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Biomedical subjects

I Cunningham

Publications and source records attributed to I Cunningham.

At least 19 recordsLinked to original sources
PubMed2001

Beta-cell function and visceral fat in lactating women with a history of gestational diabetes.

Lactation has been recommended as beneficial for the maternal metabolic abnormalities associated with glucose intolerance and diabetes risk, although associations between breastfeeding (BF), glucose tolerance, and adipose tissue distribution are unknown. Therefore, a population of women with recent gestational diabetes (GDM) was evaluated with comparison of results for lactating versus nonlactating women. A total of 26 women participated (14 BF and 12 nonbreastfeeding [nonBF]) with a singleton vaginal delivery after 36 weeks gestation. At 3 months postpartum, each woman completed a 75-g oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT), and computed tomography (CT) scanning for adipose distribution and mass. Insulin sensitivity was not significantly different between BF and nonBF groups (4.97 +/- 0.78 v 3.44 +/- 1.0 x 10(-4) min(-1)/(microU/mL) nor was glucose effectiveness (1.92 +/- 0.22 v 1.56 +/- 0.19 x 10(-2) min(-1)). However, the disposition index (DI) (insulin sensitivity [S(I)] x acute insulin response to glucose [AIRg]) was higher in the BF group (129.9 +/- 26.0 v 53.4 +/- 18.0 x 10(-4) min(-1); P =.03). Visceral fat (103 +/- 14 v 97 +/- 15 cm(2)) and subcutaneous fat (362 +/- 36 v 460 +/- 68 cm(2)) were similar between the groups. We conclude that 3 months of BF in a population with previous GDM was associated with improved pancreatic beta-cell function, but not with any difference in measures of adiposity.

Adipose Tissue↗
PubMed1999

Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia.

PURPOSE: To eliminate the risk of rejection and lower the risk of relapse after T-cell-depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation. PATIENTS AND METHODS: Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis. RESULTS: Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status. CONCLUSION: Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell-depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.

Acute Disease↗
PubMed1998

Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.

BACKGROUND: In this study we tried to achieve successful transplantation in patients with acute leukemia with the use of hematopoietic stem cells from donors who shared only one HLA haplotype with the recipient (a "full-haplotype mismatch"). To prevent graft failure, large doses of T-cell-depleted hematopoietic stem cells were transplanted after a conditioning regimen of enhanced myeloablation and immunosuppression was administered to the recipient. METHODS: Forty-three patients with high-risk acute leukemia who were scheduled for transplantation received total-body irradiation, thiotepa, fludarabine, and antithymocyte globulin. The graft consisted of peripheral-blood progenitor cells that had been mobilized in the donor with recombinant granulocyte colony-stimulating factor and also, in 28 cases, bone marrow. Bone marrow from the donor was depleted of T lymphocytes by processing with soybean agglutinin and E-rosetting. T-cell depletion of peripheral-blood mononuclear cells was achieved by E-rosetting followed by positive selection of CD34+ cells. No post-transplantation prophylaxis against graft-versus-host disease (GVHD) was administered. RESULTS: In all the patients, full donor-type engraftment was achieved. In none of the patients who could be evaluated did acute or chronic GVHD develop. Regimen-related toxicity was minimal. Eleven of the 23 patients with acute lymphoblastic leukemia had a relapse, as did 2 of the 20 patients with acute myeloid leukemia. Transplantation-related mortality was 40 percent. After a median follow-up of 18 months (range, 8 to 30), 12 of the 43 patients were alive and free of disease. All surviving patients had a good quality of life. CONCLUSIONS: The main limitations of transplantation of bone marrow from donors who are matched with the recipient for only one HLA haplotype GVHD and graft failure - can be overcome. Since most patients have a relative with one haplotype mismatch, advances in this method will increase the availability of hematopoietic-cell transplantation as curative therapy for acute leukemia.

Adolescent↗
PubMed1997

Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia.

