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Biomedical subjects

A Gee

Publications and source records attributed to A Gee.

At least 37 records · Page 2Linked to original sources
PubMed1998

Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies.

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. PATIENTS AND METHODS: Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. RESULTS: Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). CONCLUSION: These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.

Aged↗
PubMed1997

Altered ligand binding properties and enhanced stability of a constitutively active estrogen receptor: evidence that an open pocket conformation is required for ligand interaction.

To elucidate the ligand binding properties of the estrogen receptor (ER) and how ligand access to and release from the ligand binding pocket is affected by the conformational state of the receptor, we have measured the rates of estradiol association and dissociation, the equilibrium binding, and the stability of estradiol binding to denaturants, comparing wild-type human ER and a point mutant (Y537S ER) that shows full constitutive activity, i.e., the same full transcriptional activity in the absence or presence of estrogen. Ligand binding kinetics and affinity were measured with the full-length (1-595) ERs and with truncated forms of both receptors containing domains C through F (including the DNA binding, hinge, and ligand binding domains, amino acids 175-595) or domains E and F (the ligand binding domain; amino acids 304-595). With all ERs, the rates of ligand association and dissociation were considerably slower with the Y537S mutant ER than with wild-type ER (6-fold and 3-4-fold, respectively). These marked differences in ligand on and off rates for the wild-type and Y537S receptors result in a predicted (k-1/k+1) and measured Kd that is 2-fold lower for Y537S ER compared to wild-type ER. The binding of estradiol by wild-type ER was disrupted by high concentrations of urea (above 2 M), whereas the Y537S ER was distinctly more resistant to this disruption. These results are consistent with a model in which wild-type ER in the absence of ligand adopts a transcriptionally inactive collapsed pocket conformation, stabilized by specific interactions of Y537 with nearby regions of ER. When estradiol is bound, the wild-type ER adopts a transcriptionally active, closed pocket (ligand occupied) conformation. By contrast, the Y537S mutant ER favors the transcriptionally active closed pocket conformation, whether occupied by ligand or not, the latter state (closed pocket but unoccupied) accounting for its constitutive activity. Our findings suggest that the entry or exit of ligand from the binding pocket requires that ER adopt an open pocket conformation. The reduced rates of ligand association and dissociation in the constitutively active form of the ER, as well as its greater resistance to disruption of ligand binding by urea, support the supposition that the rate at which this open pocket conformation can be accessed from the unoccupied or ligand-occupied Y537S ER is slower than from the unoccupied or occupied forms of wild-type ER. Thus, the binding and release of ligand by ER require that the receptor access an open pocket state, and the ease with which this state can be accessed is affected by mutations that alter receptor conformation.

Binding Sites↗
PubMed1997

In vivo estimation of cerebral blood flow, oxygen consumption and glucose metabolism in the pig by [15O]water injection, [15O]oxygen inhalation and dual injections of [18F]fluorodeoxyglucose.

There is a need for suitable non-primate laboratory animals for studies of brain function by positron emission tomography (PET). To provide a comparative index of the circulatory physiology of the pig, we have applied novel PET tracer methodology to seven anaesthetized pigs, and measured cerebral regional oxygen consumption (CMR[O2]), cerebral blood flow (CBF), and cerebral glucose metabolism (CMR[glc]). Blood flow and flow-metabolism couple were estimated for selected cerebral regions of interest. We found an average hemispheric CMR(O2) of 171 +/- 18 micromol/100 cm3/min. Individual hemispheric CBF measurements varied between 33 and 41 ml/100 cm3/min, with an average of 37 +/- 3 ml/100 cm3/min at an average PaCO2 of 4.3 +/- 0.9 kPa. The blood flow dependency on arterial PCO2 was calculated from the results of the carbon dioxide response in two pigs in which the CBF measurements obeyed the equation CBF (ml/100 cm3/min) = 8.9 PaCO2 (kPa). In each pig, CMR(glc) was studied twice with a double-injection FDG method. In the first session, the values of CMR(glc) averaged 27 +/- 3 and 23 +/- 4 micromol/100 cm3/min, estimated by multilinear and linear regression analysis, respectively. In the second session, the corresponding averages were 27 +/- 3 and 24 +/- 3 micromol/100 cm3/min, respectively. The average oxygen extraction fraction was 0.46 +/- 0.09 and the oxygen-glucose ratio was 6.1 +/- 0.8. The findings indicate that the pig is suitable for PET studies of cerebral blood flow, cerebral oxygen consumption and glucose metabolism.

