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N Russell

Publications and source records attributed to N Russell.

At least 19 recordsLinked to original sources
PubMed2001

Immune defence against HIV-1 infection in HIV-1-exposed seronegative persons.

Rare individuals who are repeatedly exposed to HIV-1 through unprotected sexual contact fail to acquire HIV-1 infection. These persons represent a unique study population to evaluate mechanisms by which HIV-1 replication is either prevented or controlled. We followed longitudinally a group of healthy HIV-1 seronegative persons each reporting repeated high-risk sexual activities with their HIV-1-infected partner at enrollment. The volunteers were primarily (90%) male homosexuals, maintaining high risk activities with their known infected partner (45%) or multiple other partners (61%). We evaluated the quantity and specificity of HIV-1-specific T cells in 31 exposed seronegatives (ES) using a IFN-gamma ELISPOT assay to enumerate T cells recognizing epitopes within HIV-1 Env, Gag, Pol and Nef. PBMC from only three of the 31 volunteers demonstrated ex vivo HIV-1-specific IFN-gamma secretion, in contrast to nearly 30% exhibiting cytolytic responses in previous studies. These findings suggest that if T cell responses in ES are induced by HIV-1 exposure, the frequency is at low levels in most of them, and below the level of detection using the ELISPOT assay. Alternative approaches to improve the sensitivity of detection may include use of dendritic cells as antigen-presenting cells in the ex vivo assay and more careful definition of the risk behavior and extent of HIV-1 exposure in conjunction with the evaluation of T cell responses.

CD8-Positive T-Lymphocytes↗
PubMed2001

Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis, wild-type TP53, and vicinal thiol/disulfide status.

Nonresponse to remission-induction chemotherapy, which remains a major problem in acute myeloblastic leukemia (AML), has been linked to cellular resistance to apoptosis. Because the apoptosis induced by chemotherapeutic drugs is mediated by loss of mitochondrial transmembrane potential (MTP), it was postulated that sensitivity to mitochondrial membrane depolarization might be heterogeneous in AML. Using the uncoupling agent carbonyl cyanide m-chlorophenylhydrazone (mClCCP), the mitochondrial membrane sensitivity to depolarization (mClCCP concentrations that inhibit 50% of the transmembrane potential [IC(50)]) in AML blasts was measured and demonstrated marked interclonal heterogeneity, with the existence of comparatively sensitive (median mClCCP IC(50), 4 microM) and resistant (median mClCCP IC(50), 10 microM) clones. Furthermore, the mClCCP IC(50) was inversely associated with spontaneous in vitro apoptosis (P =.001). It was high in cases with mutant TP53 and correlated with the total cellular level of the multidrug resistance-associated protein (P =.019) but not of bcl-2, bax, or bcl-x. It was also found that the dithiol oxidant diamide, in contrast to the monovalent thiol oxidant diethyl maleate, increased the sensitivity of mitochondrial membranes to mClCCP. To confirm that TP53 directly affects MTP in leukemic cells and to establish the role of vicinal thiol oxidation in the TP53-dependent pathway, CEM 4G5 leukemia cells with forced, temperature-dependent expression of TP53 were studied. Monobromobimane, which inhibits mitochondrial membrane depolarization by preventing dithiol cross-linking, inhibited depolarization and apoptosis in 4G5 cells. It was concluded that in leukemia, TP53 and vicinal thiol/disulfide status are determinants of mitochondrial membrane sensitivity to depolarization, which is in turn associated with spontaneous apoptosis.

