Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 145 records · Page 8Linked to original sources

PubMed2000

The use of nicotine replacement therapy during hospitalization.

Recent findings suggest that smokers who are hospitalized experience significant craving for cigarettes. Thus, nicotine replacement therapy (NRT) may be a particularly important tool for use during hospitalization. The goal of this study is to evaluate the utilization of the transdermal nicotine patch and/or nicotine gum by hospitalized smokers. The data represented in this article are from 580 smokers who participated in a study of a motivational intervention for smoking cessation that was delivered during hospitalization. The primary outcome for this analysis was use of NRT during hospitalization. The results revealed that, among the entire sample, only 7.1% of the overall sample used NRT during hospitalization; 6% of the hospitalized smokers used the transdermal nicotine patch, and 1.1% used nicotine gum. Use of NRT was significantly greater among patients who reported that they were doing anything to help themselves quit smoking at the time of admission (OR = 4.1), those who were seriously planning to quit smoking within the next 30 days (OR = 2.36), those who were nicotine dependent (OR = 2.81), and those for whom a physician had ever offered to prescribe NRT (OR = 1.9). The finding that there is a very low rate of NRT use during hospitalization provides important information to hospital-based care providers and smoking cessation intervention planners. Barriers to NRT use among hospitalized patients should be identified, and strategies designed to maximize use when appropriate. The AHCPR Guideline on Smoking Cessation recommends routine use of NRT in health care settings. Further research is needed to determine why NRT use was so low. In addition, these data suggest that efforts to increase NRT use during hospitalization are needed.

Administration, Cutaneous↗

PubMed2000

Proximally porous coated femoral stem in total hip replacement--5- to 13-year follow-up report.

A series of total hip replacements was performed using a proximally porous coated, tapered femoral stem system. At a mean follow-up of 8.1 (5-13) years, 80 out of 107 hips were available for clinical and radiological examination. The mean age at the index procedure was 58.6 years. The mean Harris Hip Score at final follow-up was 91.7. Radiological ingrowth was observed in 77 femoral stems, 2 stems were fibrous stable and 1 stem was loose.

Female↗

PubMed2000

Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel.

PURPOSE: To determine factors which influence the sensitivity of human colorectal carcinoma cell lines to paclitaxel. METHODS: The paclitaxel sensitivity of ten human colorectal carcinoma cell lines, and a panel of RKO colon carcinoma cell lines, isogenic except for p53 status, were studied. The inhibitory concentrations causing a 50% decrease in growth (IC50) were assayed after 3, 24, and 96 h after paclitaxel exposure. The doubling time (DT) and cell cycle parameters of cells were also measured. The expression of the multidrug resistance glycoprotein-1 (MDR-1), bcl-2 and bax was quantitatively assessed by immunoblotting. RESULTS: Mean IC50 values at 24 and 96 h drug exposure were about 1.5 logs lower than the IC50 values at 3 h, regardless of the p53 status. No difference was found between the IC50 values of wild-type and mutant p53 cells, or among the RKO panel of cells. Correlation analysis showed that: (1) resistance was associated with longer DTs, but this was generally abated by a 96-h exposure; (2) with a 3-h exposure, the combination of MDR, bcl-2 and bax parameters with DT (DT + MDR + bcl-2 bax) best correlated with IC50 values (r = 0.77); (3) with a 96-h exposure, in spite of the generally decreased IC50 values, a combination of MDR-1, bcl-2 and bax parameters (MDR + bcl-2-bax) best correlated with the IC50 values (r = 0.71). CONCLUSIONS: These results suggest that the exposure duration, DT, and expression of MDR-1, bcl-2 and bax each contribute to paclitaxel sensitivity of human colorectal carcinoma cells. In assessing paclitaxel drug resistance, multiple factors should always be considered. There may be a therapeutic window for taxanes in colon cancer by optimizing pharmacokinetics and modulating MDR-1 and bcl-2 resistance factors.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Acute partial paralysis alters perceptions of air hunger, work and effort at constant P(CO(2)) and V(E).