Administration, Inhalation↗
PubMed1997

Regional distribution of 11C-labeled lidocaine, bupivacaine, and ropivacaine in the heart, lungs, and skeletal muscle of pigs studied with positron emission tomography.

The regional myocardial uptake and kinetics of 11C-lidocaine, 11C-bupivacaine, and 11C-ropivacaine were examined in the pig, utilizing positron emission tomography to determine whether disproportionate distribution exists among these agents. The three drugs were rapidly distributed to the myocardium and lung with mean peak radioactivities occurring between 0.35 and 0.48 min post-injection in myocardium and 0.35 and 0.65 min in lung. Radioactivities peaked later in skeletal muscle than in the myocardium and lung, occurring between 1.1 and 2.7 min post-end injection. Blood radioactivities for bupivacaine and ropivacaine were significantly higher than those of lidocaine, whereas myocardial, lung, and muscle uptakes for the three agents were not significantly different. Myocardium-blood partition coefficients were similar for bupivacaine and ropivacaine (0.55 and 0.49 respectively), while it was three times higher for lidocaine (1.4). A similar relationship existed for skeletal muscle- and lung-blood partition coefficients. Bupivacaine and ropivacaine t1/2z in skeletal muscle were significantly longer than those of lidocaine. The results of this study indicate that the increased cardiotoxicity associated with bupivacaine does not appear to be related to disproportionate distribution in the myocardium when compared to lidocaine and ropivacaine.

Amides↗
PubMed1997

Cortical sites of sustained and divided attention in normal elderly humans.

Human brain mechanisms subserving attention have been assigned to prefrontal, midfrontal, and posterior parietal cortices, as well as to the anterior cingulate and the thalamus. To map these mechanisms in the brain, most studies have used selective attention tasks; few studies have mapped the brain under sustained or divided attention. The present study was designed to create maps of regional activity associated with sustained and divided attention using two different sensory modalities: visual checkerboard stimulation and vibrotactile stimulation of the right hand. Five cerebral PE-tomograms of 15O-labeled water uptake were acquired from 16 elderly healthy subjects during sustained or divided attention to the frequency of stimulation. To locate active brain regions, the t-statistic map of relative changes in cerebral blood flow was coregistered to the subjects' averaged brain MR images and to the standard Talairach brain coordinate system. Attention was associated with activity in two sites, the right middle frontal gyrus (Brodmann area 46) and the right inferior parietal lobule (Brodmann area 40). The frontal site was more active when the subjects attended to the visual stimulus and when the attention was divided, while the parietal site was more active during attention to the vibrotactile stimulus and during simple sustained attention. Our observations are consistent with the hypotheses (1) that the right posterior parietal attention center subserves attention to several sensory modalities and (2) that a cortical network of specific neuronal sites subserves both sustained and divided attention. These hypotheses must be tested in further studies.

Aged↗
PubMed1997

Three-dimensional spatial compounding of ultrasound images.

One of the most promising applications of 3-D ultrasound lies in the visualization and volume estimation of internal 3-D structures. Unfortunately, the quality of the ultrasound data can be severely degraded by artefacts and speckle, making automatic analysis of the 3-D data sets very difficult. In this paper we investigate the use of 3-D spatial compounding to reduce speckle. We develop a new statistical theory to predict the improvement in signal-to-noise ratio with increased levels of compounding, and verify the predictions empirically. We also investigate how registration errors can affect automatic volume estimation of structures within the compounded 3-D data set. Having established the need to correct these errors, we present a novel reconstruction algorithm which uses landmarks to register each B-scan accurately as it is inserted into the voxel array. In a series of in vitro and in vivo trials, we demonstrate that 3-D spatial compounding is very effective for improving the signal-to-noise ratio, but correction of registration errors is essential.

Algorithms↗
PubMed1997

An audit of the treatment of carcinoma of the uterine cervix using external beam radiotherapy and a single line source brachytherapy technique.

