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Biomedical subjects

S Anderson

Publications and source records attributed to S Anderson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Stem cell mobilization in resistant or relapsed lymphoma: superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide.

We analysed the factors influencing the efficacy of peripheral blood stem cell (PBSC) collection in patients with lymphoma. Sixty-six patients underwent initial PBSC collection following mobilization with chemotherapy plus recombinant granulocyte colony-stimulating factor (300 microg/d). Patients were mobilized with one of two chemotherapy regimens, either cyclophophamide (3 g/m2 or 4 g/m2) (n = 50) or ifosphamide, etoposide and epirubicin (IVE; n = 16). The target of collecting > 2.0 x 10(6) CD34+ cells/kg was achieved in 43/66 (65%) patients with a median of two apheresis procedures. The IVE plus G-CSF mobilization regimen gave a significantly higher median yield of CD34+ cells (8.62 x 10(6)/kg) compared with cyclophosphamide plus G-CSF (3.59 x 10(6)/kg) (P = 0.045). The median yield of CD34+ cells per leukapheresis was almost twice as high in patients receiving IVE (1.94 x 10(6)/kg) compared to cyclophosphamide (1.03 x 10(6)/kg) (P = 0.035). In a univariate analysis of the factors affecting mobilization, the subtype of lymphoma (high-grade NHL) and the mobilization regimen were the only factors associated with high CD34+ cell yield. However, in a multivariate analysis of factors affecting mobilization including age, lymphoma subtype, previous chemotherapy and radiotherapy, only the use of the IVE protocol was predictive of a high yield of CD34+ cells. In 13 patients undergoing a second mobilization procedure the use of IVE was associated with a significantly higher yield of CD34+ cells compared to cyclophosphamide; three patients who failed cyclophosphamide plus G-CSF mobilization were able to proceed to transplantation following successful mobilization with IVE + G-CSF. These results demonstrate that IVE is a highly effective mobilization regimen which is superior to cyclophophamide and has the benefit of being effective salvage therapy for lymphoma patients.

Adult↗
PubMed1997

Expression and modulation of cellular receptors for interferon-gamma, tumour necrosis factor, and Fas on human bone marrow CD34+ cells.

Interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and Fas-ligand can mediate potent inhibitory signals in haemopoietic cells. Clinical and laboratory studies have suggested the involvement of these cytokines in the regulation of normal haemopoiesis and in the pathophysiology of bone marrow (BM) failure syndromes. As the effects of cytokines may also be regulated at the cellular receptor level, we studied the expression and modulation of TNF receptor (TNFR), IFN-gammaR and Fas-R on haemopoietic progenitor cells. In freshly isolated BM, using flow cytometry, TNFR1 (p55), TNFR2 (p75), IFN-gammaR, and Fas-R were detected on 5-12% of mononuclear cells. Two-colour staining showed comparable receptor expression on a CD34+ population, which includes haemopoietic progenitor and stem cells. Using reverse transcriptase-PCR (RT-PCR) transcription of mRNA coding for these receptors was demonstrated in fresh, highly purified CD34+ cells. These findings indicate that the effects of these factors on progenitor cells may be directly mediated. In cultured BM cells, expression of TNFR1 was not influenced by IFN-gamma, TNF-alpha or apoptosis-inducing anti-Fas monoclonal antibody (mAb). IFN-gamma decreased CD34+ cell TNFR2 expression. CD34+ cell Fas-R expression was increased by IFN-gamma and TNF-alpha. IFN-gammaR expression was enhanced by anti-Fas mAb and to lesser degree with TNF-alpha. Similar results were obtained with RT-PCR analysis in cultured CD34+ cells. Potentiation of anti-Fas mAb-mediated inhibition of haemopoietic colony formation by IFN-gamma and TNF-alpha was observed. Similarly, anti-Fas mAb enhanced the inhibitory effects of IFN-gamma. These results suggest that, in addition to interacting at the level of intracellular signalling pathways, IFN-gamma, TNF-alpha or Fas-ligand may potentiate or antagonize their effects through modulation of cytokine receptor expression.

Antibodies, Monoclonal↗
PubMed1997

Participatory evaluation of counselling, medical and social services of The AIDS Support Organization (TASO) in Uganda.

