti-inflammatory potential and resembled prednisolone more closely than either nedocromil sodium or sodium cromoglycate. The possible relevance of these effects in relation to the inflammation which characterizes human asthma is considered.

Animals↗
PubMed1994

Melanoma-derived interleukin 6 inhibits in vivo melanoma growth.

Malignant melanomas are capable of producing a wide range of cytokines with multiple biologic functions, including interleukin 6 (IL-6). We have observed an inverse relationship between IL-6 production of three B16-derived murine melanoma cell lines (NP133, HFH18, and HFH(M)) and the tumorigenicity of these melanoma cells in syngeneic mice. To further test the effect of IL-6 on melanoma growth, a non-IL-6-producing murine B16-derived melanoma cell line (HFH18) was transfected with a murine IL-6 expression vector, resulting in stable transfectants (HFH18/IL-6(+)) that expressed significant amounts of IL-6 mRNA and secreted high levels of bioactive IL-6. Syngeneic C57BL/6 mice inoculated subcutaneously with HFH18/IL-6(+) cells developed tumors that reached a final mean diameter of less than half the size of tumors that developed in mice inoculated with either HFH18 parental or HFH18 cells transfected with the IL-6 cDNA in the non-coding 3'-5' orientation (HFH18/IL-6(-) cells). In addition, mice bearing IL-6-producing HFH18/IL-6(+) tumors survived twice as long as mice bearing HFH18 parental or HFH18/IL-6(-) tumors. The specificity of melanoma growth inhibition by IL-6 was confirmed by the reversal of the slow-growing phenotype of HFH18/IL-6(+) cells by local peritumoral administration of neutralizing alpha-murine IL-6 antibody. IL-6-producing melanoma cells exerted a growth-inhibitory effect on distant parental tumors in a dose-dependent manner. The growth of HFH18/IL-6(+) melanomas was also decreased in nude mice, suggesting that melanoma-derived IL-6 may mediate this anti-tumor effect independently of a normal host B- and T-cell immune response. Thus, melanoma-derived IL-6 exerts a significant inhibitory effect on cutaneous melanoma growth and progression. These results indicate that melanoma cytokines may have a profound effect on tumor pathogenesis.

Animals↗
PubMed1994

In vitro culture of colony forming unit-megakaryocyte (CFU-MK) in fetal alloimmune thrombocytopenia.

Perinatal alloimmune thrombocytopenia (PAITP) causes intracranial haemorrhage in the fetus and neonate. However, the severity of the thrombocytopenia correlates poorly with maternal anti-platelet antibody titres. To test the hypothesis that reduced platelet production contributes to fetal thrombocytopenia in PAITP, maternal sera from three HPA-1a-negative mothers whose pregnancies were complicated by anti-HPA-1a (two severe cases, one mild case) were added to colony forming unit-megakaryocyte (CFU-MK) cultures from HPA-1a positive and negative individuals. Sera from the two severely affected pregnancies containing anti-HPA-1a caused 66-100% inhibition of HPA-1a-positive fetal and neonatal CFU-MK, whereas CFU-MK from two HPA-1a-negative mothers were not inhibited by the anti-HPA-1a-containing sera. Maternal serum from the case of mild PAITP caused only mild inhibition of HPA-1a-positive cord and adult CFU-MK and did not inhibit HPA-1a-positive fetal CFU-MK. Taken together, these findings suggest that reduced megakaryocyte production contributes to fetal thrombocytopenia due to maternal anti-HPA-1a antibodies and also that the degree of CFU-MK inhibition correlates with severity of fetal thrombocytopenia.

Adult↗
PubMed1994

Isolated bulbar conjunctival Kaposi's sarcoma.

We present a case of an isolated bulbar conjunctival Kaposi's sarcoma in a man with HIV infection. This is an unusual site for the initial presentation of Kaposi's sarcoma and in this site can be confused with a caroticocavernous fistula, cavernous haemangioma or chronic subconjunctival haemorrhage. Biopsy is required to confirm the diagnosis in isolated disease. Local radiotherapy is the preferred treatment for isolated Kaposi's sarcoma.

Adult↗
PubMed1994

Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer.

PURPOSE: The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS: Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS: Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION: The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.

Adenocarcinoma↗
PubMed1994

Phase II trial of megestrol in the supportive care of patients receiving dose-intensive chemotherapy.