A single line source brachytherapy (BT) technique has been developed at Clatterbridge to boost the dose to the primary tumour after whole pelvis external beam radiotherapy (EBRT) for the radical treatment of carcinoma of the cervix. 226 patients with invasive carcinoma of the uterine cervix were treated with radiotherapy alone using this technique (median age 57 years; range 25-87 years). 49 patients had Stage IB disease, 97 had Stage II, 73 had Stage III and seven patients had biopsy confirmed Stage IVA disease. Patients with low bulk disease were given 40-42.5 Gy in 20 fractions while those with bulky disease received 45 Gy in 20 fractions or 50 Gy in 25 fractions. On completion of EBRT, 186 patients (82.3%) proceeded to intracavitary BT using a linear arrangement of sources with the Selectron (Nucletron) remote afterloading unit. Most of the patients (137/226, 60.6%) received a single insertion of 20 Gy to point "A", at a preferred dose rate within the range 0.95-1.05 Gy h-1. In another 30 patients (13.3%), BT was possible at a later date after further tumour regression. Only 10 patients (4.4%) did not receive BT as part of their treatment. The 5 year actuarial cause-specific survival rate was 79% in Stage I disease, 61% in Stage II, 31% in Stage III and 71% in the small number of patients with Stage IVA disease. The 5 year pelvic control rates were 88% for Stage I, 69% for Stage II, 45% for Stage III and 71% for Stage IVA. Significant prognostic variables for survival and local pelvic control on univariate analysis included disease stage, patient age, tumour bulk, nodal status, anaemia, renal failure and overall treatment time. Tumour grade was a significant prognostic variable for survival but not for local tumour control. The extent of parametrial involvement was a significant prognostic variable for survival and local control for Stage IIB but not for Stage IIIB. There was a statistically significant decrease in survival and local tumour control for patients receiving > or = 70 Gy to point "A", or > or = 55 Gy to point "B". On multivariate analysis, the independent prognostic variables for survival and local control were disease stage, overall treatment time and renal failure. Patient age was also an independent prognostic variable for survival while nodal status was an independent prognostic variable for local control. A high proportion of the patients had adverse prognostic features resulting in a very high actuarial risk of distant metastases of 38.1% at 5 years (68.8% for Stage III patients). The overall treatment time was significantly longer in Stage III patients compared with Stage I and Stage II patients. The actuarial rate of Grade 2 late radiation morbidity was 2.7% and 4.3% for the urinary tract and bowel respectively while that of Grade 3 morbidity was only 0.6% and 1.4%, respectively. Good local control can be achieved for patients with nonbulky tumours using relatively low biological doses while minimizing the risk of late treatment related toxicity. Several changes in treatment policy have been made in an attempt to improve local tumour control and possibly survival, particularly for Stage III patients and patients with bulky disease.

Adult↗
PubMed1997

Attenuation of plasma low density lipoprotein cholesterol by select 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in mice devoid of low density lipoprotein receptors.

Low density lipoprotein (LDL) reduction independent of LDL receptor regulation was investigated using HMG-CoA reductase inhibitors in LDL receptor-deficient mice. In males, LDL cholesterol dose-dependently decreased with atorvastatin treatment after 1 week. As untreated mice grew older, their LDL cholesterol progressively rose above basal levels, but was quelled with atorvastatin treatment. In females, atorvastatin treatment time-dependently decreased LDL cholesterol levels and induced hepatic HMG-CoA reductase activity. Unlike males, cholesterol-lowering effects of the drug were sustained in females. Lovastatin, simvastatin, and pravastatin also reduced total and LDL cholesterol; however, additional studies in females demonstrated that atorvastatin caused the greatest dose-dependent and sustained effect after 2 weeks. In females, hepatic HMG-CoA reductase mRNA inversely correlated with LDL cholesterol lowering, with atorvastatin showing the greatest increase in mRNA levels (17.2-fold), followed by lovastatin (10.7-fold), simvastatin (4.1-fold), and pravastatin (2.5-fold). Atorvastatin effects on lipoprotein production were determined after acute (1 day) or chronic (2 week) treatment prior to intraperitoneal injection of Triton WR1339. Acute treatment reduced cholesterol (-29%) and apoB (-16%) secretion, with no change in triglyceride secretion. In contrast, chronic treatment elevated cholesterol (+20%), apoB (+31%), and triglyceride (+57%) secretion. Despite increased cholesterol and apoB secretion, plasma levels were reduced by 51% and 46%, respectively. Overall, under acute or chronic conditions, apoB paralleled cholesterol secretion rates, and triglyceride to cholesterol secretion ratios were elevated by 38% and 32%, respectively. We propose that atorvastatin limits cholesterol for lipoprotein assembly, which is compensated for by triglyceride enrichment. In addition, with either acute or chronic atorvastatin treatment, apoB-100 secretion was blocked, and compensated for by an increased secretion of apoB-48. The apoB-48 particles produced are cleared by LDL receptor-independent mechanisms, with an overall effect of reducing LDL production in these mice. These studies support the idea that HMG-CoA reductase inhibitors modulate lipoprotein levels independent of LDL receptors, and suggest they may have utility in hyperlipidemias caused by LDLreceptor disorders.