Apoptosis↗
PubMed2001

Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

Community-acquired respiratory virus infections are a cause of mortality after stem cell transplantation (SCT). A prospective study was performed at 37 centers to determine their frequency and importance. Additional cases were also collected to allow the analysis of risk factors for severe infection. Forty episodes were collected in the prospective study and 53 additional episodes through subsequent case collection. The frequency of documented respiratory virus infections was 3.5% among 819 allogeneic and 0.4% among 1154 autologous SCT patients transplanted during the study period. The frequency of lower respiratory tract infections (LRTI) was 2.1% among allogeneic and 0.2% among autologous SCT patients. The mortality within 28 days from diagnosis of a respiratory viral infection was 1.1% among allogeneic SCT while no autologous SCT patient died. The deaths of five patients (0.6%) were directly attributed to a respiratory virus infection (three RSV; two influenza A). On multivariate analysis, lymphocytopenia increased the risk for LRTI (P = 0.008). Lymphocytopenia was also a significant risk factor for LRTI in patients with RSV infections. The overall mortality in RSV infection was 30.4% and the direct RSV-associated mortality was 17.4%. For influenza A virus infection, the corresponding percentages were 23.0% and 15.3%. This prospective study supports the fact that community-acquired respiratory virus infections cause transplant-related mortality after SCT.

Adolescent↗
PubMed2001

Women's health after plastic surgery.

BACKGROUND: Allegations that exposure to endogenous silicone, especially related to breast implants, might be causally related to connective tissue disease originated from case studies. More recent comparative studies have implied no such increased risk. The aims of the present study were to compare the prevalence and/or incidence of autoimmune and connective tissue disorders in a population-based cohort of female Sydney residents stratified by augmentation mammoplasty status. METHODS: In this population-based retrospective cohort study, the health status of female Sydney residents who had augmentation mammoplasty for cosmetic reasons between 1979 and 1983 was compared with that of female Sydney residents who had non-silicone-associated plastic surgery over the same period. Both groups were matched for age (+/- 5 years), year of plastic surgery (+/- 2 years), plastic surgeon, anaesthetist and mode of anaesthesia. Outcome measures comprised rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, sicca symptoms polymyositis/ dermatomyositis, connective tissue disease overlap, digital vasospasm, abnormal nailfold capillaroscopy, elevated antinuclear antibody titre, carpal tunnel syndrome, tendonitis, osteoarthritis, psoriatic arthritis, livedo reticularis, thyroid disease, multiple sclerosis, axillary lymphadenopathy, fibromyalgia and breast carcinoma. RESULTS: There was no difference in the occurrence of connective tissue diseases or connective tissue disease-related parameters, thyroid disorders, fibromyalgia or multiple sclerosis between cohorts. However, axillary adenopathy and low titre positive antinuclear antibody (ANA) occurred with a significantly greater frequency in the exposed cohort (odds ratio (OR) = 3.50, 95% confidence interval (CI) = 2.10-5.84 and OR = 1.29, 95% CI = 1.03-1.62, respectively). Axillary adenopathy correlated with capsular contracture (relative risk (RR) = 2.07, 95% CI = 1.22-3.51) and also the self-reported development of digital vasospasm (RR = 3.20, 95% CI = 1.46-7.03) after breast augmentation. CONCLUSIONS: No association was found between augmentation mammoplasty exposure and various connective tissue diseases and/or their related features. However, axillary adenopathy and low titre ANA were detected more frequently in the exposed cohort. Women with axillary adenopathy were more likely to have breast capsular contracture and report digital vasospasm post-dating surgery. Given comparable frequencies of higher titre ANA of both cohorts, the finding of elevations of low titre ANA is of dubious clinical significance.

Adult↗
PubMed2000

P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway.

P-glycoprotein (pgp), which is the product of the MDR1 (multidrug resistance-1) gene, has an established role as a mediator of cytotoxic drug resistance in acute myeloid leukemia (AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7-AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a significant increase in apoptosis in the presence of the pgp-specific antibody UIC2 (mean increase: 58%; range: 11%-95%; P <. 05). Likewise, apoptosis in growth factor-deprived TF1 cells cultured for 30 hours increased 2.5-fold in the presence of 25 microg/mL UIC2. The pgp reversal agent PSC-833 (1 micromol/L) augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to a comparable degree in 6 pgp-ve samples. To determine whether the sphingomyelin-ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific IC(30) (the concentration of daunorubicin that caused apoptotic cell death in 30% of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was significantly more effective at augmenting apoptosis in pgp-ve patient blasts (median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples (median: 7%; range: 0%-27%; P =.028). Cellular accumulation of exogenous SM was associated with apoptosis and also occurred in nonapoptotic patient cells treated with PSC-833. However, this effect was not seen following treatment with the UIC2 antibody. These results indicate that pgp is able to exert a protective effect on AML cell viability and that this is associated with a reduced effect of exogenous SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp independent mechanism to alter SM distribution and to augment apoptosis induced in AML cells by serum and growth factor withdrawal. (Blood. 2000;95:2897-2904)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning.

