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Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 127 records · Page 7Linked to original sources

How we built a strong company in a weak industry.

When Roger Brown and Linda Mason decided to start a child care and early-education company 15 years ago, they knew about the challenges inherent in the industry: no barriers to entry, low margins, few economies of scale, heavy regulatory oversight--to name just a few. But that didn't stop them. They eventually built Bright Horizons Family Solutions, a company that now has more than 340 high-quality child care centers, serving 40,000 children and employing 12,000 people. How did they do it? Sheer determination helped. But even more important, they developed a business model that took advantage of industry weaknesses. When the couple sat down to hash out a plan for the company, they realized that the key to achieving profitability and creating barriers to entry was to partner with companies. They could achieve higher returns by having those companies build and outfit the centers and, at the same time, boost customer loyalty. Indeed, Bright Horizon's corporate clients came to see the state-of-the-art centers as a way to distinguish themselves in the eyes of current and prospective employees. The high-quality child care attracted the best employees and raised retention rates. Brown's first-person account describes the difficulties the couple and their company faced along the way, including the struggle for funding and a board that questioned Bright Horizons' business model and basic philosophy of good child care. But, Brown says, the commitment to a singular business model and the determination to make strengths out of weaknesses made the impossible possible.

Child↗

E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup.

PURPOSE: We analyze the expression of E-cadherin in bladder transitional cell carcinoma, areas of carcinoma in situ and lymph node metastases, and determine the value of E-cadherin immunoreactivity for predicting disease progression and survival of patients with bladder transitional cell carcinoma. MATERIALS AND METHODS: The study group consisted of 77 patients who underwent radical cystectomy. Formalin fixed paraffin sections were processed with a hot, citric acid antigen retrieval method, followed by immunostaining with anti-E-cadherin monoclonal antibody and a standard avidin biotin complex technique. E-cadherin expression was also evaluated in carcinoma in situ sections (18) and in regional lymph node metastases (17). RESULTS: Loss of normal membrane E-cadherin immunoreactivity was found in 59 (77%) patients. Abnormal expression of E-cadherin was associated with muscle invasive disease (p = 0.010) and lymph node metastasis (p = 0.044). Of the 18 carcinoma in situ specimens 15 (83%) and of the 17 metastatic lymph nodes 13 (76%) had abnormal E-cadherin expression. Concordance rates of E-cadherin status in carcinoma in situ areas and metastatic lymph nodes with the primary tumors were 85% and 88%, respectively. At a median followup of 128 months, abnormal E-cadherin expression was significantly associated with disease progression (p = 0.0219) and bladder cancer specific survival (p = 0.037). E-cadherin expression and pathological stage but not grade were independent predictors of disease progression (p = 0.042, 0.047 and 0.158, respectively). CONCLUSIONS: In bladder cancer altered E-cadherin expression is associated with the degree of invasiveness, lymph node metastasis and increased risk of death from bladder cancer. Furthermore, E-cadherin status is an independent predictor of disease progression in patients treated with cystectomy for transitional cell carcinoma of the bladder.

Aged↗

Behavioral issues in asthma management.

Despite advances in drug treatment, outcomes in asthma remain unsatisfactory. Often overlooked in developing treatment strategies are important factors that affect outcomes in asthma, namely behavioral issues such as the low rate of patient adherence to the prescribed treatment regimen, inadequate physician-patient communication, and inconsistent implementation of evidence-based treatment guidelines. The low adherence rates among asthma patients may be improved by education programs that emphasize both the potentially serious risks of this disease and a team approach to treatment that includes patients and their families in developing a treatment plan. Interactive physician education programs have been shown to improve guideline implementation and physician communication skills. Indeed, effective physician-patient communication may be the key to improving guideline implementation and patient adherence to treatment, resulting in meaningful decreases in asthma-related morbidity and mortality.

Asthma↗

Bronchiolitis in Inuit children from a Canadian central arctic community, 1995-1996.

During the winter and summer of 1996 two outbreaks of bronchiolitis occurred among Inuit children in the Canadian arctic community of Arviat. The epidemiology and clinical features of these epidemics were studied through a chart review of bronchiolitis cases occurring from September 1, 1995 to August 31, 1996. The attack rate over the year was 57% and the incidence was 1.25 cases per child-year at risk. The median age of cases was 9 months. Children developing bronchiolitis were more likely to be male (p = 0.006). Respiratory syncytial virus (RSV) was isolated from 17 cases occurring in January/February. The hospitalization rate during those two months was 38%, mortality was 3.3%, and demands upon local health care resources were high. Parainfluenza virus type 3 was isolated from 8 cases occurring during a second smaller outbreak in July/August. Hospitalized children were more likely to be bottle-fed (p = 0.01), and duration of hospitalization was greater for RSV positive versus negative children (p = 0.002). Among those hospitalized 22% required a second admission for the same illness. Identification of prevention strategies awaits an improved understanding of the role of agent, host and environmental factors in the pathophysiology of bronchiolitis in this population.