Megestrol acetate was given daily to lung cancer patients undergoing therapy with CODE and to recurrent head and neck cancer patients receiving DEB/M in an attempt to prevent weight loss. The outcomes in this study were compared with the same outcomes in similar groups of patients treated with the same chemotherapy regimens, but in which prednisone was used as the main supportive drug along with co-trimoxazole, ketoconazole, and either cimetidine or sucralfate. Weight loss was less pronounced in the current patients than in the previous ones. Nevertheless, there were several factors that led us to conclude that megestrol is not an adequate substitute for prednisone in patients receiving this kind of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Comparison of the effects of cilazapril in an elderly and nonelderly hypertensive general practice population.

The ACE inhibitor cilazapril was studied in mild to moderate hypertensive patients in general practice to evaluate the effect of age on hypotensive response to low (0.5 and 1 mg) doses. Six hundred and seventy-one patients entered a two week single-blind placebo run-in period and 524 patients were eligible to receive active treatment titrated up to a maximum dose of 5 mg. All patients received 0.5 mg of cilazapril once daily for four weeks. The dose was titrated at monthly intervals to 1, 2.5 and 5 mg once daily if DBP remained > 90 mmHg. If DBP < or = 90 mmHg patients remained at their current dose level until the end of the study. Three hundred and twenty-nine patients < 65 years old and 195 patients > or = 65 years old took active treatment. Binary logistic regression detected no statistically significant difference in response between the two groups (P > 0.2) at low doses of cilazapril. Cumulative response rates (DBP < or = 90 mmHg) for all patients were 24.5%, 40.4%, 54.5% and 62.7% for the escalating dose groups. Cumulative augmented response rate (DBP < or = 90 mmHg and/or reduction in DBP of > or = 10 mmHg) at the 5 mg dose level was 76.7% for all patients. Cilazapril was well tolerated with the pattern of adverse events reflecting those currently documented. A higher proportion of patients than expected responded to the low doses of cilazapril. This effect was not age dependent. These doses are lower than the recommended maintenance doses of 2.5-5 mg in the UK data sheet.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Small cell lung carcinoma: role of thoracic irradiation and its timing in relation to chemotherapy].

Combined modality therapy is of great importance in the management of small cell lung cancer. Randomized studies of the design chemotherapy with or without thoracic irradiation are required to demonstrate the impact of radiotherapy on rates of survival, local control and adverse effects. The method of meta-analysis allows one to analyse in a single study a set of different clinical trials of the same design. The first purpose of this paper is to briefly present the method, and the results of a meta-analysis on the role of thoracic irradiation combined with chemotherapy in the treatment of this disease. Thoracic irradiation added to chemotherapy results in a major decrease in local relapse (from 65% to 40% at 2 years), a modest increase in overall survival (from 16 to 22% at 2 years), and a small increase in lethal toxicity (from 1 to 2%). The second purpose is to discuss timing of thoracic irradiation with respect to the administration of chemotherapy using the results of a recently published trial. This Canadian study is based on the hypothesis that chemo resistant cells may develop as a result of spontaneous mutations during therapy. Limited disease patients all received the same chemotherapy (alternating 3-week cycles of CAV [cyclophosphamide, doxorubicin, vincristine] over EP [etoposide, cisplatinum] for a total of six cycles), after having been randomized to receive thoracic irradiation given either early (at 3 weeks following the beginning of treatment) or late (at 15 weeks). Of the 308 patients for analysis 155 were randomized to the "early radiotherapy" arm, and 157 to the "late radiotherapy". Prognostic factors were equally distributed between the two arms. The radiotherapy regiment consisted of a dose of 40 Gy in 15 fractions to a target volume including the primary tumor and mediastinum, and prophylactic brain irradiation (25 Gy in ten fractions in 2 weeks) to patients without progression of disease. The overall survival rate was better in the "early radiotherapy" arm, with a median survival of 21 months and on overall survival rate of 20% at 5 years, compared to a median of 16 months and a 5 years survival of 11% in the "late radiotherapy" arm. The survival curves are significantly different by the log rank (P = 0.008) and Wilcoxon (P = 0.005) tests, in favour of "early radiotherapy". After allowing for prognostic factors (sex, ECOG performance status) by the Cox model, the "early" arm retains a statistically significant advantage (P = 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