Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology.

Glioblastoma multiforme (GBM) is an aggressive brain tumor, fatal within 1 year from diagnosis in most patients despite intensive multimodality therapy. The migratory and microscopically invasive nature of GBM as well as its resistance to chemotherapy renders conventional therapies inadequate in its treatment. Although Mer receptor tyrosine kinase (RTK) inhibition has been shown to decrease the long-term survival and improve the chemosensitivity of GBM in vitro, its role in malignant cellular migration has not been previously evaluated. In this study, we report for the first time a role for Mer RTK in brain tumor migration and show that Mer inhibition profoundly impedes GBM migration and alters cellular morphology. Our data demonstrate that Mer RTK inhibition results in altered signaling through focal adhesion kinase (FAK) and RhoA GTPase and a transformation of cytoskeletal organization, suggesting both molecular and structural mechanisms for the abrogation of migration. We also describe a novel and translational method of Mer RTK inhibition using a newly developed monoclonal antibody, providing proof of principle for future evaluation of Mer-targeted translational therapies in the treatment of GBM. Previous findings implicating Mer signaling in glioblastoma survival and chemotherapy resistance coupled with our discovery of the role of Mer RTK in GBM cellular migration support the development of novel Mer-targeted therapies for this devastating disease.

A safety assessment of branched chain saturated alcohols when used as fragrance ingredients.

The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. In humans, no evidence of skin irritation was found at concentrations of 2-10%. Undiluted, 11 materials evaluated caused moderate to severe eye irritation. As current end product use levels are between 0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB light-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to elicit phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following repeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSA and three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that 2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect and mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no safety concerns regarding BCSA under the present levels of use and exposure.

A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

Role of registered nurses in error prevention, discovery and correction.

BACKGROUND: Registered nurses have a vital role in discovering and correcting medical error. OBJECTIVE: To describe the type and frequency of errors detected by American critical care nurses, and to ascertain who made the errors discovered by study participants. METHODS: Daily logbooks were used to collect information about errors discovered by a random sample of 502 critical care nurses during a 28-day period. RESULTS: Although the majority of errors discovered and corrected by critical care nurses involved medications (163/367), procedural errors were common (n = 115). Charting and transcription errors were less frequently discovered. The errors discovered by participants were attributed to a wide variety of staff members including nurses, doctors, pharmacists, technicians and unit secretaries. CONCLUSIONS: Given the importance of nurses in maintaining patient safety, future studies should identify factors that enhance their effectiveness to prevent, intercept and correct healthcare errors.

A toxicologic and dermatologic assessment of related esters and alcohols of cinnamic acid and cinnamyl alcohol when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

A toxicologic and dermatologic assessment of ionones when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

A toxicologic and dermatologic assessment of salicylates when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

The experience of hot flushes after breast cancer.

As survival from breast cancer increases, there is a corresponding rise in the number of women living with the long-term consequences of its treatment. Distressing menopausal hot flushes occur in many of these women. This article reports on interviews conducted with 8 women, exploring the experience of hot flushes after breast cancer. Women's accounts of hot flushes varied from being a mild sensation to an intensely unpleasant sensation affecting the whole body and accompanied by drenching perspiration. Flushes affected all aspects of the women's lives, including sleeping, clothing, social situations, intimate relationships, and ability to work. Emotionally, women talked about being out of control. Having cancer and menopause simultaneously made it more difficult for the women to cope, and cancer treatment could cause flushing. The women used many strategies to help relieve their difficulties. Some resorted to hormone replacement therapy, whereas others turned to herbal medications and other alternative interventions such as acupuncture. Most women adopted behavioral strategies to try to regain control. Ultimately, they found that control was gained by attitude of mind. Cognitive behavioral techniques may enhance the sense of control and contribute to coping during hot flushes.

A randomised controlled trial to assess the effectiveness and cost of a patient orientated self management approach to chronic inflammatory bowel disease.

