Exercise-induced metallothionein expression in human skeletal muscle fibres

Exercise induces free oxygen radicals that cause oxidative stress, and metallothioneins (MTs) are increased in states of oxidative stress and possess anti-apoptotic effects. We therefore studied expression of the antioxidant factors metallothionein I and II (MT-I + II) in muscle biopsies obtained in response to 3 h of bicycle exercise performed by healthy men and in resting controls. Both MT-I + II proteins and MT-II mRNA expression increased significantly in both type I and II muscle fibres after exercise. Moreover, 24 h after exercise the levels of MT-II mRNA and MT-I + II proteins were still highly increased and the MT-II mRNA expression reached a 15-fold increase. As expected, immunohistochemical detection of malondialdehyde (MDA) and nitrotyrosine (NITT) showed that formation of free radicals and oxidative stress were clearly increased in exercising muscle peaking shortly after the end of exercise in both type I and II muscle fibres. This is the first report demonstrating that MT-I + II are significantly induced in human skeletal muscle fibres following exercise. As MT-I + II are antioxidant factors that protect various tissues during pathological conditions, the MT-I + II increases post exercise may represent a mechanism whereby contracting muscle fibres are protected against cellular stress and injury.     

Is MED13L-related intellectual disability a recognizable syndrome?

Introduction

MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.

Inhibition of endogenous carcinoembryonic antigen (CEA) increases the apoptotic rate of colon cancer cells and inhibits metastatic tumor growth

It has been suggested that carcinoembryonic antigen (CEA) enhances metastatic seeding of colon cancer cells due to its homo- and heterophilic binding properties. Our recent finding that endogenous CEA protects colon cancer cells against apoptosis suggests a more complex role of CEA in cancer progression. In this study we compared the in vitro effects of endogenous CEA on tumor cell aggregation and cell cycle regulation of human HT29 colon cancer cells with the corresponding in vivo effects, i.e. tumor cell seeding and formation of metastatic lesions. Stable expression of CEA targeted ribozymes (Rz) under control of a tet-off promoter system allowed regulation of CEA levels on the mRNA and protein level by 50%. Downregulation of CEA levels inhibited tumor cell aggregation by 70%. In accordance with previous studies [1], reduction of CEA levels increased in vitro the apoptotic rate and reduced colony formation by 30% to 50%. To determine the in vivo effect of CEA-dependent aggregate formation and its growth regulating role under apoptotic stress, HT29 cells with high and low CEA levels, respectively, were injected into nude mice. Immunostaining of lung microsections revealed similar numbers of tumor cells one hour after injection. 24 h later virtually all cells were removed from the lung in both groups. However, after 6 weeks all doxycycline treated mice (Rz off = CEA high) showed 14.5 ± 4.6 metastatic lung lesions/mouse while 0.2 ± 0.2 lesions/mouse appeared in the untreated group (Rz on = CEA low) ( P<0.001). Our study demonstrates a multifunctional role of CEA and indicates a prometastatic role of CEA independent of its adhesive function possibly due to its anti-apoptotic function. This revised version was published online in July 2006 with corrections to the Cover Date.     

Chronic treatment with epidermal growth factor stimulates growth of the urinary tract in the rat

Twenty-four male Wistar rats, 8 weeks old, were allocated into three groups and treated with human recombinant epidermal growth factor (EGF) administered subcutancously in doses of 0, 30, and 150 g/kg per day for 4 weeks. Blood sampling was done every 2nd week and urine sampling was done for 2 consecutive days every week. The most striking finding was that the ureters were dose dependently enlarged, due to growth of all layers of the ureteric wall. The urothelium of the bladder showed considerable hyperplasticity with a widening of the basal proliferative compartment and a normal differentiation pattern as observed by the expression of carbohydrate epitopes, characterized with lectinohistochemistry. Blood examination revealed a decrease in blood haemoglobin concentration and a slight increase in serum creatinine concentration in the high-dose group. There were no effects of EGF on the urinary excretion of electrolytes, proteins, and endogenous EGF.     