PURPOSE: Mobilization of Philadelphia (Ph) chromosome-negative progenitors is now possible in many Ph1-positive chronic myelogenous leukemia (CML) patients who had received interferon alfa (IFN-alpha) with no cytogenetic response. In this pilot study, we used this approach in patients without prior IFN-alpha therapy to determine if the number and quality of mobilized progenitors would be increased and to evaluate the potential effect of these cells as autografts. PATIENTS AND METHODS: Twenty-two untreated patients were mobilized within 12 months of diagnosis. The treatment regimen consisted of the mini-ICE protocol. Beginning on day +8, granulocyte colony-stimulating factor (G-CSF) was used in all patients. Leukophoresis was performed as the patients were recovering from aplasia, when WBC count exceeded 0.8 x 10(9)/L. RESULTS: In 14 patients, (63%) the leukophoresis product was entirely Ph1-negative and in four patients the Ph1-positive cell rate was < or = 7%. Significant numbers of long-term culture-initiating cells (LTC-IC) and CD34+ Thy1+Lin- cells were found in most of the Ph1-negative collections that were tested. Twelve patients underwent autografting with their mobilized peripheral-blood progenitor cells (PBPC) (Ph1-negative collections, 10 patients; major cytogenetic response, two patients). All patients engrafted and are alive; six have Ph1-negative marrow 7 to 15 months after autografting. Posttransplant treatment was IFN-alpha combined with interleukin (IL)-2 because of the recent demonstration of synergistic activity in augmenting cytolytic activity. CONCLUSION: Intensive chemotherapy given in early chronic phase of CML is well tolerated and results in high numbers of circulating Ph1-negative precursor cells.

Adult↗
PubMed1996

Empowerment: the right medicine for improving employee commitment and morale in the NHS?

States that in recent years, empowerment of National Health Service (NHS) Trust employees has been given substantial political and managerial support. Examines the extent to which the commitment and morale of staff in two NHS Trust hospitals has altered following the introduction of a raft of techniques under the empowerment label. The researchers interviewed substantial numbers of staff with managerial responsibilities, personnel specialists and conducted written surveys seeking employee opinion. Reports the findings, which confirm that, under empowerment, the work of both managers and staff has become more intensive, but managers claim that their commitment has risen, while for non-managerial employees, severe problems of commitment to the Trust, declining morale and high stress were exposed. Identifies reasons for these difficulties which were: the salience of budgetary and operational priorities; lack of training; resistance to the implementation of empowerment; and recognition that little real authority was being devolved to employees. Concludes that the limited effects attributable to empowerment could be explained by its association with harder-edged manpower policies introduced to meet financial and competitive pressures. Under favourable contextual conditions, empowerment may exert more positive effects.

Attitude of Health Personnel↗
PubMed1996

Chronic lymphocytic leukaemia with upper airway obstruction.

We report a case of B-cell chronic lymphocytic leukemia in a 58 year old female in whom the clinical course was dominated by upper airway obstruction due to massive enlargement of the palatine and later the lingual tonsils. The peripheral blood morphology and immunophenotype were typical of chronic lymphocytic leukaemia with expression of CDl9+, CD20+, CD5+, CD23+ and HLA-DR+ together with weak, surface immunoglobulin with monoclonal lambda light chain. Therapy included surgical removal of the palatine tonsils and later chemotherapy, both of which provided temporary relief of obstruction before recurrence of obstruction at the site of the lingual tonsils. Lasting relief from mass effect and obstruction only occurred following localised radiotherapy to Waldeyer's ring.

Airway Obstruction↗
PubMed1995

The myelodysplastic syndromes: an analysis of prognostic factors in 226 cases from a single institution.