Breathing sensations of AIR HUNGER, WORK and EFFORT may depend on projections of central motor discharge (corollary discharge) to the forebrain. Source of motor drive (brainstem or cortex) may determine what is perceived. To test the effect of changing motor discharge at constant ventilation, we induced partial neuromuscular blockade during hypercapnic hyperpnea (31 + or - 9 L min(-1); PET(CO(2))=49 + or - 2 Torr) and during matched volitional hyperpnea (34 + or - 5 L min(-1); PET(CO(2))=41 + or - 1 Torr). Decline of vital capacity was similar between conditions (39%). Ventilation was unchanged with paralysis, indicating increased respiratory motor drive to maintain hyperpnea. Sensations were rated on a seven point ordinal scale. Median EFFORT and WORK increased 3-3.5 points with paralysis during both forms of hyperpnea (P<0.02, Wilcoxon signed rank). Median AIR HUNGER increased 2.5 points with paralysis during hypercapnic (P<0.02) but not during volitional hyperpnea. Data suggests that EFFORT and WORK arise from motor cortex activity (subjects reported engaging volitional control when paralyzed even during hypercapnia) and suggests that AIR HUNGER arises from medullary motor activity.

Adult↗

PubMed2000

Exploiting the utility of yeast in the context of programmed cell death.

Many researchers have explored the extent to which yeast can be used to dissect the mechanisms of programmed cell death in higher cells. Yeast has been used as a system to analyze protein-protein interactions and structure-function relationships, and as a cloning tool to identify novel higher eukaryote regulators of apoptosis. In addition, classic genetic strategies in yeast have been used to analyze the mechanisms of action of core pathway members. The purpose of this chapter is to describe the strategies pursued and act as a source for the technical details necessary to exploit the yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe in the context of programmed cell death.

Animals↗

PubMed2000

Pre-core mutant infections in the Canadian Inuit.

BACKGROUND/AIMS: Previous cross-sectional data suggested that chronic hepatitis B viral (HBV) infections in the Canadian Inuit were inactive. The aim of this study was to confirm these findings and document the prevalence of the subsequently described "pre-core mutant" variant of HBV in this population. METHODS: We obtained sera from residents of five remote Canadian Inuit communities. Residents were selected if they were known to be hepatitis B surface antigen (HBsAg) positive or had a history of liver disease. HBV serology, HBV-DNA, and pre-core mutant testing were performed by commercially available assays, polymerase chain reaction (PCR) and direct sequencing of the viral genome, respectively. RESULTS: Sera were obtained from 176/266 (66%) of selected individuals. Thirty-eight (22%) were HBsAg positive and 16 (9.1%) anti-HBs positive. Of HBsAg positive carriers 25/38 (66%) were male as compared to 68/138 (49%) of the remaining individuals (p<0.05). Of 37 HBsAg positive carriers, none were HBeAg positive, 36 (97%) anti-HBe positive and one (3%) HBeAg and anti-HBe negative. Liver enzyme and function tests were normal in all cases. 30/37 (81%) HBsAg positive carriers were HBV-DNA positive and 26/30 (87%) were pre-core mutant positive. CONCLUSION: The majority of HBV infections in community-based Canadian Inuit are inactive and the prevalence of pre-core mutant infections is the highest reported to date.

Adult↗

PubMed2000

A long-term study of vitamin A and polychlorinated hydrocarbon levels in otters (Lutra lutra) in south west England.

Seventy-seven wild otters (Lutra lutra) found dead in south west England between 1988 and 1996 were examined post mortem. Liver samples were analysed from 56 otters for polychlorinated hydrocarbons and from 40 for vitamin A (retinol). There was a significant decline in the levels of pollutants over the study period and this coincided with a marked increase in vitamin A levels. However, a causal relationship was not established. Low vitamin A levels were prevalent in the early years of the study but no conclusive pathological lesions due to deficiency were seen. It is suggested that vitamin A deficiency may have been widespread in Britain's otter population until recently and may have been implicated in the earlier decline.

