Cognitive dysfunction and chemotherapy: neuropsychological findings in perspective

Currently, the interest in cognitive functioning following chemotherapy is rapidly expanding as is reflected in a growing number of published studies on this topic. Although most studies are indicative of cognitive deficits after chemotherapy, definite conclusions on the role of chemotherapy on cognitive function can often not be drawn due to methodological problems. On the basis of the studies on cognitive functioning after chemotherapy that are conducted in The Netherlands Cancer Institute, the current article describes a number of such methodological topics that obscure straightforward interpretation of neuropsychological findings in toxicity research. Measurement issues that diverge from usual assessment issues encountered in psychosocial oncology will be described, and factors that might play a role in the cause of cognitive impairment will be evaluated. Also, future developments necessary to gain more insight into the prevalence, the pattern, and the impact of cognitive problems following chemotherapy are discussed     

Maternal deprivation of rat pups increases clinical symptoms of experimental autoimmune encephalomyelitis at adult age

Maternal deprivation of neonatal animals has been shown to induce long-lasting changes in the reactivity of the neuroendocrine system. The aim of the present study was to investigate whether maternal deprivation also affects susceptibility to immune-mediated diseases such as experimental autoimmune encephalomyelitis (EAE) in adult life.To this end, 9-day-old rat pups were subjected to a short-lasting maternal deprivation for a period of 24 h. At the age of 8 weeks, we induced EAE in these rats by immunization with myelin basic protein (MBP) in complete Freund's adjuvant. Our data demonstrate that short-lasting maternal deprivation induces a marked increase in the severity of EAE in the animals in later life. The histopathological evaluation of spinal cord and cerebellum corresponded with the observed differences in clinical symptoms of EAE. Moreover, neonatal maternal deprivation affects macrophage functioning at adult age. In contrast, no differences were observed in in vitro mitogen- and MBP-induced cytokine production by splenocytes. LPS-induced corticosterone release did not differ either between maternally deprived and control animals. We conclude that short-lasting neonatal maternal deprivation of rat pups has long-lasting consequences for macrophage activity and for susceptibility to the inflammatory autoimmune disease EAE.     

Physical activity and glucose tolerance in elderly men: the Zutphen Elderly study

PURPOSE: To determine whether physical activity is associated with glucose tolerance in the elderly. METHODS: We examined current and 5-yr change in physical activity in relation to glucose tolerance in 424 randomly selected male inhabitants of the Dutch town Zutphen, aged 69-89 yr, without known diabetes mellitus. Physical activity was assessed by a validated questionnaire designed for retired men. Glucose intolerance was assessed by an oral glucose tolerance test and defined as impaired glucose tolerance or diabetes mellitus. RESULTS: Men with 30 min x d(-1) or more of physical activity of at least moderate intensity had a lower prevalence of glucose intolerance as compared to men without these activities (age-adjusted odds ratio 0.32; 95% CI, 0.18-0.57). Adjustment for family history of diabetes, smoking, alcohol intake, dietary factors, body mass index, and subscapular skin-fold thickness or exclusion of men with cardiovascular diseases or disabilities did not substantially change the results. With specific activities modeled simultaneously, bicycling (P for trend = 0.01) and gardening (P for trend = 0.02) were inversely associated with glucose intolerance. Men whose amount of physical activity had decreased during the past 5 yr had significantly higher age-adjusted 2-h glucose concentrations as compared with men who remained at least as active (difference 0.7 mmol x L(-1); 95% CI, 0.1-1.3). CONCLUSION: These findings suggest that common types of physical activity such as bicycling and gardening may contribute to the prevention of glucose intolerance in elderly men     

Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells

The pro-inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) can be produced by activated glial cells and play a critical role in various neurological diseases. Using primary co-cultures of rat microglial and astroglial cells, we investigated the effects of the anti-inflammatory cytokines transforming growth factor-beta1 (TGF-beta1)/beta2, IL-4, and IL-10 on the production of (pro-) inflammatory mediators after stimulation of the cells with lipopolysaccharide (LPS; 0.1 micrograms/ml, 24 h). IL-10 (10 and 100 ng/ml) and IL-4 (5 and 50 U/ml) suppressed the LPS-induced production of NO, IL-6, and TNF-alpha in a dose-dependent manner, whereas TGF-beta1/beta2 (2 and 20 ng/ml) only suppressed NO production. LPS-induced levels of IL-1beta were suppressed by IL-10, but not by IL-4 and TGF-beta1/beta2. Conversely, co-incubation of the glial cells with LPS and antibodies to TGF-beta1/beta2 selectively enhanced LPS-induced NO production, whereas co-incubation with antibody to IL-10 enhanced LPS-induced production of all pro-inflammatory cytokines and NO. This finding strongly suggests that effective concentrations of TGF-beta1/beta2 and IL-10 are produced by LPS-stimulated glial cell co-cultures. Production of IL-10 in these co-cultures was confirmed by measurement of rat IL-10 by radioimmunoassay. We conclude that anti-inflammatory cytokines affect the production of inflammatory mediators in LPS-activated co-cultures of microglial and astroglial cells differentially.     