Two hundred and twenty-six patients were diagnosed with myelodysplastic syndrome (MDS), according to the French-American-British (FAB) criteria, over a 13-year period, and studied retrospectively in a single institution in order to study indicators which were prognostically significant. Analysis of clinical and laboratory data indicated that the FAB classification, the Bournemouth, Dusseldorf, Goasguen, Sanz and FAB Scoring Systems were all good predictors of survival. We found advancing age, haemoglobin (Hb) < or = 9 g/dl, platelet count < or = 50 x 10(9)/l, increased peripheral total white cell count (WCC) and monocytosis, increased bone marrow blasts, dysgranulopoiesis, and bone marrow fibrosis were significant adverse prognostic variables. The commonest complication and cause of death was infection; however, infective episodes were not significantly associated with low neutrophil counts (either < or = 1.5 x 10(9)/l or < or = 0.8 x 10(9)/l) and there was also no significant association between neutropenia and survival. These findings indicate that neutrophil dysfunction plays an important role in the clinical progression of patients with MDS. The effect of new therapeutic modalities, such as the haemopoietic growth factors, on reducing infective episodes may be as significant as their effect on increasing neutrophil counts.

Adult↗
PubMed1994

Gastric vascular ectasia in patients undergoing bone marrow transplantation.

The authors reviewed all gastric biopsy specimens from patients who had undergone bone marrow transplantation at our institution between 1986 and 1991. Ten of 28 patients had gastric vascular ectasia (GVE), a distinct lesion consisting of telangiectatic vessels within the superficial gastric mucosa. All patients undergoing bone marrow transplantation had received a standard chemotherapeutic transplantation regimen consisting of busulfan and cyclophosphamide without total-body irradiation. Eight of the 10 patients with GVE had evidence of upper gastrointestinal tract bleeding, as compared with 4 of 18 patients without GVE. In all 10 patients with GVE, the results of liver chemistry analyses were abnormal. Five patients had hepatic veno-occlusive disease, and 8 patients had graft-versus-host disease. Endoscopic biopsy samples of GVE showed markedly dilated vascular spaces similar to those seen in gastric antral vascular ectasia and diffuse antral vascular ectasia. However, no thrombi were identified in these enlarged vessels. Digital morphometry showed the mean cross-sectional area of GVE vessels was significantly greater (P < .001, Wilcoxon's rank-sum test) than the mean vessel areas of 10 chemical gastritis and 10 normal antral (control) biopsy samples. Gastric vascular ectasia may be a significant cause of gastrointestinal bleeding in patients undergoing bone marrow transplantation. The pathogenesis of GVE is unknown; transplantation regimen toxicity may play a role.

Adolescent↗
PubMed1994

A table-mounted stereotactic system for digital angiography: a means of standardizing arteriovenous malformation measurement.

A detachable noninvasive table-mounted stereotactic device is described for use with digital radiography. The device is designed for standard two-view orthogonal projections but may be adjusted to allow for projections angled from the axial plane. When applied to the imaging of arteriovenous malformations (AVMs), it negates the influence of a variety of geometric and mechanical factors which would otherwise interfere with the determination of size. An accurate appreciation of AVM size, in turn, would allow a more reliable means of categorization of AVMs into distinctive groups for classification purposes and prognostication.

Algorithms↗
PubMed1994

Biological characterization of stem cell present in mobilized peripheral blood of CML patients.

Peripheral blood stem cell grafts are now frequently used for autologous transplantation of patients with malignancies. In this report we address the question of whether true long-term repopulating pluripotent hematopoietic stem cells (PHSC) are mobilized into peripheral blood and whether stem cells isolated from CML patients are depleted of Philadelphia chromosome positive cells. The presence of stem cells in mobilized peripheral blood (MPB) was examined by staining the CD34+Lineage- (Lin-) population for the expression of the Thy-1 antigen. The extent and kinetics of mobilization of CD34+Thy-1+ Lin- cells into peripheral blood were studied. In our analysis the percentage of these cells was found to vary widely depending on the day of leukapheresis and the individual patient. Fluorescence activated cell sorting (FACS) was used to isolate Thy-1 subsets from MPB which were analyzed for activity in in vitro long term cultures and in two in vivo models in which SCID-hu mice were implanted with human fetal bone or thymus grafts. The long term culture assay shows that the cells which express Thy-1 are enriched for cobblestone area forming activity (CAFC), an assay which can be used as a measure of detecting PBSC's in vitro. This CD34+Thy-1+ Lin- cell population was capable of producing both B and myeloid cells, and maintaining CD34+Lin- cells in these long term cultures. Moreover, the CD34+Thy-1+Lin- cell subset possessed a higher ability to engraft and to produce multilineage hematopoietic lineages in the SCID-hu bone assay and T cells in the SCID-hu thymus assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1994

HLA-B44-directed cytotoxic T cells associated with acute graft-versus-host disease following unrelated bone marrow transplantation.