The AIDS Support Organization (TASO) is an indigenous non-governmental organization (NGO) of HIV-infected and affected people in Uganda. TASO provides counselling, social support, medical and nursing care for opportunistic infections at 7 centres affiliated to district hospitals in Uganda. Between 1993 and 1994, the services provided by TASO were evaluated through a participatory approach between staff and clients. TASO counselling services helped clients and their families to cope with HIV and AIDS, with 90.4% of clients revealing their serostatus, and 57.2% reporting consistent use of condoms in the past 3 months. TASO was also the main source of medical care for clients with opportunistic infections in the last 6 months (63.8%). As a result of counselling, over half of the clients (56.9%) made plans for the future and 51.3% wished to make wills. There was a high level of acceptance of people living with HIV/AIDS (PWAs) by families (79%) and the community (76%). Care was provided to PWAs at home mainly by women (86.2%). TASO has demonstrated that individuals and their families are able to live positively with HIV/AIDS. Through counselling, medical care and material support to clients and their families, TASO has effected change in people's attitudes, knowledge and lifestyles. In particular, TASO has demonstrated a strong capacity to overcome four problems that haunt AIDS care in most places: (1) revealing one's HIV-serostatus to relevant others; (2) accepting PWAs in family and community; (3) seeking early treatment; and (4) combining prevention and care. In general, TASO has shown that specialized services to meet AIDS care needs can be added to existing health services at district levels. As a result of the participatory evaluation, a well-accepted monitoring system was established.

AIDS-Related Opportunistic Infections↗
PubMed1997

Choice of student's t- or Wilcoxon-based confidence intervals for assessment of average bioequivalence.

An open question in the analysis of average bioequivalence is whether the nonparametric (Wilcoxon) or parametric (t) approaches to two one-sided tests is preferable. Previous work has made particular distributional assumptions as to the distribution of AUC and C(max). Instead, we simulate data according to a pharmacokinetic model for an immediate-release formulation. We find that both approaches have estimated level consistent with the nominal 5%. The only concern is a possible anticonservativeness of the parametric approach for C(max). Further, the nonparametric approach is consistently less powerful than the parametric for the cases studied.

Area Under Curve↗
PubMed1997

Production of correctly folded recombinant [13C, 15N]-enriched guinea pig [Val90]-alpha-lactalbumin.

The M90V mutant of guinea pig alpha-lactalbumin (gpLA) was expressed intracellularly in Escherichia coli using a gpLA gene fusion to the IgG-binding ('Z') domain coding sequences of staphylococcal protein A. The fusion protein was expressed as an inclusion body, then purified and refolded in vitro; CNBr cleavage of the fusion polypeptide yielded native alpha-lactalbumin. The recombinant M90V gpLA was virtually identical with natural gpLA with respect to its ability to stimulate lactose synthesis by galactosyl transferase and the recombinant and natural molecules also exhibited similar circular dichroism spectra, thermal melting profiles and NMR spectra. However, modest perturbations in the chemical shifts of amide protons in the C-helix residues, attributable to the Met-->Val mutation, were observed. In defined media, this expression system enabled the production of highly-enriched 15N- and 13C, 15N-labeled gpLA. Use of this material will allow the solution conformations of the native and molten globule states of gpLA to be characterized by high-resolution multidimensional NMR.

Animals↗
PubMed1997

Separate and joint effects of arginine and glucose on ovine fetal insulin secretion.

To determine separate and joint effects of increases (delta) in fetal plasma concentrations of arginine (Af) and glucose (Gf) on fetal insulin (If) secretion (delta If), 15 late-gestation fetal sheep were given 5-min arginine bolus infusions (40, 86, 144, 201, and 402 mumol/kg estimated fetal wt) at 90 min of 120 min steady-state glucose clamps (basal Gf, basal + 0.6 mM Gf, and basal + 1.1 mM Gr), producing absolute and percent increases above basal Af of 25.8 +/- 1.3 microM (+33%), 50.9 +/- 6.3 microM (+66%), 83.8 +/- 7.1 microM (+108%), 122.1 +/- 9.4 microM (+156%), and 302.2 +/- 28.2 microM (+386%), respectively. Acute hyperglycemia alone produced an increase above basal If of 9 +/- I microU/ml (+80%) and 19 +/- 2 microU/ml (+170%) after basal + 0.6 mM Gf and basal + 1.1 mM Gf, respectively. Increasing values of delta Af showed separate but lesser effects on delta If, which were significant only at very high values of Af (> 100% above mean normal Af) unless marked hyperglycemia (1.5- to 2-fold normal) was also present, demonstrating joint effects of delta Af and delta Gf on delta If according to a best-fit inverse polynomial response surface. We conclude that physiological increases in Af at normal glucose concentrations are not a potent-stimulus to insulin secretion in fetal sheep.

