Clinical trial participation among patients enrolled in the Glioma Outcomes Project

BACKGROUND: Patient participation in well-designed and conducted clinical trials enables researchers to test new therapies. An understanding of the variables that possibly influence patient enrollment may help in patient recruitment for future trials. The authors evaluated factors that influenced patient enrollment in clinical trials using a prospective, large, multi-institutional registry of patients with malignant glioma. METHODS: Data were examined from 708 patients who underwent first or second surgery for a malignant glioma who were enrolled in the Glioma Outcomes Project, which is a prospective observational data base that captures clinical practice patterns. The frequency of clinical trial participation and the variables that may have been associated with trial participation were evaluated. These variables included age, gender, race, household income, educational level, first versus second craniotomy, histology, and whether the patient was treated at an academic institution. RESULTS: One hundred fifty-one of 708 patients (21.3%) participated in a clinical trial, which was higher than the participation reported typically for patients with other types of primary malignancies. In univariate analysis, race, histology, and first craniotomy were significant between the two groups, with Caucasian patients and patients with glioblastoma histology showing higher participation rates. In a multivariate logistic regression model, significant predictors included young age and glioblastoma multiforme histology. CONCLUSIONS: The authors present information on factors that may influence clinical trial participation among patients with malignant glioma and compare their data with information described previously on patients with other types of malignant disease. The percent of participation among the patients in the current study was greater than among patients with other primary tumor sites. Strategies should be implemented to improve recruitment to neuro-oncology trials, especially in elderly and minority populations.     

In vitro activation of extracellular signal-regulated kinase1/2 in the inner ear of guinea pigs

Growth factors such as vascular endothelial growth factor (VEGF) exert their proliferative properties partly through activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2). Although both VEGF and inactive ERK could be detected in the inner ear of guinea pigs, under normal conditions activated ERK (phospho-ERK) was found only sparely. Cochleae of adult guinea pigs were removed, incubated with VEGF in a carbogen-gased organ-bath for 5, 15, 30 and 60 min (n=6 in each group), fixed with PFA 4%, embedded in paraffin and sectioned, followed by immunohistochemical staining to inactive and active ERK. Whereas inactive ERK was found in all cochleae, in sensory and supporting cells of the apex activated ERK was strongly detected after 5-min VEGF-incubation. After 15 min all Corti-organs showed clear staining corresponding to activated ERK, which decreased again after 30 min. Faint staining in endothelial cells of the spring-coil-vessels and in the spiral ganglion cells was found after 30 min and was increased after 60 min, while the staining in the Corti-organs vanished. Addition of the MEK-inhibitor PD 98059 to the organ-bath led to diminished phospho-ERK1/2 immunostaining. These findings provide evidence for a VEGF-dependent phosphorylation of ERK1/2 in the cochlea. Activated ERK1/2 is thought to support axonal outgrowth, enhancement of cell survival and to regulate the turnover of the NO/cGMP-pathway.     

The role of personality variables and social support in distress and perceived health in patients following myocardial infarction

Objectives: (1) To investigate whether patients with low versus high social support and satisfaction with support report less distress and health complaints following a first myocardial infarction (MI). (2) To examine whether personality traits mediate social support and its effect on distress and health complaints. Methods: A questionnaire was distributed to 112 consecutive patients with a first MI 4–6 weeks postinfarction. Objective clinical measures were obtained from the patients' medical records. Results: Patients with low social support were at increased risk of depression and posttraumatic stress disorder (PTSD). Patients less satisfied with support were at increased risk of anxiety, depression, PTSD, and reported more health complaints. Generally, larger effect sizes were found for satisfaction with support compared with social support per se in relation to distress and health complaints. Neuroticism was identified as an independent predictor of all types of distress and health complaints when including both traits and social support variables in multivariable analyses, adjusted for demographic and clinical variables. Satisfaction with support only remained an independent predictor of depression. Conclusion: These results suggest that personality traits may mediate social support and its effect on distress and health complaints. Hence, it may be important to include personality variables when investigating social support in relation to distress and health. In clinical practice, screening for particular personality traits could identify patients at risk of distress and recurrent cardiac events.     

Attachment and coping with chronic disease

BACKGROUND: In this clinical study, attachment theory was applied to research in the field of coping with chronic disease. The approach was to integrate concepts of coping within a framework of attachment theory. It was hypothesised that attachment concepts have an influence on coping strategies, and that they may predict the subjective emotional and physical health status during the course of medical treatment. METHOD: One hundred fifty patients were investigated with an adult attachment interview (AAPR coding system) and a coping interview (Bernese Coping Modes). Self-reported coping modes, social support, the subjective health status and quality of life were also assessed by self-report measures at two or more sampling points of measurement. Three subsamples of patients, suffering from (a) breast cancer, (b) chronic leg ulcers and (c) alopecia, were studied in order to include a broad range of subjective impairment caused by a disease. RESULTS: Findings indicate a moderate statistical effect of attachment patterns on coping strategies when controlling the influence of confounding variables. Insecure attachment was related to less flexible coping. Coping strategies also differed between the different types of insecure attachment; however, there were differences depending on the perspective of the coping behaviour (self- vs. observer ratings) as well. From the observer perspective, ambivalently attached individuals showed more negative emotional coping while avoidantly attached individuals showed more diverting strategies. In the self-report, ambivalently attached patients revealed hyperactivating tendencies in their coping behaviour while avoidantly attached individuals revealed deactivating tendencies. CONCLUSION: As a conclusion, two levels of coping should be differentiated. One level strongly corresponds with affect regulation, in particular the regulation of attachment-related emotions and concerns, while the other level shows a stronger tendency to outwardly oriented coping. A more secure attachment might be considered to be an important inner resource in the emotional adaptation to chronic diseases.     

Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women

The authors describe the novel occurrence of homozygosity for the CAG expansion in the androgen receptor gene causing Kennedy disease in two sisters (ages 34 and 42). Symptoms were limited to occasional muscle cramps and twitches. Physical examinations were normal apart from mild hand tremor in both women and rare perioral fasciculations in the older sibling. Electrodiagnostic studies were normal except for evidence of mild motor axonal loss in the sternocleidomastoid muscle of the older sibling.     

Comparison of in vitro closure time (PFA-100) with whole blood electrical aggregometry and platelet surface antigen expression in healthy volunteers

It was the aim of this study to compare in vitro closure time (PFA-100), reflecting platelet-related primary hemostasis, to more platelet-specific tests like whole blood electrical aggregometry and platelet surface antigen expression in healthy volunteers. In vitro closure time was measured using a PFA-100. Platelet surface antigen expression (CD63, CD62-P, CD42b, CD36, CD31) was determined in accordance with the consensus protocol for flow-cytometric characterisation of platelet function. Platelet aggregometry was performed using a whole blood electrical aggregometer (ADP and arachidonic acid as agonists). Analysis of the obtained data revealed only a few significant correlations between the different platelet function tests used. This finding can be explained by the various aspects of platelet function being focused by these tests in different extents. Whenever platelet function is analysed, the investigator should be aware of the specific and limited evidence of the method used. For screening purposes, it may be useful to introduce a platelet function index, referring to basal platelet activity, platelet adhesion and platelet aggregation at low and high shear stress forces.     

The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids

Antiplatelet therapy with acetylsalicylic acid (ASA) is commonly used to reduce the risk of cardio- and cerebrovascular events. Fish consumption has been inversely related to coronary disease, which has been partly attributed to an inhibitory effect of n-3 polyunsaturated fatty acids (n-3 PUFA) on platelet production of tromboxane A2. In this study, we investigated the acute and short-time effect of supplementation with n-3 PUFA and intravenous ASA on platelet function, platelet fatty acid composition and plasma lipids. Eighteen healthy men were randomly allocated to a daily intake of 10 g n-3 PUFA or placebo. After this supplement (14 h and 14 days), blood was sampled before and after intravenous injection of 100 mg ASA. n-3 PUFA given for 14 days caused a minor inhibition of platelet reactivity but negligible compared to 100 mg ASA. No additive effect of n-3 PUFA and ASA could be demonstrated.     

Norepinephrine transporter gene polymorphism is not associated with susceptibility to alcohol dependence

Abnormalities in monoamine neurotransmission have been implicated in the pathogenesis of alcoholism, mood disorders and schizophrenia. Murine norepinephrine transporter gene (NET) has been mapped to a region on chromosome 8 where a quantitative trait locus for ethanol sensitivity. Therefore we tested whether norepinephrine transporter (NET) gene variants confer susceptibility to either alcohol dependence or severe alcohol withdrawal symptoms. There is a highly polymorphic silent G1287A mutation in the NET gene. In our study 157 alcoholics and 185 healthy unrelated matched control subjects were analyzed for a silent G1287A mutation. No significant differences in allele and genotype distribution between control subjects f(A)=0.33 and alcoholics f(A)=0.29 were found. No significant results were found in more homogenous subgroups, i.e. alcoholics with severe alcohol withdrawal (seizures, delirium), early onset age<26 nor dependent patients with positive familial history of alcoholism. These results suggest that the NET gene polymorphism in exon 9 accession number: mRNA: NM_001043, genomic contig.: NT_019610, is unlikely to be involved in the susceptibility to alcoholism and severe alcohol withdrawal.     

Tumor necrosis factor-alpha (TNF) regulates the expression of ICAM-1 predominantly through TNF receptor 1 after chronic constriction injury of mouse sciatic nerve

Proinflammatory cytokines like tumor necrosis factor-alpha (TNF) contribute to Wallerian degeneration by enhancing the adhesion of leukocytes to the endothelium through increased expression of adhesion molecules. Here we studied the influence of TNF and TNF receptors (TNFR) on intercellular adhesion molecule-1 (ICAM-1) and macrophage influx following chronic constrictive injury (CCI) in mice by three different paradigms: (1) C57BL/Wld mice with delayed TNF up-regulation, (2) in vivo inhibition of TNFR1 and TNFR2 by neutralizing antibodies, and (3) three different types of mice with a genetic deficiency for TNFR. C57BL/Wld mice with a delayed macrophage influx had a delayed increase of ICAM-1 compared to control mice. In vivo inhibition of both TNFR significantly impaired macrophage recruitment; however, treatment with anti-TNFR1 antibodies increased endoneurial ICAM-1 expression. In TNFR1 and TNFR1+2, but not TNFR2-deficient mice, endoneurial ICAM-1 expression was significantly reduced, which correlated with prolonged Wallerian degeneration in TNFR1-deficient mice 2 weeks after CCI. Our data support the hypothesis that TNF regulates the expression of ICAM-1 predominantly through TNFR1.