Journal Article↗

PubMed2000

Variations in prudent laypersons' perceptions of the need for emergent medical care.

The objective of this study was to determine whether differences exist among distinct demographic groups' tendencies to view various medical symptoms as emergent in nature. A questionnaire containing six demographic questions and listing 29 common medical complaints was distributed to 306 respondents who agreed to participate; they were asked to indicate when (if at all) they would be likely to seek medical care for each problem. Overall, across the series of complaints, African American respondents desired statistically significantly more acute care than Caucasians. Those with a high school education or lower also wanted to be seen statistically significantly sooner for more symptoms than those with some college education or higher. We conclude that opinions as to the urgency of medical symptoms vary widely among demographic groups.

Adult↗

PubMed2000

A clinical teaching project. Evaluation of the mentor-arranged clinical practice by RN mentors.

This paper explores the relationship between nursing students and mentors and its influence on nursing students' development of professional knowledge during their clinical practice. The paper is based on an evaluation of a new initiative supplementing other clinical experiences for students of nursing, Mentor-Arranged Clinical Practice (MACP), by registered nurse mentors. Sixty-five (95.6%) mentors returned their questionnaires in a self-addressed envelope. Results of the study indicated that there were benefits and rewards for both students and mentors. The mentors felt that students gained more practicum time, confidence and independence in their practice, time management skills, rapport between staff and student, and better integration into the hospital environment. Mentors indicated that the most compelling reasons for becoming mentors were the opportunity to assist mentees to integrate into the nursing unit, to teach, share knowledge, promoting and improving the professional image of nurses, and gain job satisfaction from mentoring. The findings in this study suggest that there is a need for development of mentor relationships in the clinical setting of undergraduate nursing courses.

Attitude of Health Personnel↗

PubMed2000

Does early treatment with high-dose methylprednisolone alter the course of hepatic regimen-related toxicity?

Hepatic regimen-related toxicity (RRT) is a serious complication of stem cell transplantation. Cytokine activation may be involved in the pathogenesis. Corticosteroids are potent inhibitors of cytokine production, and, therefore could play a role in the treatment of hepatic RRT. Between January 1994 and June 1998, 28 of 782 consecutive transplant patients (3.6%) developed hepatic RRT (20 veno-occlusive disease (VOD) and eight liver dysfunction of uncertain etiology (LDUE) as defined by Seattle criteria), and were treated with high-dose methylprednisolone (MP, 500 mg/m2 i.v. every 12 h for six doses), initiated upon increase in serum total bilirubin to > or =4 mg/dl. Other causes of liver dysfunction were excluded. Response to therapy with high-dose MP was defined as reduction in total bilirubin by 50% within 10 days of initiation of MP. Overall, 17 patients (61%) responded to treatment (12 patients with VOD, five patients with LDUE). The bilirubin in responding patients decreased from a mean of 8.6 mg/dl (range, 4-17.9) at the start of MP to 4.1 mg/dl (range, 0.5-17.9) 10 days later. There were no statistically significant differences between responders and non-responders in the day treatment with high-dose MP was initiated (P = 0.38), total serum bilirubin (P = 0.17) and percent weight gain at the time high-dose MP was started (P = 0.10) or the calculated probability of fatal outcome from VOD (18% for responders, 23% for non-responders; P = 0.30). A lower pre-transplant DLCOc was observed among non-responders (P = 0.04). At 100 days post-transplant, hepatic RRT resolved in all 13 survivors who responded to high-dose MP, and in one non-responding patient. No serious toxicities due to high-dose MP were observed. We conclude that resolution of hepatic RRT occurred in the majority of patients treated with high-dose MP in this study; however, randomized controlled trials are required to determine the efficacy of high-dose MP for treatment of hepatic RRT.

