Long-term effects on the immune system following local radiation therapy for breast cancer. III. Changes of spontaneous and lectin dependent cellular cytotoxicity

Long-term effects of local radiotherapy (45 Gy) on the spontaneous and PHA-mediated cytotoxicity of the peripheral blood lymphocyte population was studied in disease-free breast cancer patients 5-6 and 10-11 years after treatment. The patients were all part of a randomized trial in which pre- or post-operative radiotherapy was evaluated against surgery only. PHA-mediated cytotoxicity for 51Cr-labelled chicken erythrocytes seemed to be somewhat increased in patients who were irradiated 5-6 years earlier (p less than 0.025). This increase was not detectable after a disease-free period of 10-11 years. No significant differences between the various treatment groups were observed for spontaneous cytotoxicity against Chang and K 562 cells. The proportion of Leu 7+ lymphocytes was significantly increased in patients who received radiation therapy 5-6 years earlier (p = 0.029) and there was a significant correlation between PHA-mediated cytotoxicity and proportion of Leu7+ cells.     

The kynurenic acid hypothesis of schizophrenia

In recent years progress in the field of schizophrenia research has led to the suggestion that dopamine only plays an intermediary role in the pathophysiology of the disease and that the main abnormalities lie elsewhere. In particular, deficits in brain glutamatergic systems are suggested to play a prominent role in the pathophysiology of the disease. Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl-D-aspartate-receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, pharmacologically elevated levels of kynurenic acid, in similarity to systemic administration of phencyclidine or ketamine, were associated with increased firing rate and burst firing activity of midbrain dopamine neurons, indicating per se that elevated levels of brain kynurenic acid is associated with psychotomimetic effects. Indeed, cerebrospinal fluid level of kynurenic acid was elevated in schizophrenic patients as compared to healthy controls. The present paper also describes a prostaglandin-mediated regulation of kynurenic acid formation as well as a relationship between brain kynurenic acid concentration and the excitatory responses of ventral tegmental area dopamine neurons by clozapine and nicotine. Our results suggest that kynurenic acid contributes to the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency in glutamatergic function in this disease.     

Development and evaluation of the Communication over Language Barriers questionnaire (CoLB-q) in paediatric healthcare

Objective

To develop a valid and reliable questionnaire addressing the experiences of healthcare personnel of communicating over language barriers and using interpreters in paediatric healthcare.

Hearing difficulties, ear-related diagnoses and sickness absence or disability pension - a systematic literature review

ABSTRACT: BACKGROUND: Hearing difficulties is a large public health problem, prognosticated to be the ninth leading burden of disease in 2030, and may also involve large consequences for work capacity. However, research regarding sickness absence and disability pension in relation to hearing difficulties is scarce. The aim was to gain knowledge about hearing difficulties or other ear-related diagnoses and sickness absence and disability pension through conducting a systematic literature review of published studies. METHODS: Studies presenting empirical data on hearing difficulties or ear-related diagnoses and sick leave or disability pension, published in scientific peer-reviewed journals, were included. Studies were sought for in three ways: in literature databases (Pub-Med, Embase, PsycInfo, SSCI, and Cochrane) through March 2011, through scrutinising lists of references, and through contacts. Identified publications were assessed for relevance and data was extracted from the studies deemed relevant. RESULTS: A total of 18 studies were assessed as relevant and included in this review, regardless of scientific quality. Fourteen studies presented empirical data on hearing difficulties/ear diagnoses and sick leave and six on these conditions and disability pension. Only two studies presented rate ratios or odds ratios regarding associations between hearing difficulties and sick-leave, and only two on hearing difficulties and risk of disability pension. Both measures of hearing difficulties and of sick leave varied considerable between the studies. CONCLUSIONS: Remarkably few studies on hearing difficulties in relation to sickness absence or disability pension were identified. The results presented in them cannot provide evidence for direction or magnitude of potential associations.     

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET

Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18⁺ cells but failed to further differentiate into K14⁺ cells (epidermis/limbus) or K3/K12⁺ cells (corneal epithelium). APR-246 (PRIMA-1^MET), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.     

Stereotactic Radiotherapy of Malignancies in the Abdomen: Methodological aspects

A method for sterotactic high-dose radiotherapy of malignancies in the abdomen has been developed. A stereotactic frame for the body has been developed and a method for fixation of the patient in the frame is described. The reproducibility in the stereotactic system of tumours in the liver and the lung was found to be within 5-8 mm for 90% of the patient set-ups. The diaphragmatic movements were reduced to 5-10 mm, by applying a pressure on the abdomen. An analytical method is used to calculate dose distributions for a continuum of beams in an isocentric treatment technique. The advantage of a heterogeneous target dose is demonstrated and proposed for the present application. A non-coplanar treatment technique, using eight individually shaped beams is proposed and has been used for patient treatments. The dose distribution for a patient with a metastasis in the liver is shown as well as dose volume histograms for the target and the liver.     

Cytocidal effects of Escherichia coli hemolysin on human T lymphocytes.

Escherichia coli hemolysin is the prototype of a large family of pore-forming toxins produced by gram-negative organisms. Besides its known cytotoxic activities against granulocytes, monocytes, endothelial cells, and renal epithelial cells, we now demonstrate that the toxin potently kills human T lymphocytes. Evidence based on different and independent approaches indicates that lymphocidal activity is due to formation of transmembrane pores. Additionally, cells prestimulated with phytohemagglutinin respond to low doses of E. coli hemolysin with DNA fragmentation similar to that observed in cells undergoing programmed cell death. Kinetic considerations lead us to conclude that DNA degradation may, however, represent an epiphenomenon. Killing of T cells is another means through which E. coli hemolysin could directly impair host defense.     

Activation interferes with the APO-1 pathway in mature human T cells

One of the mechanisms to terminate a specific immune responsemay involve elimination of antigen activated T cells by programmedcell death, apoptosis. Apoptosis in activated T cells may beinduced via the TCR-CD3 complex or/and cell surface moleculeslike the APO-1 (Fas) antigen, a new member of the nerve growthfactor/tumor necrosis factor receptor superfamily. To investigateapoptosis in activated T cells we studied expression of APO-1and sensitivity to APO-1 mediated apoptosis in human peripheralT lymphocytes. APO-1 is not expressed on cord blood and themajority of resting T cells, but on activated T cells. One dayactivated T cells in culture showed activation induced resistanceto apoptosis (ARA). However, after prolonged in vitro culture,6 day activated T cells acquired sensitivity to activation inducedsensitivity to apoptosis (ASA). Restimulation of the ASA⁺ activatedT cells by triggering TCR-CD3 or CD2 induced prollferation andapoptosis in a fraction of the cells. In the surviving fractionof ASA⁺ activated T cells, however, this treatment reinduceda transient ARA⁺ phenotype. Thus, activation of resting matureT cells or restimulation of activated T cells may induce a translentresistance to apoptotic signals. Activation signals may interferewith the APO-1 pathway and may prevent elimination of activatedT cells in the periphery (peripheral selection).