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Biomedical subjects

C McDonald

Publications and source records attributed to C McDonald.

At least 37 records · Page 2Linked to original sources

T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement.

Nine patients with tumour stage mycosis fungoides (MF) have been entered into a pilot study of T-cell depletion and autologous stem cell transplantation (SCT). Eight patients had detectable rearrangements of the T-cell receptor (TCR) gamma-gene demonstrated by polymerase chain reaction (PCR)/single-stranded conformation polymorphism (SSCP) in the peripheral blood. The median age was 47 years and the median duration of disease before SCT was 61 months; Peripheral blood progenitor cells were mobilized using high-dose etoposide (1.6 g/m2) and granulocyte colony-stimulating factor (G-CSF). The apheresis products underwent rigorous T-cell depletion with immunomagnetic methods. Double CD34-positive and CD4/CD8-negative selection achieved a median reduction of 3.89 log of T cells. All nine patients have been transplanted. Conditioning included carmustine (BCNU), etoposide and melphalan (BEM) in seven patients and total body irradiation plus etoposide or melphalan in two. Eight patients engrafted promptly and one patient died of septicaemia. All survivors entered complete remission. Seven patients have relapsed at a median of 7 months (2-14) post SCT. However, most patients have relapsed into a less aggressive stage, which has responded to conventional therapy. Four out of seven evaluable patients had detectable TCR rearrangements in the T-cell depleted graft. A T-cell clone was also detected in the peripheral blood before relapse in four cases. Autologous SCT is feasible, safe and can result in complete remission in a significant proportion of patients with tumour stage mycosis fungoides. Despite a short relapse-free survival, most patients achieved good disease control at the time of relapse.

Adult↗

Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation.

PURPOSE: To evaluate the efficacy of inhaled fluticasone propionate (Flovent) as prophylaxis against delayed pulmonary toxicity syndrome (DPTS) and decline in pulmonary function in breast cancer patients undergoing high-dose chemotherapy with the conditioning regimen of cyclophosphamide, cisplatin, and carmustine (CPB) followed by autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Sixty-three consecutive patients with multinode-positive or metastatic breast cancer undergoing high-dose chemotherapy with CPB and ASCT who were treated at the Duke University Adult Bone Marrow Transplant Program. All patients were started on inhaled fluticasone propionate, 880 microg every 12 hours, for 12 weeks from the start date of their CPB conditioning regimen. Pulmonary function tests (PFTs) with a single-breath diffusing capacity of carbon monoxide (DLCO) were performed pre-ASCT as well as approximately 6 and 12 weeks post-ASCT. DPTS was defined as follows: (1) development of a nonproductive cough and dyspnea with or without fever, plus a fall in DLCO to less than 60% predicted; or (2) decline in DLCO to less than 50% predicted with or without symptoms. RESULTS: Pulmonary function tests were done on all patients pre-ASCT, on 56 of the 63 patients at a median of 44 days (range, 25 to 73 days) post-ASCT, and on 51 of the 63 patients at a median of 96 days (range, 50 to 190 days) post-ASCT. The PFTs showed an average of an 8% (+/-26%) and 21% (+/-22%) decline in DLCO. These declines compare favorably with our historical control group of 45 consecutive breast cancer patients undergoing ASCT with CPB as a conditioning regimen, who experienced average declines in DLCO of 29% (+/-18%) (P < .001) and 33% (+/-18%) (P < .001) at comparable time periods post-ASCT. Delayed pulmonary toxicity syndrome occurred in 35% of treated patients compared to 73% of the historical controls (P = .0003). No patients died of DPTS or pulmonary problems, and there were no fungal pneumonias. CONCLUSION: Inhaled fluticasone propionate may decrease the incidence of DPTS in patients treated with CPB as a conditioning regimen for ASCT, as well as help to preserve pulmonary function as measured by DLCO. These results are worthy of further study in a randomized clinical trial.

Administration, Inhalation↗

Ultrasonographic evaluation of diaphragmatic motion.