Adult↗

PubMed2000

CD34+ selection of autologous peripheral blood stem cells for transplantation following sequential cycles of high-dose therapy and mobilization in multiple myeloma.

A potential problem of autologous transplantation in the treatment of multiple myeloma (MM) is the infusion of tumor cells. CD34+ selection has been used to purge autografts in MM and it is also possible to reduce tumour cell contamination of autografts by cytotoxic drug therapy prior to peripheral blood stem cell (PBSC) collection. To evaluate the effectiveness of a protocol combining multiple cycles of high-dose therapy and CD34+ selection to reduce tumour contamination of PBSC autografts, 34 MM patients were entered on a treatment schedule comprising two sequential cycles of mobilisation, CD34+ selection, and transplantation following high-dose therapy. In the second cycle of mobilisation there was a five-fold reduction in tumour contamination of the stem cell harvest (0.5 x 106/kg) compared with the first cycle (2.5 x 106/kg). In the 97 CD34+ selection procedures performed a median of 185 x 108 mononuclear cells (MNC) were processed yielding a median of 0.98 x 108 CD34+-enriched cells. CD34+ cells were enriched 68-fold from 1. 3% to 88.6%. The median yield of CD34+ cells was 42.2%. Following CD34+ selection the tumour cell contamination of the leukapheresis product was reduced by a median of 2.7 logs. This study demonstrates that in multiple myeloma a significant reduction in the malignant contamination of stem cell autografts can be achieved by combining the in vivo purging effect of cytotoxic therapy with in vitro purging by CD34+ selection.

Adult↗

PubMed2000

Adverse side-effects associated with G-CSF in patients with chronic myeloid leukemia undergoing allogeneic peripheral blood stem cell transplantation.

Administration of the myeloid growth factor G-CSF after allogeneic hematopoietic stem cell transplantation is usually well tolerated, and associated with rapid hematopoietic engraftment. We report a high incidence (50%) of side-effects associated with post-transplant G-CSF in patients with chronic phase chronic myeloid leukemia undergoing allogeneic HLA-identical sibling peripheral blood stem cell transplantation. One or more of the following signs and symptoms were observed shortly after the subcutaneous injection of G-CSF: dyspnea, chest pain, nausea, hypoxemia, diaphoresis, anaphylaxis, syncope and flushing. These reactions led to discontinuation of G-CSF in the majority of patients. Predictive factors could not be identified, and the underlying mechanism leading to these reactions is unknown.

Adult↗

PubMed2000

Allogeneic peripheral blood stem cell transplantation following CD34+ enrichment by density gradient separation.

GVHD is a significant cause of morbidity and mortality following allogeneic peripheral blood stem cell transplantation (AlloPBSC). CD34+ cell selection could reduce GVHD by negative selection of T cells. In an attempt to reduce the T cell content of alloPBSC we carried out a trial in which 11 patients with hematologic malignancies received alloPBSC from HLA-matched siblings following density gradient separation using an isotonic colloidal silica solution (BDS 60; Dendreon Corporation). Cyclosporine and methylprednisone were used for GVHD prophylaxis. The mean yield of CD34+ cells was 69 +/- 15.6% with a purity of 2.9 +/- 1.7%. The mean number of CD3+ cells infused was 1.0 +/- 1.2 x 107/kg, representing a 1.3 log depletion. A high risk of acute GVHD was observed: grade II-IV in 7/11 (64%) and grade III-IV GVHD in 5/11 (45%) patients. Nine of the 11 (82%) patients died with a median survival of 68 days. Cytokine expression in PBSC was compared pre and post processing. Interferon-gamma was detected only following density gradient separation while IL-8 expression increased 3- to 6-fold post processing. Therefore, processing with this device may augment production of pro-inflammatory cytokines. Bone Marrow Transplantation (2000) 25, 1223-1228.

Antigens, CD34↗

PubMed2000

Outcomes of high-dose chemotherapy and autologous stem cell transplant in isolated locally recurrent breast cancer: a multicenter evaluation.