Animals↗
PubMed1997

Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer.

PURPOSE: Based on preclinical data that demonstrated synergy between alkylating agents and topoisomerase (topo) I poisons, we determined the maximum-tolerated dose (MTD) of topotecan, using a 5 day bolus schedule, that could be given in combination with a single, fixed dose of cyclophosphamide. Pharmacodynamics of this combination were explored by analyzing biochemical effects of treatment in peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Patients with refractory cancer were treated with cyclophosphamide 600 mg/m2 on day 1, followed by topotecan given as a 30-minute infusion for 5 consecutive days. Cycles were repeated every 3 weeks. Once the MTD was defined, granulocyte colony-stimulating factor (G-CSF) was added to the regimen in an attempt to escalate further the dose of topotecan. Plasma concentrations of topotecan were determined during the first treatment cycle by high-performance liquid chromatography. PBMCs were sampled at baseline and throughout the 5-day treatment period for analysis of topo I protein concentrations and to determine drug-induced DNA fragmentation. RESULTS: Twenty-six patients were treated with topotecan at doses that ranged from 0.5 mg/m2/d to 1.2 mg/ m2/d for a total of 74 cycles. Reversible neutropenia was dose-limiting, with mild to moderate suppression of the other blood-cell elements commonly occurring. Transfusions of RBCs and platelets were required in 24% and 7% of treatment cycles, respectively. The most prominent nonhematologic toxicities were fatigue and weight loss. Compared with previously published data in which topotecan was administered alone, cyclophosphamide did not appear to alter the pharmacokinetics of topotecan. Significant increases in topo I concentration were identified in PBMCs following the administration of cyclophosphamide on day 1 and there was a significant decrease in topo 1 during the 5-day course of treatment (P < .01, sign test). DNA fragmentation as a result of drug treatment was identified in 11 of 15 (73%) cycles analyzed. CONCLUSION: For previously treated patients, the recommended dose of topotecan in this schedule is 0.75 mg/m2/d without growth factor support and 1.0 mg/ m2/d if it is administered with G-CSF. Biochemical changes in cells induced by exposure to camptothecins can be measured in vivo and these effects may have important implication in the design of combination therapies and the optimal scheduling of this class of agents.

Adult↗
PubMed1997

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-22) to determine if intensifying but maintaining the total dose of cyclophosphamide (Cytoxan, Bristol-Myers Squibb Oncology, Princeton, NJ) in a doxorubicin (Adriamycin, Pharmacia, Kalamazoo, MI)-cyclophosphamide combination (AC), or if intensifying and increasing the total dose of cyclophosphamide improves the outcome of women with primary breast cancer and positive axillary nodes. PATIENTS AND METHODS: Patients (N = 2,305) were randomized to receive either four courses of standard AC therapy (group 1); intensified therapy, in which the same total dose of cyclophosphamide was administered in two courses (group 2); or intensified and increased therapy, in which the total dose of cyclophosphamide was doubled (group 3). The dose and intensity of doxorubicin were similar in all groups. Disease-free survival (DFS) and overall survival were determined using life-table estimates. RESULTS: There was no significant difference in DFS (P = .30) or overall survival (P = .95) among the groups through 5 years. At 5 years, the DFS of women in group 1 was similar to that of women in group 2 (62% v 60%, respectively; P = .43) and to that of women in group 3 (62% v 64%, respectively; P = .59). The 5-year survival of women in group 1 was similar to that of women in group 2 (78% v 77%, respectively; P = .86) and to that of women in group 3 (78% v 77%, respectively; P = .82). Grade 4 toxicity increased in groups 2 and 3. Failure to note a difference in outcome among the groups was unrelated to either differences in amount and intensity of cyclophosphamide or to dose delays and intervals between courses of therapy. CONCLUSION: Intensifying or intensifying and increasing the total dose of cyclophosphamide failed to significantly improve either DFS or overall survival in any group. It was concluded that, outside of a clinical trial, dose-intensification of cyclophosphamide in an AC combination represents inappropriate therapy for women with primary breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Engraftment and molecular monitoring of CD34+ peripheral-blood stem-cell transplants for follicular lymphoma: a pilot study.