OBJECTIVE: To evaluate the technical feasibility and utility of ultrasonography in the study of diaphragmatic motion at our institution. METHODS: The study consisted of 2 parts. For part I, in 23 volunteers we performed 23 studies on 46 hemidiaphragms with excursions documented on M-mode ultrasonography For part II, in 22 patients we performed 52 studies in 102 hemidiaphragms. In 50 studies both hemidiaphragms were studied, and in another 2 studies only 1 hemidiaphragm was studied. Patients' ages ranged from birth to 66 years (mean, 23 years). There were 16 male and 6 female patients. Indications for the study were (1) suggestion of paralysis of the diaphragm (n = 22); (2) if the diaphragm was already known to be paralyzed, for evaluation of response to phrenic nerve or pacer stimulation (n = 9); and (3) follow-up of previous findings (n = 21). Patients were examined in the supine position in the longitudinal semicoronal plane from a subcostal or low intercostal approach. Motion was documented with real-time ultrasonography and measured with M-mode ultrasonography. RESULTS: Of the 102 clinical hemidiaphragms studied, findings included normal motion (n = 42), decreased motion (n = 22), no motion (n = 6), paradoxical motion (n = 10), positive pacer response (n = 13), negative pacer response (n = 2), positive phrenic stimulation (n = 6), and negative phrenic stimulation (n = 1). There were no failures of visualization. CONCLUSIONS: Ultrasonography proved feasible and useful in evaluating diaphragmatic motion. In our practice it has replaced fluoroscopy. Ultrasonography has advantages over traditional fluoroscopy, including portability, lack of ionizing radiation, visualization of structures of the thoracic bases and upper abdomen, and the ability to quantify diaphragmatic motion.

Adolescent↗

Correction of early subnormal superior hemiretinal DeltaPO(2) predicts therapeutic efficacy in experimental diabetic retinopathy.

PURPOSE: To test the hypothesis that regional retinal oxygenation responses to a hyperoxic inhalation challenge are associated with reported retinopathy outcomes after different therapies in rat models of diabetic retinopathy. METHODS: Six groups of rats were maintained for 3 months: controls (n = 8), untreated diabetic (n = 8), aminoguanidine (AMG)-treated diabetic (2.5 g/kg of diet; n = 6), untreated galactosemic (n = 7), AMG-treated galactosemic (n = 10), and WAY-509-treated (25 mg/kg body weight per day) galactosemic (n = 7). After 3 months, the change in oxygen tension was measured noninvasively from the superior to the inferior ora serrata, using a novel functional magnetic resonance imaging (fMRI) technique and a carbogen (a gas mixture of 5% carbon dioxide and 95% oxygen that has been used clinically, instead of 100% oxygen, to minimize the vasoconstrictive effects of pure O(2) on retinal blood flow and oxygenation) inhalation challenge. Retinal morphometric measurements were also obtained. RESULTS: Retinal lesions (acellular capillaries and pericyte ghosts) were not significantly (P > 0.05) present at 3 months in any experimental groups compared with the control group. Superior but not inferior hemiretinal change in partial pressure of oxygen (DeltaPO(2)) became significantly subnormal (P < 0.05) at 3 months of diabetes or galactosemia. Aminoguanidine, which has been found to inhibit the development of retinopathy in diabetic but not galactosemic rats, inhibited the development of a subnormal DeltaPO(2) in diabetes but not in galactosemia. WAY-509, which has been reported to inhibit retinopathy in galactosemic rats, inhibited the DeltaPO(2) defect in galactosemic rats. CONCLUSIONS: An early subnormal superior hemiretinal DeltaPO(2) after treatment appears to be a good predictor of the risk of development of retinopathy, as well as for assessing therapeutic efficacy in experimental diabetic retinopathy.

Aldehyde Reductase↗

The intersection of relational and cultural narratives: women's abortion experiences.

Although a great deal has been written on women's personal deliberations in deciding to have and seeking an abortion, little has been written on the experience of living with this decision or on the meanings an abortion generates in the context of a particular life. In this hermeneutic phenomenological study, 14 women aged 19-44 expressed a need for professionals and others to accept the reality of unplanned pregnancy and to acknowledge that the choice of abortion cannot be fully understood in isolation from women's other reproductive choices. Using a feminist analysis of the tensions and contradictions in the women's accounts, the authors explore the intersections between their experiences and the cultural narratives in which they are situated, in a search for new possibilities for women and new understandings of women's experience of abortion.

Abortion, Legal↗

Nuclear export signal located within theDNA-binding domain of the STAT1transcription factor.

