Glutathione deficiency in HIV infection

The tripeptide glutathione (GSH) is the quantitatively most important cysteine derivative of low molecular weight and has numerous important cellular functions. Decreased plasma cysteine and cystine concentrations, decreased intracellular GSH levels, and increased plasma glutamate levels have been found in HIV-infected persons at all stages of the disease and in rhesus macaques within 2 weeks after infection with the closely related simian immunodeficiency virus (SIVmac2). Elevated glutamate levels inhibit the membrane transport of cystine and aggravate thereby the consequences of the cysteine deficiency. Complementary experiments In laboratory animals have shown that glutathione potentiates T cell functions in vivo and in vitro. And studies with healthy human subjects have shown that persons with a combination of a higher than median plasma cystine and lower than median glutamate level have significantly more CD4 T cells than persons with low cystine and high glutamate levels. On the basis of these findings we have proposed that the immunopathology of HIV infection may be largely the consequence of a virus-induced dysregulation of plasma amino acid concentrations. Studies on the mechanistic details revealed that the cysteine and intracellular glutathione deficiency may have several immunologically relevant consequences that affect the antigen presenting cells as well as the responding T lymphocytes. The redox regulation of the transcription factor NFκB accounts at least for some of the consequences.Biomedical Reviews 1993; 2: 9-13

Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis

The initiation of mammalian puberty and the maintenance of female reproductive cycles are events controlled by hypothalamic neurons that secrete the decapeptide gonadotropin-releasing hormone (GnRH). GnRH secretion is, in turn, controlled by changes in neuronal and glial inputs to GnRH-producing neurons. The hierarchical control of the process is unknown, but it requires coordinated regulation of these cell-cell interactions. Here we report the functional characterization of a gene (termed enhanced at puberty 1 [EAP1]) that appears to act as an upstream transcriptional regulator of neuronal networks controlling female reproductive function. EAP1 expression increased selectively at puberty in both the nonhuman primate and rodent hypothalamus. EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity. Inhibition of EAP1 expression, targeted to the rodent hypothalamus via lentivirus-mediated delivery of EAP1 siRNAs, delayed puberty, disrupted estrous cyclicity, and resulted in ovarian abnormalities. These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.This work was supported by grants from the NIH, the National Institute of Child Health and Human Development/NIH (to S.R. Ojeda), the European Society for Paediatric Endocrinology (to H. Jung), the German Research Foundation (to S. Heger), and the European Commission (PIONEER to S. Heger)

Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro

Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis

Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression

<p>Abstract</p> <p>Background</p> <p>As cell-free circulating DNA exists predominantly as mono- and oligonucleosomes, the focus of the current study was to examine the interplay of circulating nucleosomes, DNA, proteases and caspases in blood of patients with benign and malignant breast diseases.</p> <p>Methods</p> <p>The concentrations of cell-free DNA and nucleosomes as well as the protease and caspase activities were measured in serum of patients with benign breast disease (n = 20), primary breast cancer (M0, n = 31), metastatic breast cancer (M1, n = 32), and healthy individuals (n = 28) by PicoGreen, Cell Death Detection ELISA, Protease Fluorescent Detection Kit and Caspase-Glo^®3/7 Assay, respectively.</p> <p>Results</p> <p>Patients with benign and malignant tumors had significantly higher levels of circulating nucleic acids in their blood than healthy individuals (p = 0.001, p = 0.0001), whereas these levels could not discriminate between benign and malignant lesions. Our analyses of all serum samples revealed significant correlations of circulating nucleosome with DNA concentrations (p = 0.001), nucleosome concentrations with caspase activities (p = 0.008), and caspase with protease activities (p = 0.0001). High serum levels of protease and caspase activities associated with advanced tumor stages (p = 0.009). Patients with lymph node-positive breast cancer had significantly higher nucleosome levels in their blood than node-negative patients (p = 0.004). The presence of distant metastases associated with a significant increase in serum nucleosome (p = 0.01) and DNA levels (p = 0.04), and protease activities (p = 0.008).</p> <p>Conclusion</p> <p>Our findings demonstrate that high circulating nucleic acid concentrations in blood are no indicators of a malignant breast tumor. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the elevated serum levels of nucleosomes and DNA in blood are linked to breast cancer progression.</p

How Is the Issue of Overageing of Cocoa Farming Households Influenced by their Endowment with Livelihood Capitals?