Arctic Regions↗

Rural interprofessional education: promoting teamwork in primary health care education and practice.

In a climate of increasing incentives to work effectively within a primary health care team, the ability of various health care professionals to collaborate comes into focus. The principles of effective teamwork can be learned and this learning is most effectively achieved in the field under the supervision of experienced preceptors. It is also enhanced if learners have the opportunity to participate actively in the team and do so from undergraduate level. A 3 year project is underway in Victoria involving rural primary care placements for mixed groups of nursing and medical students. The students are educated in the field by medical and nursing tutors and preceptors who are currently working closely together. The learning objectives include understanding the principles of collaboration, teamwork and various roles in the health care team within a primary health care framework. The present paper describes the context for an evolving interprofessional education project in rural primary care, designed to promote collaboration. It outlines the policy underpinning the project's development. It provides a brief review of the associated evidence base, highlighting barriers to and enablers of interprofessional education. Lessons learnt during the implementation and evaluation of this project will guide efforts to extend the reach of interprofessional education across the primary health care sector.

Allied Health Personnel↗

Patient self-testing of prothrombin time after hip arthroplasty.

We determined whether total hip arthroplasty (THA) patients could test their own prothrombin time reliably over 6 weeks of anticoagulation prophylaxis with a portable device that measures prothrombin time and whether self-testing would improve or maintain the quality of care at a lower cost than our standard procedure. Forty-six THA patients participated in the study and were compared with a matched group managed with our standard protocol using a home health-care nurse. Seven patients (15%) could not be trained to obtain the blood sample, and others required multiple finger sticks to obtain valid results. However, the results from the 29 patients completing the study showed high reliability when compared with results obtained through standard protocol. Self-testing saved about $260 per patient over the cost of venipuncture. Patient self-testing of prothrombin time using the device in this study is reliable and cost-effective for monitoring the anticoagulation status after THA in a select group of elderly patients.

Adult↗

v-Abl protein-tyrosine kinase up-regulates p21WAF-1 in cell cycle arrested and proliferating myeloid cells.

v-Abl protein-tyrosine kinase (PTK) promotes cell survival without cell proliferation in interleukin (IL)-3-deprived IC.DP premast cells (1). We now show that in these conditions v-Abl PTK transcriptionally up-regulated the cyclin-dependent kinase inhibitor (CDKI) p21(WAF-1) and inhibited CDK2 and CDK4. When readdition of IL-3 stimulated cell proliferation, p21(WAF-1) was inactivated as a CDKI despite maintenance of elevated protein level. p21(WAF-1) was also up-regulated yet was nonfunctional as a CDKI when v-Abl PTK was activated in cells maintained in IL-3, but this occurred without increased p21(WAF-1) transcription. Using a C-terminal epitope-specific p21(WAF-1) antibody, v-Abl PTK-mediated increase in p21(WAF-1) could be detected in intact cells only in the presence of IL-3. This indicated different binding partners of p21(WAF-1) and/or protein conformation in nondividing or proliferating cells, respectively. The binding of CDK2, CDK4, or proliferating cell nuclear antigen to p21(WAF-1) and its subcellular localization were unchanged in the presence or absence of IL-3. However, two-dimensional analysis revealed different forms of up-regulated p21(WAF-1) in IL-3-deprived, nondividing cells compared with IL-3-stimulated proliferating cells. These data demonstrate that elevation of the CDKI p21(WAF-1) is not always sufficient for cell cycle arrest and indicate an IL-3-sensitive pathway for the inactivation of p21(WAF-1) function as a CDKI.

Animals↗

Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter.

Loss of DNA mismatch repair because of hypermethylation of the hMLH1 gene promoter occurs at a high frequency in a number of human tumors. A role for loss of mismatch repair (MMR) in resistance to a number of clinically important anticancer drugs has been shown. We have investigated whether the demethylating agent 2'-deoxy-5-azacytidine (DAC) can be used in vivo to sensitize MMR-deficient, drug-resistant ovarian (A2780/cp70) and colon (SW48) tumor xenografts that are MLH1 negative because of gene promoter hypermethylation. Treatment of tumor-bearing mice with the demethylating agent DAC at a nontoxic dose induces MLH1 expression. Re-expression of MLH1 is associated with a decrease in hMLH1 gene promoter methylation. DAC treatment alone has no effect on the growth rate of the tumors. However, DAC treatment sensitizes the xenografts to cisplatin, carboplatin, temozolomide, and epirubicin. Sensitization is comparable with that obtained by reintroduction of the hMLH1 gene by chromosome 3 transfer. Consistent with loss of MMR having no effect on sensitivity in vitro to Taxol, DAC treatment has no effect on the Taxol sensitivity of the xenografts. DAC treatment does not sensitize xenografts of HCT116, which lacks MMR because of hMLH1 mutation. Because there is emerging data on the role of loss of MMR in clinical drug resistance, DAC could have a role in increasing the efficacy of chemotherapy for patients whose tumors lack MLH1 expression because of hMLH1 promoter methylation.

