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R Brown

Publications and source records attributed to R Brown.

At least 55 records · Page 3Linked to original sources
PubMed2004

Supraventricular tachyarrhythmias after hematopoietic stem cell transplantation: incidence, risk factors and outcomes.

Recent studies suggest that cancer patients may be at increased risk for supraventricular tachyarrhythmias (SVTA). We have observed clinically significant SVTA in patients undergoing hematopoietic stem cell transplantation occurring at a median of 6 days post transplant, manifesting as atrial fibrillation/flutter or regular narrow-complex tachycardia and persisting for a median of 3 days (range, 0-8). All patients received aggressive medical therapy and/or electrical cardioversion to restore sinus rhythm and to re-establish hemodynamic stability. Non-Hodgkin's lymphoma (NHL) was the most common diagnosis (53%), and a case control analysis in those patients demonstrated that SVTA occurred in 12% of patients and was associated with older age and pre-existing cardiac conditions. In conclusion, patients undergoing HSCT are at moderate risk for developing SVTA, particularly older patients with a diagnosis of NHL. These arrhythmias are clinically significant, and are a marker for increased mortality and prolonged hospital stay. Additional studies are needed to identify high-risk patients who may benefit from prophylactic anti-arrhythmic therapy.

Adult↗
PubMed2004

Control of gene expression by CpG island methylation in normal cells.

The role of DNA methylation in the control of mammalian gene expression has been the subject of intensive research in recent years, partly due to the critical role of CpG island methylation in the inactivation of tumour suppressor genes during the development of cancer. However, this research has also helped elucidate the role that DNA methylation plays in normal cells. At present, it is also clear that DNA methylation forms an important part of the normal cell-regulatory processes that govern gene transcription. Methylation, targeted at CpG islands, is an important part of the mechanisms that govern X-chromosome inactivation; it is also essential for the maintenance of imprinted genes and, at least in some cases, is critical in determining the cell-type-specific expression patterns of genes. Study of these examples will be important in identifying the mechanisms that control targeting of DNA methylation and how these processes are disrupted during disease pathogenesis.

Animals↗
PubMed2004

CpG-island methylation and epigenetic control of resistance to chemotherapy.

Aberrant methylation of CpG islands (CpG-rich regions of DNA associated with the promoters of many genes) is associated with transcriptional inactivation of genes involved in tumour development. Genes involved in key DNA damage response pathways, such as cell-cycle control, apoptosis signalling and DNA repair can frequently become epigenetically silenced and methylated in tumours. This may lead to differences in intrinsic sensitivity of tumours to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, chemotherapy itself may exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Clinical trials of epigenetic therapies are now in progress, and epigenetic profiling using DNA methylation will provide guidance on optimization of the use of these therapies with conventional chemotherapy, as well as helping to identify patient populations who may particularly benefit from such approaches.

Animals↗
PubMed2004

Epigenetic approaches to cancer therapy.

Histone deacetylation and DNA methylation have a central role in the control of gene expression, including transcriptional repression of tumour suppressor genes. Loss of DNA mismatch repair due to methylation of the hMLH1 gene promoter results in resistance to cisplatin in vitro and in vivo. The cisplatin-resistant cell line A2780/cp70 is 8-fold more resistant to cisplatin than the non-resistant cell line, and has the hMLH1 gene methylated. Treatment with an inhibitor of DNA methyltransferase, DAC (2-deoxy-5'-azacytidine), results in a partial reversal of DNA methylation, re-expression of MLH1 (mutL homologue 1) and sensitization to cisplatin both in vitro and in vivo. PXD101 is a novel hydroxamate type histone deacetylase inhibitor that shows antitumour activity in vivo and is currently in phase I clinical evaluation. Treatment of A2780/cp70 tumour-bearing mice with DAC followed by PXD101 results in a marked increase in the number of cells that re-express MLH1. Since the clinical use of DAC may be limited by toxicity and eventual re-methylation of genes, we suggest that the combination of DAC and PXD101 could have a role in increasing the efficacy of chemotherapy in patients with tumours that lack MLH1 expression due to hMLH1 gene promoter methylation.

Antineoplastic Agents↗
PubMed2004

Hand-held thoracic sonography for detecting post-traumatic pneumothoraces: the Extended Focused Assessment with Sonography for Trauma (EFAST).