To determine the outcomes of women with isolated loco-regional recurrence (LRR) of breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) following conventional therapy, we conducted a retrospective review of 58 patients from five institutions treated between 1990 and 1998. Forty-five patients (78%) had > or = 2 poor prognostic factors (PPF) (defined as disease-free interval preceding LRR < or = 2 years, hormone receptor negative/refractory disease, and incomplete resection). At median follow-up of 14.2 (0.5-72) months, 36 patients (62%) developed progressive disease. Disease progression usually occurred at local (27 patients) vs distant (nine patients) sites. Median time to disease progression following ASCT was 6.1 (1.3-31.4) months. At last follow-up, 23 patients (40%) had expired (all due to disease progression), and 13 (22%) were alive with, and 22 (38%) without progressive disease. By Kaplan-Meier analysis, the estimated median PFS and OS was 20.3 and 29.2 months, respectively. In a multivariate model, complete remission at time of HDCT and estrogen-receptor positive disease were predictive of significantly longer PFS and OS. The survival of this cohort was similar to previous reports of those treated with conventional therapy alone, and to those with distant metastases treated with HDCT. Frequent progression locally, suggests that strategies to improve local disease control are needed.

Adult↗

PubMed2000

Efficacy of a replication-selective adenovirus against ovarian carcinomatosis is dependent on tumor burden, viral replication and p53 status.

Intraperitoneal (i.p.) recurrence of cisplatin-refractory and p53 mutant ovarian cancer is a major clinical problem, despite surgery and chemotherapy. dl1520 (ONYX-015) is an E1B-55 kDa gene-deleted adenovirus engineered selectively to replicate in and destroy cancer cells lacking functional p53. However, a correlation between efficacy and p53 function has not been definitively studied in vivo to date, and efficacy following i.p. administration had not been previously described. We therefore carried out experiments to address these issues in three nude mouse-human ovarian carcinomatosis xenograft models. Intraperitoneal treatment with dl1520 led to complete tumor eradication and/or significantly improved survival in two p53(-) nude mouse-human ovarian tumor xenograft models. OVCAR3 i.p. xenografts underwent complete regressions in 11 of 12 mice (versus one of seven controls; P = 0.001), while mice bearing cisplatin-resistant A2780 tumors had significantly improved survival versus controls (P = 0.05). In contrast, the A2780 p53(+) ovarian cancer xenograft was resistant to dl1520. The efficacy of i.p. dl1520 in the p53(-) models correlated strongly with tumor burden present at the time of treatment initiation, and no efficacy was seen with non-replicating/UV-inactivated dl1520. Selectively replicating viruses such as dl1520 hold promise as i.p. therapies for p53-deficient and chemotherapy-resistant ovarian carcinomas. A phase I clinical trial of i.p. dl1520 (ONYX-015) is underway in patients with cisplatin-resistant ovarian carcinoma.

Adenoviridae↗

PubMed2000

Renal NO production and the development of hypertension.

The juxtaglomerular apparatus (JGA) has the very important functions of detecting the fluid flow rate to the distal tubule and thus controlling the glomerular filtration rate (GFR) (tubuloglomerular feedback mechanism [TGF]) and renin release from the afferent arteriole. In studies of the TGF it has been evident that the sensitivity of this mechanism can be reset. Volume expansion will reset it to a low sensitivity leading to a high GFR and urine excretion rate, while dehydration will sensitize the TGF mechanism, giving rise to a low GFR and low urine excretion rate. Furthermore, we have found that in animals that spontaneously develop hypertension there is initially a sensitization of the TGF, leading to a reduced GFR and urine excretion rate, with fluid volume retention in the body and a consequent rise in blood pressure. When the pressure is raised, the TGF characteristics are normalized. In the macula densa (MD) cells in the JGA, there is a large production of NO from neuronal NOS. This production continuously reduces TGF sensitivity and is apparently impaired in animals that spontaneously develop hypertension. When we added an nNOS inhibitor to the drinking water for several weeks while measuring blood pressure, we found an increase in blood pressure after 3-4 weeks of treatment. This effect was abolished by a high salt diet. From these investigations, it also appeared as if nNOS-derived NO inhibited renin release. Experiments have also indicated that NO may resensitize inhibited G-protein coupled purinergic receptors.