Latent signal transducers and activators of transcription (STATs) reside in the cytoplasm but rapidly accumulate in the nucleus following cytokine stimulation. Nuclear accumulation requires specific tyrosine phosphorylation and STAT dimerization. The presence of STATs in the nucleus is transient, however, and within hours the STATs reappear in the cytoplasm. Results indicate that STAT1 can be dephosphorylated in the nucleus and actively exported by the chromosome region maintenance 1 (CRM1) export receptor. CRM1 recognizes a specific amino acid sequence located within the DNA-binding domain of STAT1. This region shares sequence and functional properties of characterized nuclear export signals. The location of this sequence within STAT1 suggests that it is not accessible to CRM1 when STAT1 is bound to DNA. Evidence is presented to support a model in which STAT1 is tyrosine dephosphorylated in the nucleus and dissociates from DNA, allowing recognition by CRM1 and nuclear export. The regulated export of STAT1 may contribute to silencing of the signal pathway and/or to re-establish STAT1 in the cytoplasm to monitor activity of receptor-kinase signals.

Amino Acid Sequence↗

The Variability of Seyfert 1.8 and 1.9 Galaxies at 1.6 Microns.

We present a study of Seyfert 1.5-2.0 galaxies observed at two epochs with the Hubble Space Telescope (HST) at 1.6 µm. We find that unresolved nuclear emission from nine of 14 nuclei varies at the level of 10%-40% on timescales of 0.7-14 months, depending upon the galaxy. A control sample of Seyfert galaxies lacking unresolved sources and galaxies lacking Seyfert nuclei show less than 3% instrumental variation in equivalent aperture measurements. This proves that the unresolved sources are nonstellar and associated with the central parsecs of active galactic nuclei. Unresolved sources in Seyfert 1.8 and 1.9 galaxies are not usually detected in HST optical surveys; however, high angular resolution infrared observations will provide a way to measure time delays in these galaxies.

Journal Article↗

Early and late environmental risk factors for schizophrenia.

Although a high proportion of liability to schizophrenia is under genetic control, a number of environmental risk factors have been identified. The earliest of these are complications of pregnancy and birth, though whether these cause or reflect disturbed brain development is not absolutely clear. Neurodevelopmental deviance is also indicated by neurological dysfunction, social, behavioural and cognitive deficits during childhood. Immigrant status is a significant risk factor, especially prominent among the African Caribbean population in England, though the mechanism is unknown. Later environmental risk factors include adverse life events and substance abuse. An additive model of multiple genetic and environmental risk factors of small effect may be too simplistic and an interactive model where genetic predisposition is compounded by environmental effects is more in keeping with current evidence. The nature of such interactions can be explored more fully when susceptibility genes for schizophrenia are identified.

Brain↗

Minimal-model estimates of insulin sensitivity are insensitive to errors in glucose effectiveness.

The minimal-model method allows for estimation of insulin sensitivity (S(I) = P(3)/P(2)) and glucose effectiveness (S(G) = P(1)) from the time course of glucose and insulin after a glucose bolus. We previously demonstrated that the minimal-model results in overestimates of S(G) in subjects with normal insulin secretory function. To determine whether overestimation of S(G) has an impact on estimation of S(I), we examined model estimation of S(I) when S(G) was constrained to levels below that found by the regular minimal-model fit. Fifty-six glucose tolerance tests from lean and obese women, with and without polycystic ovary syndrome, were used. S(I) ranged from 0.2-22.6 x 10(-4) min(-1)/(microU/mL), and S(G) ranged from 0.8-3.8 x 10(-2) min(-1) for the standard minimal-model fits. Constraining S(G) to as low as 40% of the unconstrained value resulted in a 4-fold increase in P2 and P3, but only a 3% reduction in S(I). We conclude that estimation of the insulin sensitivity index is independent of errors in minimal-model-derived estimates of glucose effectiveness.

Adult↗

Winter mortality in relation to climate.

We report further details of the Eurowinter survey of cold related mortalities and protective measures against cold in seven regions of Europe, and review these with other evidence on the relationship of winter mortality to climate. Data for the oldest subject group studied, aged 65-74, showed that in this vulnerable group, high levels of protection against indoor and outdoor cold at given outdoor temperatures were found mainly in countries with cold winters, and were associated with low levels of excess mortality at a given level of outdoor cold. Regions such as London that had poor protection against cold and/or high baseline mortalities had higher levels of winter excess mortality than expected for the coldness of their winters.

Aged↗

Risk of breast cancer in women with palpable breast cysts: a prospective study. Edinburgh Breast Group.