BACKGROUND: Thoracic ultrasound (EFAST) has shown promise in inferring the presence of post-traumatic pneumothoraces (PTXs) and may have a particular value in identifying occult pneumothoraces (OPTXs) missed by the AP supine chest radiograph (CXR). However, the diagnostic utility of hand-held US has not been previously evaluated in this role. METHODS: Thoracic US examinations were performed during the initial resuscitation of injured patients at a provincial trauma referral center. A high frequency linear transducer and a 2.4 kg US attached to a video-recorder were used. Real-time EFAST examinations for PTXs were blindly compared with the subsequent results of CXRs, a composite standard (CXR, chest and abdominal CT scans, clinical course, and invasive interventions), and a CT gold standard (CT only). Charts were reviewed for in-hospital outcomes and follow-up. RESULTS: There were 225 eligible patients (207 blunt, 18 penetrating); 17 were excluded from the US examination because of battery failure or a lost probe. Sixty-five (65) PTXs were detected in 52 patients (22% of patients), 41 (63%) being occult to CXR in 33 patients (14.2% whole population, 24.6% of those with a CT). The US and CXR agreed in 186 (89.4%) of patients, EFAST was better in 16 (7.7%), and CXR better in 6 (2.9%). Compared with the composite standard, the sensitivity of EFAST was 58.9% with a likelihood ratio of a positive test (LR+) of 69.7 and a specificity of 99.1%. Comparing EFAST directly to CXR, by looking at each of 266 lung fields with the benefit of the CT gold standard, the EFAST showed higher sensitivity over CXR (48.8% versus 20.9%). Both exams had a very high specificity (99.6% and 98.7%), and very predictive LR+ (46.7 and 36.3). CONCLUSION: EFAST has comparable specificity to CXR but is more sensitive for the detection of OPTXs after trauma. Positive EFAST findings should be addressed either clinically or with CT depending on hemodynamic stability. CT should be used if detection of all PTXs is desired.

Adult↗
PubMed2004

Mechanisms for macula densa cell release of renin.

The juxtaglomerular apparatus in the kidney is important in controlling extracellular fluid volume and renin release. The fluid load to the distal tubule is first sensed at the macula densa site via the entry of NaCl, through a Na, K, 2Cl co-transport mechanism. The next step is unclear, but there is recent evidence of an increased macula densa cell calcium concentration with a reduction in fluid load to the macula densa. An increase in macula densa cell calcium could activate phospholipase A2 to release arachidonic acid, the rate-limiting step in the formation of prostaglandins. Recent evidence suggests that the prostaglandin formed is PGE2, a potent stimulator for renin release. Recent evidence has also shown that adenosine has an important function in the juxtaglomerular apparatus. It stimulates calcium release in afferent arteriolar smooth muscle cells, leading to contraction of the afferent arteriole as part of the tubuloglomerular feedback mechanism, and inhibits renin release. Thus, renin release from the afferent arteriole is mediated partly through formation of PGE2, and partly through the reduction of adenosine formation that inhibits renin production.

Animals↗
PubMed2004

Long-term follow up of sequential mobilisation and autologous transplantation with CD34-selected cells in multiple myeloma: a multimodality approach.

BACKGROUND: Even after high dose chemotherapy (HDT) and autologous haemopoietic stem cell transplantation, the majority of patients with multiple myeloma eventually relapse. AIM: The aim of the present study was to study the -feasibility and outcome of delivering a regimen including in vivo and in vitro purging and double HDT in patients with multiple myeloma. METHODS: Thirty-four patients with advanced multiple myeloma were enrolled in a program of vincristine, doxorubicin and dexamethasone chemotherapy, high dose cyclophosphamide/granulocyte macrophage colony stimulating factor (GM-CSF) stem cell mobilisation, CD34 selection of harvested stem cells (in vitro purging), double HDT (cyclophosphamide/epirubicin in the first, busulphan/melphalan in the second) rescued by CD34(+)-selected cells, the second rescue using cells harvested following the first HDT (in vivo purging) and interferon maintenance. RESULTS: Forty-four per cent of patients completed the program. Fifty-three per cent of withdrawals were as a result of insufficient stem cells. This correlated to previous chemotherapy. Therapy-related mortality was 6%. CD34(+) selection achieved more than a 2-log reduction of CD38(++) cells; in vivo purging achieved 80%. Although similar numbers of CD34(+) cells were reinfused at both HDT, platelet recovery was slower after the second HDT. Additional complete remissions were achieved after each phase of therapy, 3% at the end of vincristine, doxorubicin and dexamethasone and 33% after completing planned HDT. Factors associated with longer overall survival included age less than 60 years (P = 0.044), serum beta-2-microglobulin below 3 micro gamma/L at entry (P = 0.042) and less than 2 months between the two HDT (P = 0.024). The only factor associated with a longer event-free survival was less than 2 months between HDT on study (P = 0.038). CONCLUSIONS: (i) dose intensification with two HDT delivered within 2 months might be associated with a better patient outcome, (ii) early mobilisation should be incorporated in multiple myeloma HDT programs and (iii) higher CD34(+) doses may be required for tandem transplants.

