Protein aggregation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.     

Nocturnal back pain; a misdiagnosed symptom of spinal tumor]

Four patients had nocturnal back pain or pain that worsened when lying down. In one of these, a 49-year-old man, the medical history mentioned a malignancy, as a result of which a spinal metastasis was suspected. In the other three patients, a 52-year old woman and two men aged 48 and 60 years, the nocturnal back pain and the back pain worsening when lying down was not recognised as indication of a spinal tumour. As objective neurological symptoms were not established at initial investigation, a long period of discomfort and frustration followed before the spinal tumour was diagnosed eventually. The importance of recognising these early complaints is stressed. Nowadays, MRI is the technique of choice to answer the question whether there is a space occupying process in the spine.     

Canada's national initiative to advance access to electronic journals

This paper describes a national experiment in the licensing of full text information in journals, primarily in the fields of science, technology and medicine. It discusses the initiative of the federal government of Canada through the creation of the Canada Foundation for Innovation as a new funding agency, with an objective of improving research and creativity in Canadian science. The successful efforts initiated by the Canadian Association of Research Libraries/Association des bibliothèques de recherche du Canada to create a funding opportunity to develop the 'information infrastructure' for Canadian researchers and the resulting Canadian National Site Licensing Project (CNSLP) progress is discussed. The evolution of a project governance structure to maintain the support of the 64 participating institutions is reviewed and the need to develop an appropriate exit strategy at the conclusion of the federal funding is also considered.     

Psychosomatic aspects of Menière's disease

The author presents a study of the personality structure, youth development and the role of interhuman conflicts in the work situation and the family, in the causation and course of Menière's disease, the somatopsychic reactions of the patients to the illness, and the principles of a form of psychotherapy which was combined with the regular E.N.T. check-ups and treatment. The results confirm and extend previous work by other researchers. A testable hypothesis about the specific psychosomatic etiology of Menière's disease is formulated and presented.     

JM216-, JM118-, and cisplatin-induced cytotoxicity in relation to platinum-DNA adduct formation,glutathione levels and p53 status in human tumour cell lines with different sensitivities to cisplatin

The aim of this study is to establish anti-tumour potency of the new oral platinum drug JM216 and its metabolite JM118 in relation to the platinum (Pt)-DNA adduct formation, glutathione (GSH)-levels, and p53 status in human cancer cell lines with different sensitivities to cisplatin (CDDP). These parameters were studied in the CDDP sensitive human germ cell cancer cell line Tera and the small-cell lung cancer cell line GLC4 and their sublines with in vitro acquired CDDP resistance, Tera-CP and GLC4-CDDP, in a human ovarian cancer cell line transfected with mutant p53 (A2780/mt273) and with an empty vector as control (A2780/cmv), and in the intrinsic CDDP resistant human non-small-cell lung cancer cell line SW1573/S1 and colon carcinoma cell line Caco-2. Cytotoxicity was tested with the microculture tetrazolium (MTT)-assay. Pt-DNA adduct levels were assessed immunocytochemically. Quantitative analysis was performed by double fluorescence video microscopy. Results were correlated with GSH levels and p53 status of the cell lines. This study showed that both JM216 and JM118 can partially circumvent intrinsic and acquired resistance to CDDP. Drug-induced cytotoxicity only correlated negatively with GSH levels for JM216 and CDDP in the tested unselected cell lines. At equimolar basis, JM216 induced lower levels of Pt-DNA adducts in the various cell lines than JM118 and CDDP, whereas the JM118-induced amount and pattern of Pt-DNA adducts was comparable to CDDP. No difference in initial Pt-DNA adducts levels was observed between cell lines sensitive, acquired or intrinsic resistant to CDDP suggesting a Pt-resistance mechanism based on tolerance or increased repair, rather than decreased initial Pt-DNA adduct formation.