Animals↗
PubMed1996

Highly purified CD34-positive cells reconstitute hematopoiesis.

PURPOSE: The objective of this study was to characterize CD34+ cell grafts, obtained using a novel technique, from children undergoing autologous bone marrow transplantation (BMT) for cancer therapy. In particular, we wanted to determine if the CD34+ marrow cell grafts generated hematopoietic reconstitution, since a positive result would motivate further development and use of this methodology. PATIENTS AND METHODS: This pilot feasibility clinical trial involved 13 patients < or = 25 years of age with advanced solid tumors, including seven children with neuroblastoma. Harvested bone marrow underwent immunomagnetic CD34+ selection. RESULTS: In three of 13 enrolled patients, low purities of the CD34+ preparations disqualified the use of the CD34+ marrow grafts. Ten patients received myeloablative chemotherapy with etoposide, carboplatin, and cyclophosphamide, then were transplanted with CD34+ marrow grafts. In the 10 patients transplanted with CD34(+)-selected cells, the CD34+ cell purity (nucleated RBCs excluded) in the cell graft preparation was 91% total cell recovery from the starting light-density cells 2.2%, CD34+ cell recovery 38%, colony-forming unit-granulocyte-macrophage (CFU-GM) recovery 23%, and estimated tumor-cell depletion 2.6 logs (medians). The CD34+ marrow grafts administered to these patients contained a median of 2.3 x 10(6) nucleated cells, 1.4 x 10(6) CD34+ cells, and 1.3 x 10(4) CFU-GM per kilogram patient weight. Most patients experienced only the toxicities previously observed with this myeloblative chemotherapy regimen, although two unusual toxicities were observed. All 10 patients transplanted with CD34+ cell grafts engrafted. CONCLUSION: The CD34+ purified grafts were enriched in stem/progenitor cells, with five of these 10 preparations containing > or = 94% CD34+ cells. Engraftment with CD34(+)-purified cell grafts as pure as 99% confirms that autologous CD34+ cells, alone, are sufficient to provide hematopoietic rescue for myeloablated patients. The best purification results were obtained on small marrow harvests from patients with neuroblastoma. The engraftment of highly purified CD34+ cells obtained by this technology and the antitumor effect of the transplant, by which two of 10 poor prognosis patients remain clinically free of tumor, have stimulated further clinical trials.

Adolescent↗
PubMed1996

Survival of contaminating bacteria in over-the-counter artificial tears.

BACKGROUND: The use of OTC artificial tears is becoming increasingly widespread. Unintentional contamination of artificial tear products potentiates a risk of developing bacterial keratitis or exacerbating an existing eye infection. Presently, no published study has investigated recovery from bacterial contamination of artificial tear products. METHODS: Four different over-the-counter (OTC) artificial tear products were contaminated with two types of bacteria. Staphylococcus aureus and pseudomonas aeruginosa were analyzed for the survivability of the microorganisms at various times following contamination. RESULTS: In this cross-sectional study, it was found that all the preserved brands showed a significant recovery rate from contamination compared to the preservative-free brand. After 9 hours, the preservative-free brand did not completely regain sterility after contamination with either bacteria. CONCLUSIONS: This study indicates that preserved artificial tears recover from bacterial contamination at a significantly faster rate than preservative-free products. It is likely that the recovery from bacterial contamination is not solely attributed to the preservative, but that other variables may contribute.

Colony Count, Microbial↗
PubMed1995

Purging of peripheral blood stem cell grafts.

The shortage of HLA-matched sibling donors for bone marrow transplant patients has stimulated interest in the use of alternative donors. As a result, there has been a dramatic increase in the use of autologous marrow transplantation, which avoids the complications of graft-versus-host disease, but may deprive the patient of a potentially beneficial graft-versus-disease response and runs the risk of returning occult tumor cells with the graft. There is increasing evidence that these cells may be associated with disease relapse post-transplant, and many methods have been developed for their removal ex vivo. Combinations of negative and positive selection may achieve elimination of tumor cells to the limits of detection of the most sensitive assays currently available. The marked trend toward the use of autologous grafts derived from blood rather than marrow has raised the question as to whether peripheral blood stem cell (PBSC) preparations should be purged of tumor. Data indicate that these grafts generally contain a lower tumor burden, although the stem cell mobilization procedure may recruit tumor cells into the peripheral circulation. Enrichment of CD34+ cells from apheresis products appears, at present, to be less efficient than from marrow and provides at best about a 2-3 log depletion of tumor. This has prompted proposals to follow positive selection by a small-scale purging procedure. Technical issues, such as preprocessing and pooling of collections prior to purging, remain to be addressed. Ultimately, the development of successful purging procedures for PBSC grafts will simply reemphasize the necessity of improving the efficacy of high-dose therapy.