Adult↗
PubMed2004

Face value?

Explore the source record for details and available documents.

Accidental Falls↗
PubMed2004

Methadone: applied pharmacology and use as adjunctive treatment in chronic pain.

This article reviews the unique pharmacological properties of methadone and outlines its appropriate clinical application, with focus upon its use in the treatment of chronic pain. Although methadone is most widely known for its use in the treatment of opioid dependence, methadone also provides effective analgesia. Patients who experience inadequate pain relief or intolerable side effects with other opioids or who suffer from neuropathic pain may benefit from a transition to methadone as their analgesic agent. Adverse effects, particularly respiratory depression and death, make a fundamental knowledge of methadone's pharmacological properties essential to the provider considering methadone as analgesic therapy for a patient with chronic pain.

Analgesics, Opioid↗
PubMed2003

Hydroxychloroquine for the prevention of acute graft-versus-host disease after unrelated donor transplantation.

Hydroxychloroquine (HCQ) is an immunosuppressive agent that interferes with antigen presentation and with activity against graft-versus-host disease (GVHD). In a phase II trial assessing the GVHD prophylactic effects of HCQ, 51 consecutive unrelated donor transplant recipients received HCQ in addition to cyclosporin A, methylprednisolone, and methotrexate. HCQ was initiated on pretransplantation day -21 at 800 mg/d and continued until day +100 after transplantation. HCQ was extremely well tolerated and was not associated with side effects. Pharmacokinetic analyses demonstrated large inter- and intrapatient variability. The addition of HCQ did not affect posttransplantation immune recovery. Grade II to IV acute GVHD was observed in 56% of patients, and grade III and IV GVHD was observed in 17%. Day +100 mortality was 22%. When compared with a matched cohort of patients reported to the International Bone Marrow Transplant Registry, patients receiving HCQ had comparable cumulative incidences of grade II to IV acute GVHD. However, lower incidences of grades III and IV GVHD and better GVHD-free survival were observed in HCQ-treated patients (P =.01). We conclude that prophylactic HCQ is well tolerated and associated with a low incidence of severe acute GVHD. An ongoing placebo-controlled randomized trial will further determine what role HCQ plays in preventing GVHD after allografting.

Adolescent↗
PubMed2003

Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 International Study.

The tests that are currently available for the measurement of overexpression of the human epidermal growth factor-2 (HER2) in breast cancer have shown considerable problems in accuracy and interlaboratory reproducibility. Although these problems are partly alleviated by the use of validated, standardised 'kits', there may be considerable cost involved in their use. Prior to testing it may therefore be an advantage to be able to predict from basic pathology data whether a cancer is likely to overexpress HER2. In this study, we have correlated pathology features of cancers with the frequency of HER2 overexpression assessed by immunohistochemistry (IHC) using HercepTest (Dako). In addition, fluorescence in situ hybridisation (FISH) has been used to re-test the equivocal cancers and interobserver variation in assessing HER2 overexpression has been examined by a slide circulation scheme. Of the 1536 cancers, 1144 (74.5%) did not overexpress HER2. Unequivocal overexpression (3+ by IHC) was seen in 186 cancers (12%) and an equivocal result (2+ by IHC ) was seen in 206 cancers (13%). Of the 156 IHC 3+ cancers for which complete data was available, 149 (95.5%) were ductal NST and 152 (97%) were histological grade 2 or 3. Only 1 of 124 infiltrating lobular carcinomas (0.8%) showed HER2 overexpression. None of the 49 'special types' of carcinoma showed HER2 overexpression. Re-testing by FISH of a proportion of the IHC 2+ cancers showed that only 25 (23%) of those assessable exhibited HER2 gene amplification, but 46 of the 47 IHC 3+ cancers (98%) were confirmed as showing gene amplification. Circulating slides for the assessment of HER2 score showed a moderate level of agreement between pathologists (kappa 0.4). As a result of this study we would advocate consideration of a triage approach to HER2 testing. Infiltrating lobular and special types of carcinoma may not need to be routinely tested at presentation nor may grade 1 NST carcinomas in which only 1.4% have been shown to overexpress HER2. Testing of these carcinomas may be performed when HER2 status is required to assist in therapeutic or other clinical/prognostic decision-making. The highest yield of HER2 overexpressing carcinomas is seen in the grade 3 NST subgroup in which 24% are positive by IHC.