We describe the recipient of a marrow graft from an HLA-serologically identical unrelated donor from whom highly potent host-reactive CTL of donor origin were isolated in association with acute GVHD. Extensive sequence and biochemical analysis of the HLA complex of this donor and recipient revealed several disparities in class I and class II HLA with the potential to be recognized by T cells from the donor or the host. The donor-derived CTL exclusively recognized a class I HLA difference associated with HLA-B44. Nucleotide sequencing of donor and recipient cells revealed that the patient possessed the HLA-B*4402 allele recognized by IEF as B44.2 while the donor possessed HLA-B*4403 (IEF variant B44.1). These alleles differ at one amino acid residue located at position 156 in the alpha 2 domain. The donor-derived CTL were shown to be specific for B44.2 by blocking studies and by the lysis of five different B44.2+ unrelated cell lines, two of which were confirmed by sequencing to be homozygous for B*4402. A host-specific difference involving a HLA-DRB1 allele was not recognized by the CTL, neither did HLA differences unique to the donor HLA-B*4403 and HLA-DQ8 elicit a host response. These data show that certain HLA disparities may be tolerated at the same time that other disparities elicit a potent immunologic response. The chemical nature of the difference, its structural impact, as well as the conditions of transplant appear to influence the type of response which occurs.

Acute Disease↗
PubMed1993

Rapid diagnosis of cytomegalovirus pneumonia in marrow transplant recipients by bronchoalveolar lavage using the polymerase chain reaction, virus culture, and the direct immunostaining of alveolar cells.

The objective was to compare the use of the polymerase chain reaction (PCR), virus culture, and immunostaining of alveolar cells used alone and in combination as diagnostic methods for the rapid diagnosis of cytomegalovirus (CMV) pneumonia in marrow transplant recipients. Seventy-five marrow transplant recipients with clinical and radiological evidence of pneumonitis were used as subjects. Bronchoalveolar lavage was performed on all patients to obtain material for conventional and/or rapid CMV culture, immunostaining of alveolar cells with monoclonal antibodies (MoAbs), and amplification of CMV-DNA by PCR. Assay results were then prospectively correlated with clinical outcome. Seven of the 75 patients (9.3%) had CMV pneumonitis and 6 patients (8%) had CMV infection without pneumonia. PCR is the most sensitive assay for the detection of CMV in bronchoalveolar lavage fluid. For the diagnosis of CMV pneumonitis, the sensitivity of alveolar cell immunostaining and PCR were both 100%. The sensitivity of virus culture was 85.7%. The positive predictive value for each test, used alone, for the identification of CMV pneumonitis was low. However, when the result of the PCR assay was assessed in combination with CMV immunostaining of alveolar cells, the sensitivity, specificity, positive, and negative predictive value of this strategy was 100%. The concomitant use of PCR and the rapid immunostaining of alveolar cells for CMV has facilitated the development of a sensitive and specific diagnostic algorithm for the detection and early treatment of CMV pneumonitis in transplant recipients.

Animals↗
PubMed1993

Effect of GVHD on the recovery of NK cell activity and LAK precursors following BMT.

The mechanism by which GVHD augments the graft-versus-leukemia (GVL) effect of marrow transplants has not been ascertained. One possibility involves the secondary activation of natural killer (NK) cells by cytokines released during the GVHD process. To evaluate this possibility we have compared NK activity and lymphokine-activated killer cell precursor (LAKp) frequencies in serially sampled PBMC from recipients of unmanipulated autologous or allogeneic marrow with and without active GVHD. NK activity recovered rapidly after BMT and was elevated during episodes of acute GVHD. However, NK activity did not differ between recipients of autologous or allogeneic marrow without GVHD nor was NK activity increased in association with chronic GVHD. Endogenously-activated NK cells were detected only in recipients of allogeneic marrow but this did not correlate with GVHD status. In contrast to NK activity, LAKp frequencies fell below the control range during the first 8 weeks after BMT. By 9-14 weeks the median LAKp frequency was normal and did not differ between the three groups then or later after transplant. We conclude that acute GVHD may serve to increase the lytic activity of NK cells but does not result in increased LAKp. LAKp frequencies are below normal during the first two months after BMT, a finding not previously recognized from bulk culture LAK studies. The role of LAK effectors in GVL may involve more the degree of cellular activation rather than the number of cells activated.