BACKGROUND: 7% of women in the western world develop palpable breast cysts. Studies of the relation between cysts and breast cancer have conflicting results. There are two clearly defined types of cyst. We investigated whether one cyst type is associated with a higher rate of breast-cancer development than the other. METHODS: We studied 1374 women with palpable breast cysts presenting between 1981 and 1987, who had cysts aspirated between 1981 and 1989. Cysts were classified as type I if the sodium/potassium (Na+/K+) ratio in the cyst fluid was less than 3, or type II if the Na+/K+ ratio was 3 or more. Data on incidence of breast cancer were available until January, 1995, and we compared them with the expected numbers of cancers calculated from age-specific breast-cancer incidence in Scotland in 1988. FINDINGS: 65 cancers developed during follow-up. The overall standardised incidence rate of breast cancer in patients with palpable cysts was 2.81 (95% CI 2.17-3.59). The relative incidence rate was increased for all cyst types. The standardised incidence rate of developing breast cancer among women younger than 45 years was highest at 5.94 (2.97-10.63), with a significant trend for decreasing relative incidence rate with age (p<0.05). Women older than 54 years had a standardised incidence rate of 1.73 (0.86-3.10). The standardised incidence rate of breast cancer was highest in the first year after aspiration (7.02 [3.73-12.00]) but the risk was still raised after 5 years (2.68 [1.84-3.76]). INTERPRETATION: Women with breast cysts are at an increased risk of breast cancer, especially at younger ages. The type of cyst did not alter the associated relative incidence rate of breast-cancer development.

Adult↗

CD34+-selected peripheral blood progenitor cell transplantation in patients with multiple myeloma: tumour cell contamination and outcome.

Thirty-six patients with multiple myeloma (23 PR1, nine PR2, four stable disease) were entered into a pilot study evaluating the use of CD34+-selected peripheral blood progenitor cell transplantation (PBPCT) following high-dose melphalan alone or high-dose melphalan and total body irradiation. Peripheral blood progenitor cells (PBPCs) were mobilized with cyclophosphamide and granulocyte colony stimulating factor (G-CSF). CD34+ selection using the Cellpro Ceprate-SC system was performed in 22 cases with an adequate yield in 20. 10 patients failed to mobilize sufficient cells to permit selection and in four cases selection was not performed for other reasons. 16 patients therefore received unselected PBPC. Tumour cell contamination was evaluated by IgH gene fingerprinting (fpPCR). Harvested PBPC were fpPCR positive in 13/20 CD34+-selected cases and remained positive after selection in seven. Harvested PBPC were studied in 9/16 patients receiving unselected cells; fpPCR was positive in five and negative in four. There was no difference in event-free survival (EFS) between the CD34+-selected group and the unselected group (median 21 and 26 months, respectively, P=ns). The CD34+-selection process therefore reduced contamination but did not eliminate it completely, and in this small non-randomized study there was no apparent clinical benefit of CD34+ selection.

Adult↗

Lexical priming on Neely's (1977) paradigm in Parkinson's disease: where do we stand?

In two published studies, we used a variant of Neely's (1977) lexical decision paradigm to study shifts of attention and automatic lexical activation in nondemented individuals with Parkinson's disease (McDonald, Brown, & Gorell, 1996; Spicer, Brown, & Gorell, 1994). Arnott and Chenery (in press) noticed differences between Neely's results and the results we observed in our control group that raise questions about some of the conclusions presented in the McDonald et al. (1996) and Spicer et al. (1994) papers. Even when considering the important differences between Neely's (1977) results and those in our control groups, we argue that our results support the conclusions of normal automatic semantic activation and deficient set-shifting in Parkinson's disease. We also introduce the notion of generalized priming to account for some of the priming effects observed in our studies.

Adult↗

Cooperation of the transcriptional coactivators CBP and p300 with Stat6.

Interleukin-4 (IL-4) functions as a critical regulatory cytokine of the immune response. A major effect of IL-4 is the induction of specific gene expression mediated by activation of a latent transcription factor, Stat6. To understand the mechanism by which Stat6 induces gene transcription, the effects of two histone acetylase coactivators, CREB binding protein (CBP) and p300, were evaluated. Both CBP and p300 were found to cooperate with Stat6 for induction of Stat6-dependent transcription. This cooperation does not appear to be due to acetylation of Stat6. The adenoviral E1A oncoprotein, known to bind CBP and p300, can inhibit the ability of CBP and p300 to function as coactivators of Stat6. The cooperative effect of CBP and p300 depends on the presence of a carboxyl-terminal region of Stat6. Stat6 molecules lacking this region behave as negative interfering molecules for Stat6-dependent transcription. Point mutations within this region also affect transcription by Stat6 in response to IL-4, identifying a motif that appears to be required for transcription, possibly through functional cooperation with CBP/p300.

Acetylation↗