We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.

Adult↗
PubMed2000

High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin's disease: a report on toxicity and efficacy.

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ïfosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.

Adolescent↗
PubMed2000

The effect of Bcr-Abl protein tyrosine kinase on maturation and proliferation of primitive haematopoietic cells.

BACKGROUND: Chronic Myeloid Leukaemia (CML) is characterised by the chromosomal translocation resulting in expression of the Bcr-Abl protein tyrosine kinase (PTK) in early stem cells and their progeny. However the precise nature of Bcr-Abl effects in primitive CML stem cells remains a matter of active debate. MATERIALS AND METHODS: Extremely primitive Bcr-Abl fusion positive cells were purified from patients with CML using multiparameter flow cytometric analysis of CD34, Thy, and lineage marker (Lin) expression, plus rhodamine-123 (Rh-123) brightness. Progenitor cells of increasing maturity were examined for cycling status by flow cytometry and their proliferative status directly correlated with cell phenotype. The activation status of a key transcription factor, signal transducers and activators of transcription (STAT-5), was also analyzed by immunocytochemistry. RESULTS: The most primitive stem cells currently defined (CD34+Lin-Thy+ Rh-1231o) were present as a lower proportion of the stem cell compartment (CD34+Lin-) of CML patients at presentation than of normal individuals (2.3% +/- 0.4 compared with 5.1% +/- 0.6 respectively). Conversely there was a significantly higher proportion of the more mature cells (CD34+Lin-Thy-Rh-123 hi) in CML patients than in normal individuals (79.3 +/- 1.8 compared with 70.9 +/- 3.3). No primitive subpopulation of CML CD34+Lin- cells was cycling to a significantly greater degree than cells from normal donors, in fact, late progenitor cells (CD34+Lin+) were cycling significantly less in CML samples than normal samples. STAT5, however, was observed to be activated in CML cells. CONCLUSIONS: We conclude that no subpopulation of CML stem cells displays significantly increased cell cycling. Thus, increased cycling cannot be a direct consequence of Bcr-Abl PTK acquisition in highly enriched stem cells from patients with CML. In vivo CML need not be considered a disease of unbridled stem cell proliferation, but a subtle defect in the balance between self renewal and maturation.

Cell Division↗
PubMed1999

Mobilisation of peripheral blood stem cells with IVE and G-CSF improves CD34+ cell yields and engraftment in patients with non-Hodgkin's lymphomas and Hodgkin's disease.

The transplantation of mobilised peripheral blood stem cells is associated with more rapid engraftment than marrow transplantation. We have previously reported that G-IVE (G-CSF, ifosphamide, VP-16, epirubicin) improves the yield of CD34+ cells mobilised in patients with lymphoproliferative disorders compared with cyclophosphamide 3 g/m2 and G-CSF (G/CYCLO). In this study we have extended these observations to a larger series of patients including different lymphoma subtypes. Ninety-seven patients undergoing stem cell mobilisation were studied. Forty-two patients with lymphoproliferative disorders received G-IVE for mobilisation and 55 patients G/CYCLO. The median number of mobilised CD34+cells per leucapheresis was significantly higher for those patients receiving G-IVE: 5.82 x 106/kg (0.19-36) compared with 1.2 x 106/kg (0.04-17), P < 0.001 which resulted in a significantly reduced number of leucapheresis procedures performed in the G-IVE group. When patients were analysed dependent on underlying disease G-IVE mobilised significantly more CD34+cells per leucapheresis for all lymphoma types reaching 8.41 x 10(6)/kg (0.2-32) compared to 1.32 x 10(6)/kg (0. 06-17) for patients with high-grade NHL mobilised with G-IVE and C-GCSF respectively (P = 0.012). For patients with low-grade NHL 3. 12 x 10(6)/kg (0.10-24.39) compared to 1.08 x 10(6)/kg (0.04-9.74) were collected (P = 0.04) and for patients with Hodgkin's disease 3.02 x 10(6)/kg (1.48-36) and 1.04 x 10(6)/kg (0.1-12.3) (P = 0.001). Mobilisation with G-IVE resulted in the achievement of clinically significant CD34+ cell thresholds in a significantly higher proportion of patients compared to cyclophosphamide and G-CSF reaching >2.5 x 10(6)/kg CD34+ cells in 88% vs 62% (P = 0.004), >5 x 10(6)/kg in 67% vs18% (P = 0.001) and >10 x 10(6)/kg in 31% vs 14.5% (P = 0.05). Furthermore, an analysis of engraftment demonstrated that there was a significant reduction in the time to achieve platelet counts of >20 and >50 x 10(9)/l in patients receiving each incremental dose of CD34+ cells. We conclude that G-IVE mobilizes significantly more CD34+cells than G/CYCLO in patients with lymphoproliferative disorders. This effect is consistent in patients with high-grade NHL, low-grade NHL and HD and results in fewer failed stem collections and increased CD34+ cells available for transplantation which results in significantly accelerated platelet engraftment post transplant.