Acute Disease↗
PubMed1992

T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission.

We prospectively evaluated the efficacy of T-cell-depleted bone marrow transplantation (BMT) in adults with de novo acute nonlymphocytic leukemia (ANLL) in first complete remission (CR), with regard to relapse-free survival and incidence of graft-versus-host disease (GvHD). Thirty-one patients older than 16 years (range, 16.5 to 43.2) received T-cell-depleted grafts for this purpose from related HLA/MLC-compatible donors. Twelve of the patients were older than 30 years at the time of transplantation. Patients were prepared with hyperfractionated total body irradiation (HFTBI; 1,375 to 1,500 cGy) and high-dose cyclophosphamide (120 mg/kg). T cells were removed from the marrow grafts by a two-step soybean lectin agglutination and sheep red blood cell (sRBC)-rosette procedure, achieving a 2.5- to 3-log depletion of clonable T lymphocytes. No additional prophylaxis against GvHD was administered. The median age at transplantation was 28.8 years; the median interval from diagnosis to transplantation was 3.8 months, and from CR was 2.7 months. Seventy-four percent received consolidation after remission induction therapy. The product-limit estimate of disease-free survival (DFS) at 3 years is 45% (95% confidence interval [CI], 24% to 66%), and the cause-specific probability of relapse is 13%. The median follow-up of the survivors is 72 months (range, 34.5 to 95.6). Median time to achieve a sustained absolute neutrophil count of 500 or greater was 16 days, and to maintain an untransfused platelet count of 20,000 or greater was 20 days. Five patients suffered immune-mediated graft rejection. Three patients developed grade I to II acute GvHD limited to the skin, which resolved promptly with brief courses of systemic steroids. None of the patients has developed clinically apparent chronic GvHD or a secondary lymphoproliferative disorder, and no patient is receiving immunosuppressive therapy. T-cell-depleted BMT by the method reported here is a favorable option as postremission therapy for adults with de novo ANLL in first remission who have an HLA/MLC-compatible related donor, and it is not associated with an increased risk of relapse posttransplant.

Adolescent↗
PubMed1992

Radiation-free preparation for allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia.

PURPOSE: The study was undertaken to investigate the effectiveness of allogeneic bone marrow transplantation from HLA-identical siblings after preparation with busulfan and cyclophosphamide in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Thirty-nine patients aged 15 to 42 years underwent transplantation at three different centers from November 1984 through November 1990. All patients received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide as preparative therapy. Cyclosporine plus methotrexate or cyclosporine plus corticosteroids with or without methotrexate were given for prevention of graft-versus-host disease (GVHD). RESULTS: Twelve patients died of treatment-related complications, 12 patients relapsed, and 15 patients are leukemia-free survivors. For 27 patients in group 1 (first remission, second remission, first relapse), the estimated leukemia-free survival (LFS) rate is 42.3% (95% confidence interval [CI], 22.9% to 71.7%) at 3 years. For 12 patients with more advanced disease (group 2), the 1-year LFS rate is 13.5% (95% CI, 0% to 37.1%). Chronic GVHD occurred at an estimated incidence of 63.3% and developed significantly more frequently among patients who received corticosteroids for prevention of acute GVHD. Chronic GVHD was associated with a significantly lower incidence of relapse and with improved LFS rates. CONCLUSION: LFS rate in this study is comparable to that obtained with radiation-containing regimens; however, the effectiveness of this preparative regimen in ALL requires further study.

Actuarial Analysis↗