OBJECTIVES: We developed a patient centred approach to chronic disease self management by providing information designed to promote patient choice. We then conducted a randomised controlled trial of the approach in inflammatory bowel disease (IBD) to assess whether it could alter clinical outcome and affect health service use. DESIGN: A multicentre cluster randomised controlled trial. SETTING: The trial was conducted in the outpatient departments of 19 hospitals with randomisation by treatment centre, 10 control sites, and nine intervention sites. For patients at intervention sites, an individual self management plan was negotiated and written information provided. PARTICIPANTS: A total of 700 patients with established inflammatory bowel disease were recruited. MAIN OUTCOME MEASURES: Main outcome measures recorded at one year were: quality of life, health service resource use, and patient satisfaction. Secondary outcomes included measures of enablement-confidence to cope with the condition. RESULTS: One year following the intervention, self managing patients had made fewer hospital visits (difference -1.04 (95% confidence interval (CI) -1.43 to -0.65); p<0.001) without increase in the number of primary care visits, and quality of life was maintained without evidence of anxiety about the programme. The two groups were similar with respect to satisfaction with consultations. Immediately after the initial consultation, those who had undergone self management training reported greater confidence in being able to cope with their condition (difference 0.90 (95% CI 0.12-1.68); p<0.03). CONCLUSIONS: Adoption of this approach for the management of chronic disease such as IBD in the NHS and other managed health care organisations would considerably reduce health provision costs and benefit disease control.

Safety assessment of allylalkoxybenzene derivatives used as flavouring substances - methyl eugenol and estragole.

This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavouring substances under conditions of intended use. In this review, scientific data relevant to the safety evaluation of the allylalkoxybenzene derivatives methyl eugenol and estragole is critically evaluated by the FEMA Expert Panel. The hazard determination uses a mechanism-based approach in which production of the hepatotoxic sulfate conjugate of the 1'-hydroxy metabolite is used to interpret the pathological changes observed in different species of laboratory rodents in chronic and subchronic studies. In the risk evaluation, the effect of dose and metabolic activation on the production of the 1'-hydroxy metabolite in humans and laboratory animals is compared to assess the risk to humans from use of methyl eugenol and estragole as naturally occurring components of a traditional diet and as added flavouring substances. Both the qualitative and quantitative aspects of the molecular disposition of methyl eugenol and estragole and their associated toxicological sequelae have been relatively well defined from mammalian studies. Several studies have clearly established that the profiles of metabolism, metabolic activation, and covalent binding are dose dependent and that the relative importance diminishes markedly at low levels of exposure (i.e. these events are not linear with respect to dose). In particular, rodent studies show that these events are minimal probably in the dose range of 1-10 mg/kg body weight, which is approximately 100-1000 times the anticipated human exposure to these substances. For these reasons it is concluded that present exposure to methyl eugenol and estragole resulting from consumption of food, mainly spices and added as such, does not pose a significant cancer risk. Nevertheless, further studies are needed to define both the nature and implications of the dose-response curve in rats at low levels of exposure to methyl eugenol and estragole.

Green tea extracts decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture.

Epidemiological evidence suggests tea (Camellia sinensis L.) has chemopreventive effects against various tumors. Green tea contains many polyphenols, including epigallocatechin-3 gallate (EGCG), which possess anti-oxidant qualities. Reduction of chemically induced mammary gland carcinogenesis by green tea in a carcinogen-induced rat model has been suggested previously, but the results reported were not statistically significant. Here we have tested the effects of green tea on mammary tumorigenesis using the 7,12-dimethylbenz(a)anthracene (DMBA) Sprague-Dawley (S-D) rat model. We report that green tea significantly increased mean latency to first tumor, and reduced tumor burden and number of invasive tumors per tumor-bearing animal; although, it did not affect tumor number in the female rats. Furthermore, we show that proliferation and/or viability of cultured Hs578T and MDA-MB-231 estrogen receptor-negative breast cancer cell lines was reduced by EGCG treatment. Similar negative effects on proliferation were observed with the DMBA-transformed D3-1 cell line. Growth inhibition of Hs578T cells correlated with induction of p27(Kip1) cyclin-dependent kinase inhibitor (CKI) expression. Hs578T cells expressing elevated levels of p27(Kip1) protein due to stable ectopic expression displayed increased G1 arrest. Thus, green tea had significant chemopreventive effects on carcinogen-induced mammary tumorigenesis in female S-D rats. In culture, inhibition of human breast cancer cell proliferation by EGCG was mediated in part via induction of the p27(Kip1) CKI.

A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy.