Adult↗
PubMed2003

Mucoepidermoid carcinoma arising within nevus sebaceus of Jadassohn.

BACKGROUND: Nevus sebaceus (NS) of Jadassohn is a common congenital lesion associated with numerous benign and malignant tumors. However, mucoepidermoid carcinoma (MEC) has not been described in association with NS. METHODS: We describe an unusual case of MEC arising within NS. RESULTS: A 72-year-old man presented with an enlarging plaque on his forehead, along the hairline. Physical examination revealed a mounded, erythematous lesion that was completely excised. Histological evaluation revealed a typical MEC with areas of squamous and adenomatous differentiation with foci of typical intermediate cells. CONCLUSION: The diagnosis of MEC is an important one, because it portends a poor prognosis, requiring long follow-up. This is, to our knowledge, the first report of MEC arising within NS.

Aged↗
PubMed2003

Low-dose short-course intravenous ganciclovir as pre-emptive therapy for CMV viremia post allo-PBSC transplantation.

In contrast to allogeneic bone marrow transplantation (allo-BMT), there is a paucity of data on cytomegalovirus (CMV) infection and preemptive therapy (PT) strategies following allogeneic peripheral blood stem cell (allo-PBSC) transplantation. We report here on the patterns of CMV infection in a cohort of 225 patients following sibling donor allo-PBSC transplantation. In an attempt to reduce neutropenia, we used intravenous low-dose short-course (LDSC) ganciclovir (GCV) 5 mg/kg once daily for 21 days as preemptive therapy. A total of 165 recipient-donor pairs were CMV seropositive. An initial episode of viremia (detected by shell vial/tube culture) occurred in 75/165 (45%) at a median of day +35 (17-445) post allo-PBSC. In all, 58 patients received PT with LDSC GCV. Among 58, 55 (94%) completed the 21-day course of PT. A second episode of viremia occurred in 19/58 (33%) at day+80 (50-174) and a third episode in 5/58 (9%) at day+134 (103-218). Among patients receiving LDSC GCV, 5/58(9%) developed disease (four pneumonia, one colitis) at day+211 (63-487). No patient on LDSC GCV exhibited a decline in their ANC below 500/microl and none required growth factors. LDSC GCV is extremely well tolerated and cost-effective as PT for CMV viremia following allo-PBSC transplantation.

Adolescent↗
PubMed2003

Visualization of nitric oxide production and intracellular calcium in juxtamedullary afferent arteriolar endothelial cells.