PURPOSE: A pilot study to validate the use of CD34+ selection (Ceprate SC) of blood stem-cell collection in patients with advanced follicular lymphoma receiving myeloablative chemoradiotherapy. PATIENTS AND METHODS: Seventeen patients were entered onto the protocol. Thirteen of 17 patients have undergone transplantation; the median age is 42.5 years (range, 33 to 51), seven of 13 are stage IVB, two stage IVA, three stage IIIB, and one stage IIB. All except two patients were treated after first or subsequent relapses after receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to achieve a good partial (six of 13) or complete (seven of 13) response before stem-cell mobilization with cyclophosphamide 3 g/m2 and filgrastim 300 microg once daily. RESULTS: Eleven of 13 patients had a detectable t(14;18) by nested polymerase chain reaction (PCR). Median CD34+ count before selection was 2.9 x 10(6)/kg (range, 1.17 to 11.3) and after CD34+ selection was 1.54 x 10(6)/kg (range, 0.88 to 7.6) with a median CD34+ yield of 62.4% (range, 17% to 95%) and purity of 60% (range, 39.3% to 73%). Of the 11 patients known to have t(14;18), 10 had PCR-detectable contamination of stem-cell harvests that became PCR negative in six of the 10 after CD34+ selection. Engraftment was rapid with a median day to absolute neutrophil count (ANC) greater than 0.5 x 10(9)/L of 13 days (range, 11 to 21) and platelet count greater than 20 x 10(9)/L of 14 days (range, 10 to 44). With a median follow-up duration of 15 months, three patients have remained persistently PCR-positive, two of whom received PCR-positive stem cells. Two have relapsed. Of the seven patients who received PCR-negative stem cells, five have had no PCR-detectable disease in posttransplant bone marrow samples. CONCLUSION: Longer follow-up duration is required to determine the significance of these findings, but we have confirmed the feasibility of CD34+ selected cells to deplete peripheral-blood stem cells of tumor cells from patients undergoing high-dose therapy for follicular lymphoma.

Adult↗
PubMed1997

Interactions of the kallikrein-kinin and renin-angiotensin systems in experimental diabetes.

The kallikrein-kinin system (KKS) has been postulated to play a role in modulation of hemodynamic function in diabetes and to contribute to the hemodynamic effects of angiotensin-converting enzyme inhibition (CEI). To further explore the KKS and its interactions with the renin-angiotensin system (RAS), studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic rats. In protocol 1, control and diabetic rats were studied before and after administration of one of two dissimilar B2 kinin receptor antagonists (BK2As), or vehicle. At a low dose (0.5 microg x kg-1 x min-1), the first generation antagonist D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin significantly reduced the glomerular filtration rate (GFR) and renal plasma flow rate in diabetic rats, despite variable effectiveness in blocking the hypotensive response to injected bradykinin. However, a similar hemodynamic effect occurred in nondiabetic rats, suggesting that the observed effect was not specific to diabetes. Higher doses (20 microg bolus, then 1 microg x kg-1 x min-1 infusion) did not affect hemodynamics in either group, perhaps because of partial agonist effect. The second BK2A tested was the newer compound, icatibant (Hoe 140; D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). Hoe 140 consistently blocked the vasodepressor action of injected bradykinin, but had no effect on systemic or renal hemodynamics in either control or diabetic rats. In protocol 2, control and diabetic rats were pretreated with the CEI ramipril for 1-2 weeks, after which renal function was studied before and after Hoe 140 (0.1 mg s.c. and i.v.) or vehicle. CEI lowered blood pressure in both groups. Hoe 140 did not affect renal function in control rats, but in diabetic rats pretreated with ramipril, it induced a modest but significant decline in GFR. Ramipril induced the predicted changes in the systemic and intrarenal RAS, while acute BK2A had no consistent effect on RAS parameters. These studies suggest that the endogenous KKS has only a minor role in modulation of renal hemodynamics in the euvolemic diabetic rat, in the absence of KKS stimulation by CEI. However, angiotensin-converting enzyme is also kininase II, which serves to increase endogenous kinin activity. The increased kinin activity resulting from CEI treatment may participate, to a modest degree, in hemodynamic regulation of the diabetic kidney.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

HIV-testing study of immigrants with pulmonary tuberculosis.