The ageing of rural populations will negatively affect agricultural productivity and impact the socio-economic structure of rural communities. In Alto Beni, Bolivia, 70 % of the cocoa producers are over 50 years old and this ageing of cocoa farmers could lead to less productive cocoa farming and accelerate migration to urban areas. This study aims to describe the problem of ageing cocoa farmers in Alto Beni, how coping with old age is linked to households’ endowment with livelihood capitals and proposes measures to address the problem of ageing. 11 qualitative interviews were used to identify different perspectives on the problem of ageing in cocoa production in Alto Beni. Based on a survey with 120 farming households, it was assessed how households are equipped with different livelihood capitals and how a household’s livelihood endowment influences the way they deal with old age. The analysis of the qualitative interviews showed that older cocoa farmers work as long as their health permits. The main reasons for continuing working in old age are insufficient financial resources, a lack of formal pension and social security systems. If elderly farmers lived with their children, they were taken care of. Such farmers living alone belonged to the most impoverished group in Alto Beni with the lowest livelihood endowment. In addition, it is difficult for the older cocoa farmers to secure the farm take-over. The younger and partly also the older generation do not consider cocoa farming to be a livelihood-securing activity. Reasons for that perception are mainly low and fluctuating cocoa market prices and the use of inefficient cocoa production practices. The analysis of the livelihood survey showed that how cocoa farming households cope with ageing does not depend on the family’s endowment with livelihood capitals. The main influences on coping with old age are socio-cultural perceptions of cocoa farming and the insufficient pension system. Training and education in cocoa farming practices, more collaboration between cocoa farmers, their cooperatives and actors from international organisations, science and government could offset the ageing of cocoa farmers in Alto Beni

Die Nationalitätenfrage im Russischen Reich: Auswertung der Volkszählung von 1897

Zu den grundlegenden Vorrausetzungen nationaler Konflikte gehört die Verbindung nationaler mit sozialen Faktoren. Die Analyse der sozio-ethnischen Struktur des Russischen Reiches ist deshalb ein Desiderat historischer Forschung. Die einzige übergreifende Quelle für eine solche Untersuchung ist die russische Volkszählung von 1897. Der vorliegende Beitrag berichtet über ein Forschungsprojekt des Seminars für osteuropäische Geschichte der Universität Köln, das aus den 89 Bänden der Volkszählung eine Datenbank angelegt hat und auf dieser Basis die Nationalitätenfrage im Russischen Reich studiert. Über 130 ethnische Gruppen sind (aufgrund ihrer Muttersprache) registriert, und diese Daten sind mit einer Anzahl anderer Kategorien (Alter, Religion/Konfession, Beruf, Stand, Bildung, Krankheiten usw.) korreliert und in Tabellen zusammengefaßt. (pmb)'One of the basic preconditions for national conflicts is the connection and interdependancy of national and social factors. The analysis of the socio-ethnic structure of the late Russian Empire, the complex network of social strata and ethnic composure of the population was the main purpose of a research project which was carried out by A. Kappeler and his team at the Seminar for East-European History of the University of Cologne. As an outstanding source for this objective, the first Russian census of 1897 was evaluated which contains a wide variety of information. More than 130 ethnic groups have been registered with additional aggregated information about age, denomination, occupation, social position etc. All this data have been integrated after intensive operations concerning source criticism into a database which is now available at the Center for Historical Social Research for further research.' (author's abstract