AIM: Nitric oxide (NO) is an important signal transmitter with multiple haemodynamic functions in the kidney. Study of these is complicated by the difficulty in measuring NO directly or visualizing its production. Recently the synthesis of a group of new NO-sensitive fluorescent dyes, diaminofluoresceins (DAF), suitable for imaging applications has been reported. We attempted to use one DAF (DAF-2 DA) to investigate the relationship between endothelial calcium, NO production and afferent arteriolar reactivity. METHODS: We used the isolated, perfused juxtamedullary nephron preparation (JMN) and loaded the afferent arteriolar endothelium with Fura-2 AM and DAF-2 DA (4,5-diaminofluorescein-2-diacetyl). After in vitro calibration of the imaging system, we measured Fura-2 and DAF-2 fluorescence in single endothelial cells of afferent arterioles (AA) perfused at a pressure of 100 mmHg. RESULTS: Carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO) (10-3 m), a specific NO scavenger, decreased DAF-2 fluorescence in the endothelium by 16.1% and the mid-afferent arteriolar diameter by 10.2%, and increased endothelial calcium by 17.8%. Nomega-nitro-l-arginine methyl ester (l-NAME) (10-4 m) decreased fluorescence intensity of DAF-2 by 18.6%, increased cellular calcium level by 19.7% and constricted the vessels by 11.6%. Addition of carbachol (10-4 m) increased average DAF-2 fluorescence by 22.8% and endothelial calcium concentration by 28.9%, whereas the arteriolar diameter remained essentially unchanged. Carbachol failed to increase DAF-2 fluorescence when administered after l-NAME pre-treatment. CONCLUSION: We conclude that endothelial NO homeostasis is an important determinant of AA reactivity and suggest that DAF are suitable for real-time imaging of afferent arteriolar NO production in the isolated, perfused JMN and may be used in combination with calcium-sensitive fluorophores. We have found that NO reduction by carboxy-PTIO or l-NAME increases endothelial calcium, suggesting involvement of calcium signalling in an autocrine NO production feedback in the endothelium. This method should help to further clarify the role of endothelial NO in renal haemodynamics.

Animals↗
PubMed2002

Fluctuations in attention: PD dementia vs DLB with parkinsonism.

BACKGROUND: Marked impairments in and fluctuation of attention are characteristic of dementia with Lewy bodies (DLB). The comparative impairment of these cognitive domains in PD and PD dementia (PD dementia) has not been studied, and is important to the conceptual understanding of parkinsonian dementias. METHOD: Detailed evaluations of attention and fluctuating attention (Cognitive Drug Research computerized battery) were undertaken in 278 subjects (50 DLB, 48 PD dementia, 50 PD, 80 AD, 50 elderly controls) from the Newcastle dementia register and the Stavanger PD register (controls, PD, and PD dementia patients were recruited from both centers). DLB, AD, PD, and PD dementia were diagnosed using operationalized criteria. RESULTS: Impairments in reaction time, vigilance, and fluctuating attention were comparable in patients with DLB and PD dementia, but were less substantially impaired in patients with DLB without parkinsonism. Patients with PD had significantly greater impairment of cognitive reaction time than elderly controls, and comparable impairments of cognitive reaction time to patients with AD. Patients with PD, however, did not exhibit fluctuation of attention. CONCLUSION: The profile of attentional impairments and fluctuating attention is similar in PD dementia and DLB with parkinsonism. The current findings do not support the current arbitrary distinctions between these patient groups. Importantly, patients with PD do not experience fluctuating attention.

Aged↗
PubMed2002

Activation of bovine peripheral blood gammadelta T cells for cell division and IFN-gamma production.

Bovine peripheral blood gammadelta T cells have been evaluated for effector function (IFN-gamma production) and clonal expansion in a variety of systems including following activation by mitogens, IL-12, and stimulation, through the T cell receptor (TCR) with anti-CD3 monoclonal antibody (mAb), a cell-bound molecule and a soluble antigenic extract. To evaluate cell division, carboxyfluorescein succinimidyl ester (CFSE) loading of cells and flow cytometric analysis were used, while IFN-gamma production was evaluated by intracytoplasmic staining. It was found that bovine gammadelta T cells produced IFN-gamma and clonally expanded when stimulated through the TCR/CD3 complex by a cell-associated autologous molecule on monocyte, by bacterial components following in vivo sensitization of gammadelta T cells with a leptospira vaccine or by anti-CD3 mAb. In addition, gammadelta T cells were activated efficiently for effector function but not clonal expansion by culturing with IL-12. In contrast, stimulation by Con A or PMA/ionomycin induced efficient replication but only low level IFN-gamma production which was not enhanced by the presence of IL-12. In several systems the amount of IFN-gamma produced per cell by gammadelta T cells was less than that produced by CD4 T cells in the same cultures.

Animals↗
PubMed2002

Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans.

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via "corollary discharge" to higher centers; absence of dyspnea during low inspired Po(2) may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po(2) = 60-40 Torr) and hypercapnic hyperoxia (end-tidal Pco(2) = 40-50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, "matched" by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. "Air hunger" was rated every 30 s on a visual analog scale. Air hunger-Pet(O(2)) curves rose sharply at Pet(O(2)) <50 Torr. Air hunger was not different between matched stimuli (P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.

Adult↗