Adult↗
PubMed1999

Generation of anti-idiotype immune responses following vaccination with idiotype-protein pulsed dendritic cells in myeloma.

Myeloma cells produce immunoglobulin which is unique to the malignant clone and presents antigenic determinants, or idiotypes, which may function as a tumour-specific antigen. The availability of significant quantities of idiotype protein in the serum makes immunotherapeutic strategies utilizing this protein to generate an anti-idiotype immune response an attractive prospect. We treated two patients with advanced refractory myeloma with a series of four vaccinations using autologous idiotype-protein pulsed dendritic cells combined with adjuvant GM-CSF. The vaccinations were well tolerated with a mild fever post-vaccination in one patient. An idiotype-specific T-cell proliferative response developed in both patients. This T-cell response was associated with the production of gamma-interferon, indicating a TH-1-like response. Furthermore, one patient developed anti-idiotype IgM antibodies. However, no idiotype-specific cytotoxic T-cell response could be demonstrated. Further investigation is warranted to define the optimal conditions for dendritic cell culture and priming to maximize the anti-tumour immune response.

Antibodies, Anti-Idiotypic↗
PubMed1998

The effect of dietary vitamin D3 on the intracellular calcium gradient in mammalian colonic crypts.

A physiological gradient in intracellular calcium ([Ca2+]i) has been hypothesized to exist along the colonic crypt base-mouth axis, which may be involved in the regulation of colonocyte proliferation, differentiation and apoptosis. In addition [Ca2+]i may be modulated by dietary vitamin D3 which is thought to be protective against colorectal cancer. CF1 mice were maintained for 6 weeks on a defined diet containing either high or low vitamin D3. A colonic crypt base-mouth [Ca2+]i gradient of 201 +/- 79 nM (mean +/- SEM, P < 0.05) was observed in animals maintained on a high vitamin D3 diet and was abolished in mice maintained on a low vitamin D3 diet. The [Ca2+]i gradient was independent of extracellular calcium and elevated levels of [Ca2+]i observed in the basal regions of the crypt in animals maintained on low levels of vitamin D3 were also associated with an increase in intracellular calcium stores. Therefore, a [Ca2+]i gradient exists in colonic crypts and is dependent on dietary vitamin D3.

Animals↗
PubMed1998

Spontaneous cervical epidural hematoma: case report.

Spontaneous spinal epidural hematoma (SSEH) is an uncommon cause of acute nontraumatic myelopathy. We report a 14 year-old boy who had tetraplegia on awakening. Diagnosis of spinal epidural hematoma was made by magnetic resonance imaging. Despite spinal cord decompression within 9 h from onset, he remained tetraplegic. No cause for the bleeding was found. The pathogenic hypotheses of SSEH are discussed and the importance of rapid diagnosis and treatment is emphasized.

Adolescent↗
PubMed1997

The use of an all oral chemotherapy (idarubicin and etoposide) in the treatment of acute myeloid leukaemia in the elderly: a report of toxicity and efficacy.