STUDY OBJECTIVE: To determine if the combination of scheduled sleep periods and stimulant medications were more effective than stimulant medications alone in controlling the excessive daytime sleepiness experienced by narcoleptic patients. DESIGN: Twenty-nine treated narcoleptic subjects were randomly assigned to one of three treatment groups: 1) two 15-minute naps per day; 2) a regular schedule for nocturnal sleep; or 3) a combination of scheduled naps and regular bedtimes. Measures of symptom severity and unscheduled daytime were obtained at baseline and at the end of the two-week treatment period, using the Narcolepsy Symptom Status Questionnaire (NSSQ) and 24-hour ambulatory polysomnographic monitoring. No alterations were made in stimulant medications during the study period. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The addition of two-15 minute naps did not alter either symptom severity or the duration of unscheduled daytime sleep. Regular times for nocturnal sleep reduced perceived symptom severity, but did not reduce the amount of unscheduled daytime sleep. Only the combination of scheduled naps and regular nocturnal sleep times, significantly reduced both symptom severity and the amount of unscheduled daytime sleep in treated narcoleptic subjects. The type of sleep schedule prescribed, however, was less important than the severity of the patients' pre-treatment daytime sleepiness. Subjects with severe daytime sleepiness benefited from the addition of scheduled sleep periods, while those who were only moderately sleepy or able to maintain alertness did not benefit from scheduled sleep periods. CONCLUSIONS: Scheduled sleep periods are helpful for only those patients who remain profoundly sleepy despite stimulant medications and should not be prescribed for all patients with narcolepsy.

Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis.

Exposure to ubiquitous environmental chemicals, such as polycyclic aromatic hydrocarbons (PAH), may contribute to human breast cancer. In animals, PAH induce tumors in part by activating the aryl hydrocarbon receptor (AhR)/transcription factor. Historically, investigations into AhR-regulated carcinogenesis have focused on AhR-dependent transcriptional regulation of cytochrome P450 (CYP) enzymes which oxidize PAH to mutagenic intermediates. However, recent studies suggest that the AhR directly regulates cell growth. Given the postulated role of the AhR in carcinogenesis, we predicted that: (1) tissue predisposed to PAH tumorigenesis would express the AhR and (2) aberrant AhR and/or AhR-regulated gene expression would accompany malignant transformation. To test these hypotheses, AhR and CYP1 protein and/or mRNA levels were evaluated in rat mammary tumors induced with 7, 12-dimethylbenz[a]anthracene (DMBA), a prototypic PAH and AhR ligand. Results indicate modest AhR expression in normal mammary myoepithelial and ductal epithelial cells. In contrast, high AhR levels were detected in DMBA-induced tumors. Nuclear AhR localization in tumors suggested constitutive AhR activation. In situ hybridization and quantitative RT-PCR assays indicated high AhR mRNA levels in neoplastic epithelial cells. While both AhR-regulated CYP1A1 and CYP1B1 mRNAs were induced in breast tissue within 6 h of DMBA gavage, only CYP1B1 mRNA remained elevated in tumors. These results: (1) help explain targeting of breast tissue by carcinogenic PAH, (2) imply that AhR and CYP1B1 hyper-expression represent molecular biomarkers for, at least, PAH-induced mammary cell transformation, and (3) suggest mechanisms through which the AhR may contribute to carcinogenesis well after exogenous AhR ligands have been eliminated.

Knowledge and communication difficulties for patients with chronic heart failure: qualitative study.

OBJECTIVES: To explore patients' understanding of chronic heart failure; to investigate their need for information and issues concerning communication. DESIGN: Qualitative analysis of in-depth interviews by a constant comparative approach. PARTICIPANTS: 27 patients identified by cardiology and care of the elderly physicians as having symptomatic heart failure (New York Heart Association functional class of II, III, or IV) and who had been admitted to hospital with heart failure in the past 20 months. RESULTS: Participants were aged 38-94 (mean 69 years); 20 had a New York Heart Association classification of III or IV. All had at least one concurrent illness. Participants sought information from the research interviewer about their heart failure, their prognosis, and likely manner of death. They also described several factors that could inhibit successful communication with their doctors. These included difficulties in getting to hospital appointments, confusion, short term memory loss, and the belief that doctors did not want to provide patients with too much knowledge. CONCLUSIONS: Good communication requires the ability both to listen and to impart relevant information. Effective and better ways of communicating with patients with chronic heart failure need to be tested. Disease specific barriers to effective communication, such as short term memory loss, confusion, and fatigue should be addressed. Strategies to help patients ask questions, including those related to prognosis, should be developed.