The increasing prevalence of tuberculosis (TB) and human immunodeficiency virus (HIV), particularly in Africa and Asia, led us to investigate the prevalence of HIV infection in immigrants with pulmonary TB at the time of arrival in the UK. We performed anonymous HIV testing of stored sera from 39/65 immigrants referred to our unit between January 1991 and December 1994, who had culture-positive pulmonary TB. None of the 39 patients tested was positive for either HIV-1 or HIV-2, and the characteristics of the 26 patients for whom no serum was available were similar to those of the tested group. Despite the need to consider concomitant HIV infection in any patient with TB, particularly those from an area of HIV endemnicity, the present data do not suggest that recently arrived refugees, asylum seekers, immigrants or long-term visitors to the UK constitute a group in whom dual infection of HIV and Mycobacterium tuberculosis is common.

AIDS Serodiagnosis↗
PubMed1997

Telomerase activation in cervical cancer.

It has been hypothesized that infection with high-risk human papillomaviruses (HPVs), in conjunction with other cellular events, plays a critical role in the development of cervical cancer. Activation of telomerase, a ribonucleoprotein enzyme complex that synthesizes telomere repeats, has been associated with acquisition of the immortal phenotype in vitro and is commonly observed in human cancers. In this study, we have examined 10 high-grade cervical cancers for telomerase activity and for the presence of HPV. Telomerase activity was detected in all of the cancers but in none of the paired histopathologically normal uterine tissues or in normal cervical epithelium. Analysis of these same tissues for HPV nucleic acids by polymerase chain reaction (PCR) using primers from the HPV L1 and E6 open reading frames demonstrated that 7 of 10 cancers were positive for HPV, 3 for HPV type 16 (HPV-16), and 4 for HPV-18. In one case, HPV-16 was detected in histopathologically normal uterine tissue, the same type as that detected in the cancer from the same patient. HPV DNA was not detected in 3 of 10 cancers. These results indicate that telomerase activation is common in high-grade cervical cancers and suggests that telomerase activity may be a useful diagnostic marker for the disease.

Adenocarcinoma↗
PubMed1997

MR imaging of musculoskeletal tumors in the elbow region.

MR imaging is useful in the evaluation of benign and malignant osseous and soft-tissue masses in the elbow. It allows for multiplanar, high-contrast images that provide precise definition of local tumor extent. The paucity of fat and a high concentration of small soft-tissue structures such as tendons, ligaments, and nerves in this area makes MR imaging more advantageous than CT for delineating tumor margins in the soft tissue. This article describes some of the more common tumors around the elbow with emphasis on their MR imaging characteristics.

Bone Neoplasms↗
PubMed1997

Role of angiotensin II in diabetic nephropathy.

Classically, the renin-angiotensin system (RAS) in diabetes was thought to be suppressed, and relatively unimportant in the regulation of hemodynamics and the development of complications. However, recent developments have caused reconsideration of this notion. Studies of pharmacological interruption of the RAS with angiotensin converting enzyme (ACE) inhibition have implicated this hormonal system in the progression of diabetic nephropathy, both experimentally and clinically. Preliminary evidence also suggests a beneficial effect of angiotensin II (ANG II) receptor antagonists. The relative roles of the systemic versus intrarenal RAS in the pathogenesis of diabetic nephropathy have recently been evaluated. Although plasma renin level is generally low, it is not yet clear whether RAS component processing is normal in diabetes; there may be subtle changes in ANG II metabolism that sustain relatively higher plasma ANG II levels. Furthermore, the intrarenal RAS may not be suppressed. Renal renin levels tend to be disproportionately elevated, as compared with plasma renin values. Renal ANG II levels are normal, and renal mRNAs for RAS components have been variable. In general, lack of RAS suppression (despite plasma volume and increased exchangeable sodium) may indicate inappropriate activity of the RAS in diabetes. RAS-mediated injury may occur via stimulation of a number of sclerosing mediators, and there is evidence that hyperglycemia acts synergistically with ANG II to promote cellular injury. Finally, various RAS candidate genes for development of diabetic nephropathy have been examined and, although controversy remains, ACE gene polymorphisms may be involved. Together, these recent investigations lend further support to the notion that the RAS plays an important role in diabetic nephropathy, and are beginning to shed light on the mechanisms of progressive renal injury.

Angiotensin II↗