Pharmacodynamic differences between species exemplified by the novel anticancer agent CHS 828

When a candidate drug enters clinical trials, decisions regarding dosing are mainly based on animal data. Occasionally, toxicity problems are faced in the clinic because of unexpected species differences in pharmacokinetics or pharmacodynamics between humans and preclinical species. Fludarabine and topotecan are examples of such drugs. In the first clinical trials of the new agent CHS 828, the maximum tolerated dose was reached earlier than expected from animal data. This paper discusses the issue of species differences in the development of anticancer drugs, and preclinical models for detection and quantification of such differences. Pharmacokinetic and hematological toxicity data of CHS 828 from studies in rats and humans are presented. In vitro sensitivity to CHS 828 and some established cytotoxic agents was measured in lymphocytes from humans and rats and in a panel of human and rodent cell‐lines. 10–100 times higher CHS 828 exposure was tolerated by rats than by patients. In both in vitro cell systems, CHS 828 showed higher potency in human cells compared to rodent cells. A species difference was evident also for fludarabine, but not for doxorubicin and cisplatin. CHS 828 pharmacokinetics were similar across species. In conclusion, the lower tolerance of CHS 828 in humans than in rats could be detected in vitro in cultures of peripheral lymphocytes. Preclinical studies of species differences could help the interpretation of in vivo effect studies as well as the choice of starting dose for clinical trials. We suggest peripheral lymphocytes from different species as a potential model system for such studies. Drug Dev. Res. 61:218–226, 2004. © 2004 Wiley‐Liss, Inc.     

Promoting and sustaining health through increased vegetable and fruit consumption among European schoolchildren: The Pro Children Project

Aim The Pro Children consortium consists of the following partners: Knut-Inge Klepp (Coordinator), Department of Nutrition, University of Oslo, Norway; Carmen Perez Rodrigo, Unidad de Nutricion Comunitaria, Bilbao, Spain; Inga Thorsdottir, Unit for Nutrition Research, Landspitali University Hospital, Reykjavik, Iceland; Pernille Due, Department of Social Medicine, University of Copenhagen, Denmark; Maria Daniel Vaz de Almeida, Faculdade de Ciências da Nutrição e Alimentação da Universidade do Porto, Portugal; Ibrahim Elmadfa and Alexandra Wolf, Institute of Nutrition, University of Vienna, Austria; Jóhanna Haraldsdóttir, Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Copenhagen, Denmark; Johannes Brug, Erasmus Medical Center Rotterdam, Department of Public Health, The Netherlands; Michael Sjöström and Agneta Yngve, Unit for Preventive Nutrition, Karolinska Institutet, Stockholm, Sweden; Ilse De Bourdeaudhuij, Department of Movement and Sport Sciences, Ghent University, Belgium.The Pro Children study is designed to assess vegetable and fruit consumption and determinants of the consumption patterns among European school children and their parents. A second objective is to develop and test strategies for promoting increased consumption of vegetables and fruits among school children and their parents.Subjects and methods Surveys of national, representative samples of 11-year-old school children and their parents were conducted in nine countries during October–November 2003, i.e. in Austria, Belgium, Denmark, Iceland, The Netherlands, Norway, Portugal, Spain and Sweden. Comprehensive school-based educational programmes were developed and tested in three settings, i.e. in the Bilbao region, Spain, in Rotterdam, The Netherlands, and in Buskerud county of Norway. A 24-h recall format and frequency items assessing regular intake were used to assess vegetable and fruit consumption. Determinants were assessed employing the theoretical framework of the ASE model (Attitudes, Social Influences and Self-Efficacy), including cognitive factors, normative influences, skills and environmental barriers related to vegetable and fruit consumption. The intervention programmes were tested employing a group-randomized trial design where schools were randomly allocated to an intervention arm and a delayed intervention arm. Surveys among all participating children and their parents were conducted prior to the initiation of the intervention (September 2003; month 0), immediately after the end of the intervention (at month 8) and at the end of the subsequent school year (month 20).Results Preliminary data from the project indicate that girls eat vegetables and fruit significantly more often than do boys across all participating countries. There are no sex differences, however, with respect to perceived availability of vegetables and fruit at home and outside the home setting. In all countries, perceived availability appears to be significantly associated with reported frequency of both vegetable and fruit consumption.Conclusion Experience so far indicates that the Pro Children Project will succeed in producing valid and reliable research instruments for assessing vegetable and fruit consumption among school children and their parents and that comparable, comprehensive intervention programmes can be implemented across geographic and cultural settings within Europe.