Animals↗

PubMed2000

Apoptosis in factor-dependent haematopoietic cells is linked to calcium-sensitive mitochondrial rearrangements and cytoskeletal modulation.

Apoptosis in murine haematopoietic interleukin (IL)3-dependent cell lines is induced within 6-8 h by IL-3 withdrawal. Direct introduction of cytochrome c by electroporation induces apoptosis within 2 h and was inhibited by caspase inhibitors, such as Z-VADfmk and Z-Dfmk. We report here that apoptosis induced by IL-3 withdrawal was refractory to these inhibitors but was accompanied by striking redistribution of mitochondria, which aggregated into an area associated with centrioles without loss of Deltapsim. Both mitochondrial redistribution and apoptosis were inhibited by the calcium ionophore, ionomycin. Nocodozole, an inhibitor of microtubule assembly, also induced apoptosis, which was unaffected by caspase inhibitors. Although nocodozole did not alter mitochondrial distribution, it significantly reduced Deltapsim, and both reduction of Deltapsim and apoptosis were inhibited by ionomycin. Oligomycin, which inhibits the mitochondrial FoF1 ATPase, similarly induced apoptosis, which was unaffected by caspase inhibitors but was inhibited by ionomycin. Further, oligomycin stimulated the novel formation and release of surface membrane-derived vesicles containing mitochondria with intact Deltapsim; ionomycin also inhibited their production. In all these conditions, Bcl-2 protected cells from apoptosis. Our studies show that apoptosis induced by three very different agents shares insensitivity to caspase inhibitors, suppression by ionomycin and effects on mitochondria, which all appear to be linked to cytoskeletal/microtubule activity. They suggest that microtubules and the cytoskeleton play an important role in apoptosis through mechanisms affecting mitochondria but which are independent of cytochrome c release.

Animals↗

PubMed2000

Metaplastic carcinoma of the breast arising within complex sclerosing lesion: a report of five cases.

AIMS: This study presents a series of five cases in which metaplastic carcinoma, predominantly low-grade adenosquamous carcinoma, of the breast is seen arising within a background of a complex sclerosing lesion. This association has been recognized previously but has not been documented in detail. This study describes the characteristics of the components present in each case and discusses the existing literature. This observation adds further evidence to support an association between some types of invasive breast carcinoma and sclerosing lesions of the breast. METHODS AND RESULTS: Four of these cases were received as referral cases for opinion. The fifth was received as part of the routine surgical workload within our own institution. Two patients presented following mammographic screening and three symptomatically; their mean age was 62 years (range 49-68). The mean lesion size was 16 mm (range 7-24). All five lesions showed features of a complex sclerosing lesion/radial scar in the form of central sclerosis with elastosis and radiating benign entrapped tubules. One had associated benign papillary structures and two had focal benign squamous metaplasia. Four cases showed coexisting but distinct areas of low-grade adenosquamous carcinoma with glandular and squamous epithelial differentiation in a spindle cell background. One case had associated undifferentiated spindle cell carcinoma. Detailed immunophenotypic characteristics of two cases are presented. CONCLUSIONS: This series illustrates a postulated but previously unconfirmed association between an unusual form of metaplastic breast carcinoma (adenosquamous carcinoma) and complex sclerosing lesions. The mechanisms of induction of breast carcinoma are poorly understood but these observations further emphasize the potential for sclerosing lesion of the breast to be associated with, and possibly give rise to, invasive carcinoma of different types. The precise nature of the interaction between the pathological processes remains unclear.

Aged↗