Acute myeloid leukaemia (AML) is predominantly a disease of the elderly but such patients are not always appropriate candidates for intensive intravenous (i.v.) based treatment regimens. The development of the anthracycline idarubicin which is highly effective in the treatment of AML and is active when given orally has made it possible to design anti-leukaemic regimens which may be given orally and be particularly useful in those elderly patients with AML considered unsuitable for standard intensive aggressive treatments. We have assessed an oral regimen combining idarubicin 30 mg/m2 and etoposide 80 mg/m2 for 3 consecutive days as initial treatment in 28 elderly patients with AML (median age 69 years, range 56-81) who were not considered suitable for more intensive i.v. chemotherapy schedules. Following informed consent, two patients died before treatment began and one patient withdrew prior to treatment. Twenty-five patients underwent one to four courses of treatment. The schedule was well tolerated with minor nonhaematological toxicity. The first course was given in hospital, eight of 21 subsequent courses of treatment were given entirely as an out-patient. Eleven patients responded to treatment with nine (36%) achieving complete remission (CR). The median survival for all patients was 3 months, but for the nine who achieved a CR it is 9 months with six patients still alive, five in first CR and one in second CR. We conclude that a combination of idarubicin and etoposide given orally as first-line treatment in elderly patients with AML is safe and effective. In some patients this means treatment and follow-up can be given entirely on an out-patient basis.

Acute Disease↗
PubMed1996

Non-traumatic cerebral hemorrhage in Saudi Arabs: a hospital-based study of 243 cases.

This is a retrospective study involving 243 Saudi Arabs with non-traumatic cerebral hemorrhages confirmed by CT scan. Intracerebral hemorrhages accounted for about 20% of all strokes in this population. THe male to female ratio was 2.74 which is slightly higher than those reported from elsewhere. Peak frequency was around 60 years. Hypertension was the most common cause accounting for 64% of the cases, hemopathies/coagulopathies for 10% and arteriovenous malformations (AVMs) for 6%. THe cause was undetermined in 21% of patients. Amyloid angiopathy was probably underrepresented due to lack of autopsy correlation. The etiologies were, however, age-related with a clear predominance of AVMs and coagulation disorders before the age of 40 years. Hypertensive hemorrhages were located in the putamen in 46% of cases compared to 20% in non-hypertensive patients while 52% of non-hypertensive hemorrhages were lobar in location compared to 20.5% in hypertensives. Early mortality (19%) in our series was relatively low compared to reports from the industrialized world.

Adolescent↗
PubMed1996

Stem cell mobilization in normal donors for allogeneic transplantation: analysis of safety and factors affecting efficacy.

The use of peripheral blood stem cells instead of bone marrow as the source of haemopoietic cells for allogeneic transplantation is being increasingly explored. We have analysed data from 17 normal donors who underwent stem cell mobilization for allogeneic transplantation with an identical protocol using G-CSF at a dose of 10 micrograms/kg/d, with the first leukapheresis (LP) on the day following the fourth dose of G-CSF. Both G-CSF administration and leukapheresis were well tolerated. Donors under-went a median of two leukaphereses (range one to three) and a median of 6.80 x 10(6) CD34+ cells/kg recipient weight (range 2.4-15.6 x 10(6)) were collected. The median number of CD34+ cells per kg donor weight was 6.05 x 10(6), when corrected for a 12 litre leukapheresis, this gave a median total of 3.89 x 10(6) CD34+ cells/kg donor weight. When analysed with respect to factors which might influence the efficacy of mobilization, male donors were associated with a superior yield. The median number of CD34+ cells/kg/LP harvested was 4.96 x 10(6) in males and 2.79 x 10(6) in females (P < 0.05). The results suggested that, given a recipient of 75 kg, in a male donor a single 12 litre leukapheresis should yield sufficient CD34+ cells (4 x 10(6)/ kg), whereas a female donor would be likely to need two leukaphereses. Age was not found to affect donor yield. In summary, these data confirm that leukapheresis is a safe procedure in normal donors and suggest that males may be more efficient mobilizers of stem cells than females.

Adult↗