CXC-chemokines, a new group of cytokines in congestive heart failure--possible role of platelets and monocytes

OBJECTIVES: The purpose of the present study was to examine the circulating levels of CXC-chemokines in patients with various degree of congestive heart failure (CHF). BACKGROUND: CXC-chemokines may be important mediators in the persistent immune activation observed in CHF patients by activation of circulating neutrophils, T-cells and monocytes and possibly by the recruitment of these cells into the failing myocardium. METHODS: Levels of interleukin (IL)-8, growth-regulated oncogene (GRO) alpha and epithelial neutrophil activating peptide (ENA)-78 were measured both in serum and in platelet-free plasma by enzyme immunoassay in 47 patients with CHF and in 20 healthy controls. RESULTS: (i) CHF patients had significantly elevated levels of all the three CXC-chemokines with IL-8 and GRO alpha showing a gradual increase along with increasing NYHA class. (ii) There was an inverse correlation between IL-8 and left ventricular ejection fraction (EF) and cardiac index (CI). (iii) Both unstimulated and lipopolysaccharide (LPS)-stimulated monocytes from CHF patients released markedly elevated amounts of all three CXC-chemokines. (iv) Platelets from patients with severe CHF were characterised by decreased content of GRO alpha and ENA-78 as well as decreased release of these chemokines upon thrombin receptor stimulation. (v) Activated platelets stimulated peripheral blood mononuclear cells in vitro to enhanced release of IL-8, and neutralising antibodies against ENA-78 inhibited this interaction. CONCLUSIONS: This study demonstrates for the first time elevated levels of CXC-chemokines in CHF, which may be of importance for progression of heart failure. Our findings further suggest that activated monocytes and platelets may contribute to enhanced CXC-chemokine levels in CHF.     

Public Attitudes Toward Epilepsy in Denmark

Social acceptance of persons with epilepsy very often constitutes a considerable problem for patients and their relatives. Nationwide opinion pools on the knowledge of and public attitude toward epilepsy have been taken in several countries, but never in Denmark. We report a Gallup survey of the general knowledge of and attitude toward epilepsy. A representative population of 1,500 persons aged greater than or equal to 15 years was selected in a four-state proportional sampling procedure. Ninety-seven percent of respondents had heard or read about epilepsy, 60% of these knew a person with epilepsy, and 50% had seen an epileptic seizure. The attitudes toward social acceptance and employment of persons with epilepsy were generally favorable, but 7% had objections to social contact between their children and persons with epilepsy in the playground and at school and 7% had objections to equal employment. Familiarity with persons with epilepsy was correlated to questions about attitudes and general knowledge of epilepsy. Such knowledge and public attitude in Denmark are mainly positive, but we believe that a continuous information campaign about epilepsy is essential, especially among youth.     

One year follow-up study to assess the prevalence and incidence of Lyme borreliosis among dutch forestry workers

A one-year serological and clinical follow-up study was conducted to assess the prevalence and incidence of asymptomatic and symptomatic infection withBorrelia burgdorferi among 151 Dutch forestry workers. The prevalence of antibodies toBorrelia burgdorferi among the forestry workers and among office employees as control group was compared. Antibodies toBorrelia burgdorferi were detected by enzyme immunoassay. Forestry workers were examined physically at the start of the study. Clinical follow-up of forestry workers whose first blood sample was positive and of persons showing seroconversion was done by telephone interview. If Lyme borreliosis was suspected, clinical and laboratory data were obtained. The seroprevalence was significantly higher among forestry workers (28 %) than among controls (5 %). Of 127 forestry workers who were examined, 7 (18 %) of the 39 seropositive persons but none of the seronegative persons had a history of Lyme borreliosis. None of 32 asymptomatic seropositive forestry workers had developed Lyme borreliosis one year later. The incidence of infection withBorrelia burgdorferi as demonstrated by seroconversion among 95 initially seronegative forestry workers was 5%. None of them had Lyme borreliosis. Infection withBorrelia burgdorferi among forestry workers is frequent but seems to take a benign course.     

A study of the reliability,validity and responsiveness of the HIV Overview of Problems Evaluation System (HOPES) in assessing the quality of life of patients with AIDS and symptomatic HIV infection

The objective of this study was to evaluate the feasibility, reliability, validity and responsiveness of the HIV Overview of Problems Evaluation System (HOPES) in a Dutch sample. The HOPES was administered three times in a one-year period to a sample of 106 outpatients with a symptomatic HIV-infection (n=23) or AIDS (n=83). The HOPES is a self-report HIV-specific quality of life (QOL) questionnaire including five scales: physical, psychosocial and sexual functioning, medical interaction and partner relationship. QOL was also assessed with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), a 30-item self-report instrument. Clinical data included Centers for Disease Control and Prevention (CDC) stage, date of diagnosis and CD4 cell count. Patients needed approximately 20–30 minutes to complete the questionnaire. The five scales had good internal consistency reliability. Multitrait scaling analysis provided moderate support for item discriminant and convergent validity. The HOPES exhibited adequate levels of construct validity: (1) the inter-scale correlations and correlations with the EORTC QLQ-C30 were in the predicted direction; (2) it discriminated clearly between patients with AIDS and ARC and (3) it was able to document changes in QOL over time. Moreover, the HOPES was responsive to changes in clinical status over time as indicated by CD4 counts. This study provides further evidence of the reliability and validity of the HOPES and shows that this instrument is responsive to changes in CD4 cell counts.This research was made possible by a grant from the Dutch Ministry for Welfare, Public Health and Culture (grant no. 88-52).