Adaptor Proteins, Signal Transducing↗

Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study.

BACKGROUND: Inhaled corticosteroids are currently the cornerstone of asthma treatment. Some studies of high-dose fluticasone propionate in patients with no or mild asthma have, however, suggested substantial systemic absorption. We investigated the pharmacokinetics of fluticasone propionate in patients with asthma receiving appropriate doses for severity. METHODS: We did a double-blind, randomised, crossover study in 11 patients with asthma and 13 matched healthy controls (age 20-65 years; asthma patients forced expiratory volume in 1 s <75% and stable on high-dose inhaled corticosteroids). Patients received one 1000 microg intravenous dose or 1000 microg daily for 7 days inhaled (via spacer device) fluticasone propionate. In the 12 h after dosing, we monitored plasma fluticasone propionate and cortisol concentrations by mass spectrometry and competitive immunoassay with use of direct chemiluminescence. Analysis was by intention to treat. FINDINGS: After inhalation, geometric mean values were significantly lower in the asthma group than in controls for fluticasone propionate plasma area under curve (1082 [95% CI 850-1451] vs 2815 pg mL(-1) h(-1) [2262-3949], -62% difference [45-72]; p<0.001), maximum concentrations (117 [91-159] vs 383 pg/mL [302-546], -68% [-50 to -81]; p<0.001), and systemic bioavailability (10.1 [7.9-14.0] vs 21.4% [15.4-32.2], -54% [-27 to -70]; p=0.001). Intravenous-dose clearance, volume of distribution at steady state, plasma half-life, and mean residence time, were similar in the two groups. Less suppression of plasma cortisol concentrations was seen in the asthma group than in controls 4-12 h after inhaled fluticasone propionate. INTERPRETATION: Systemic availability of fluticasone propionate is substantially less in patients with moderate to severe asthma than in healthy controls. Inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severity, and not in normal volunteers.

Administration, Inhalation↗

Urinary-type plasminogen activator (uPA) expression and uPA receptor localization are regulated by alpha 3beta 1 integrin in oral keratinocytes.

Expression of urinary-type plasminogen activator (uPA) and its receptor (uPAR) is correlated with matrix proteolysis, cell adhesion, motility, and invasion. To evaluate the functional link between adhesion and proteolysis in gingival keratinocytes (pp126), cells were treated with immobilized integrin antibodies to induce integrin clustering. Clustering of alpha(3) and beta(1) integrin subunits, but not alpha(2), alpha(5), alpha(6), or beta(4), enhanced uPA secretion. Bead-immobilized laminin-5 and collagen I, two major alpha(3)beta(1) ligands, also induced uPA expression. Coordinate regulation of the serpin plasminogen activator inhibitor 1 was also apparent; however, a net increase in uPA activity was predominant. alpha(3)beta(1) integrin clustering induced extracellular signal-regulated kinase 1/2 phosphorylation, and both uPA induction and extracellular signal-regulated kinase activation were blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059. Integrin aggregation also promoted a dramatic redistribution of uPAR on the cell surface to sites of clustered alpha(3)beta(1) integrins. Co-immunoprecipitation of beta(1) integrin with uPAR provided further evidence that protein-protein interactions between uPAR and beta(1) integrin control uPAR distribution. As a functional consequence of uPA up-regulation and uPA-mediated plasminogen activation, the globular domain of the laminin-5 alpha(3) subunit, a major pp126 matrix protein, was proteolytically processed from a 190-kDa form to a 160-kDa species. Laminin-5 containing the 160-kDa alpha(3) subunit efficiently nucleates hemidesmosome formation and reduces cell motility. Together, these data suggest that multivalent aggregation of the alpha(3)beta(1) integrin regulates proteinase expression, matrix proteolysis, and subsequent cellular behavior.

Calcium-Calmodulin-Dependent Protein Kinases↗

Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation.

Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the growth hormone receptor (GHR) signaling domain. The entire extracellular domain of the GHR was replaced by the hemagglutinin-tagged zipper sequence of either the c-Fos or c-Jun transcription factor (termed Fos-GHR and Jun-GHR, respectively). Transient transfection of Fos-GHR or Jun-GHR resulted in activation of the serine protease inhibitor 2.1 promoter in Chinese hamster ovary-K1 cells to a level equal to that achieved by fully activated wild type GHR. Furthermore, stable expression of Jun-GHR alone or Fos-GHR and Jun-GHR together in the interleukin 3-dependent BaF-B03 cell line resulted in cell proliferation after interleukin 3 withdrawal at a rate equal to maximally stimulated wild type GHR-expressing cells. Activation of STAT 5b was also observed in Fos-Jun-GHR-expressing cells at a level equal to that in chronically GH-treated GHR-expressing cells. Thus, forced dimerization of the transmembrane and cytoplasmic domains of the GHR in the absence of the extracellular domain can lead to the constitutive activation of known GH signaling end points, supporting the view that proximity of Janus kinase 2 (JAK2) kinases is the essential element in signaling. Such constitutively active GH receptors may have particular utility for transgenic livestock applications.

Amino Acid Sequence↗

Accelerated prediction of recombinant protein production in Saccharomyces cerevisiae by using rapid monitoring techniques.

The use of a stopped-flow analyser for the monitoring of the production of a secreted recombinant protein, a wild-type cutinase, from S. cerevisiae CEN.PK111-32D pUR7320 is described. Induction is through use of a galactose promoter, and the monitoring facility is used to record the formation of the cutinase and cell density with optical density measurements. A range of induction conditions was studied with a view to using the monitoring to predict the likely level of cutinase formation. Results achieved within 4 to 5 h of induction were of sufficient quality to allow the use of simple modelling relating cutinase formation and cell production to predict likely final specific activities of the product. The utility of such monitoring and prediction is discussed with regards to improved process confidence and definition during fermentation production.

Journal Article↗

Effect of leukocyte compatibility on neutrophil increment after transfusion of granulocyte colony-stimulating factor-mobilized prophylactic granulocyte transfusions and on clinical outcomes after stem cell transplantation.

The primary limitations of granulocyte transfusions include low component cell dose and leukocyte incompatibility. Component cell dose improved with granulocyte colony-stimulating factor (G-CSF) mobilization, and the transfusion of G-CSF-mobilized, human leukocyte antigen (HLA)-matched granulocyte components resulted in significant, sustained absolute neutrophil count (ANC) increments. However, the effect of leukocyte compatibility on outcomes with G-CSF-mobilized granulocyte transfusions is unclear. The objectives were to determine the effect of leukocyte compatibility on ANC increments and selected clinical outcomes after transfusion of prophylactic, G-CSF-mobilized granulocyte components into neutropenic recipients of autologous peripheral blood stem cell (PBSC) transplants. Beginning on transplant day 2, 23 evaluable recipients were scheduled to receive 4 alternate-day transfusions of granulocyte components apheresed from a single donor given G-CSF. G-CSF was also given to recipients after transplantation. Recipient ANC was determined before and sequentially after each granulocyte transfusion to determine the peak ANC increment. Leukocyte compatibility was determined at study entry only by a lymphocytotoxicity screening assay (s-LCA) against a panel of HLA-defined cells. Eight recipients had positive s-LCA. On days 2 and 4, the mean peak ANC increments after granulocyte transfusion were comparable between the cohorts with positive and negative s-LCA. However, the mean peak ANC increments on day 6 (246/microL vs 724/microL; P =.05) and day 8 (283/microL vs 1079/microL; P =.06) were lower in the cohort with positive s-LCA, in spite of the transfusion of comparable component cell doses. Adverse reactions occurred with only 5 of 87 (5.7%) granulocyte transfusions and were not associated with leukocyte compatibility test results. Platelet increments, determined 1 hour after granulocyte transfusion, were comparable between the cohorts. Although the 2 cohorts received PBSC components with similar CD34(+) cell doses, the cohort with a positive s-LCA had delayed neutrophil engraftment and a greater number of febrile days and required more days of intravenous antibiotics and platelet transfusions. Leukocyte incompatibility adversely affected ANC increments after the transfusion of G-CSF-mobilized granulocyte components and clinical outcomes after PBSC transplantation.

ABO Blood-Group System↗

Solid-phase combinatorial synthesis using MicroKan reactors, Rf tagging, and directed sorting.

A modular system for high-output solid-phase combinatorial synthesis has been designed and developed. The system employs three technological innovations to achieve its high efficiency and reliability: (1) application of microreactors as the reaction units in solid-phase synthesis; (2) use of radiofrequency tagging as the non-chemical tracking method; and (3) development of the directed sorting technology for split & pool synthesis. The system has been successfully applied in the synthesis of compound libraries of several hundred to several thousand compounds in multi-milligrams per compound quantity by many organizations.

Chemistry, Organic↗

S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial.

We report a pilot study of S-adenosyl-methionine (SAM) in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAM was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and was 9.55 +/- 7.29 after SAM treatment (p < 0.0001). Although uncontrolled and preliminary, this study suggests that SAM is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease.

Aged↗