Bone Marrow Purging↗
PubMed1995

Stem cell isolation.

High-dose chemotherapy with autologous hematopoietic progenitor cell support is increasingly used to treat a variety of malignant diseases. A drawback of this technique is the potential for infusing clonogenic tumor cells with the autograft, producing relapse of the disease in the patient. The use of positive selection techniques to isolate stem cells and thus reduce or eliminate tumor cell contamination has been extensively studied over the past few years. Preliminary clinical results have demonstrated that these procedures deplete 2 to 7 logs of tumor cells and do not impair engraftment. It is too early to assess the ultimate clinical benefit of this strategy. Additional applications of CD34-selection include ex vivo expansion of and gene transfer into hematopoietic progenitor cells and T-cell depletion of allogeneic grafts to reduce the incidence of graft-versus-host disease.

Antigens, CD34↗
PubMed1995

Immunotherapy with donor leukocyte infusions for patients with relapsed acute myeloid leukemia following partially mismatched related donor bone marrow transplantation.

Donor leukocyte infusions (DLI) were used to treat 2 patients with AML who relapsed within 4 months of treatment with partially mismatched related donor (PMRD) BMT representing 1-2 HLA-mismatches. No other form of cytoreductive therapy was given to these patients. Both patients developed GVHD (grade II-III) following DLI requiring steroid therapy. One of these patients went into complete remission following development of GVHD and immunophenotypic analysis of peripheral blood showed increased numbers of CD3+/CD8+ T cells, CD56+/CD8+ lymphokine activated killer (LAK) cells and CD16+/CD56+ natural killer (NK) cells expressing intermediate affinity IL-2 receptor P75. Unfortunately, the response was of short duration and the patient relapsed 8 weeks later ultimately resulting in death. The second patient did not show any response to DLI and died of progressive leukemia in conjunction with active GVHD. We conclude that DLI from PMRD carries a high risk for the development of GVHD and may have an anti-leukemia effect for relapsed AML. The anti-leukemic effect from PMRD DLI may be mediated by cytotoxic T lymphocytes, LAK cells and NK cells.

Acute Disease↗
PubMed1995

Effects of CD34+ selection and T cell immunodepletion on cord blood hematopoietic progenitors: relevance to stem cell transplantation.

Cord blood (CB) has been used recently for stem cell transplantation. We have investigated two different approaches to deplete CB samples of T cells capable of mounting graft-vs.-host disease (GVHD). The methods used were selection of CD34+ cells using avidin-biotin columns (CellPro) and T cell immunodepletion with T10B9 monoclonal antibody (mAb) plus complement. Using the avidin-biotin columns, 10.3% of the original CD34+ cells were recovered. Although this technique yielded a population containing 60 +/- 5.5% CD34+ cells, about 1 log of CFU-GM progenitors were lost. In contrast, after the T10B9 mAb and complement immunodepletion, 75 +/- 19% and 62 +/- 7% of the CD34+ cells and CFU-GM were recovered, respectively. T cell depletion was 3.6 logs using the CellPro columns and 2.2 logs after immunodepletion. To investigate whether cell losses following T cell depletion could be overcome by ex vivo expansion, cells were cultured in the presence of recombinant human interleukin-3 (rhIL-3) and recombinant human c-kit ligand (stem cell factor [rhSCF]) for 7 days. There were 14- and six-fold expansions in the number of progenitors recovered after CellPro and immunodepletion, respectively. To asses the engraftment potential of expanded cells, we used a murine transplantation model in which the presence of human cells was identified by the anti-CD45 mAb. Cells expanded in vitro engrafted in irradiated BNXid mice as efficiently as nonexpanded cells, suggesting that expansion did not affect their transplantability. This study shows that both techniques resulted in significant T cell depletion of CB. Furthermore, in vitro expansion could overcome cell losses sustained during the separation techniques without impairing the engraftment potential of the expanded cells.

Animals↗