Adenoviral p53 gene transfer and gemcitabine in three patients with liver metastases due to advanced pancreatic carcinoma

Background. Current therapies for adenocarcinoma of the pancreas do not improve the life expectancy of patients. Methods. In a non-randomized pilot trail we tested whether a local therapy based upon an adenoviral gene transfer of wild type p53 in combination with gemcitabine administration would be safe in patients with liver metastases due to pancreatic carcinoma. We report on the clinical course of three patients with respect to safety, tolerability and tumor response. Results. Transient grade III toxicities occurred with fever, leucopenia, elevation of AP, ALT, AST, GGT, while grade IV toxicity occurred for bilirubin only. Laboratory tests suggested disseminated intravascular coagulation in all three patients, but fine needle biopsies of liver did not show any histological evidence of thrombus or clot formation. Progression of liver metastases was documented in one and stable disease in another patient two months after treatment. However, a major improvement with regression of the indexed lesion by 80% occurred in a third patient after a single administration of 7.5×10¹² viral particles, and time to progression was extended to six months. Conclusion. The combination therapy of viral gene transfer and chemotherapy temporarily controls and diminishes tumor burden. Improvement of the toxicity profile is necessary. Further trials are warranted to improve treatment and life expectancy of patients suffering from fatal diseases such as pancreatic carcinoma.     

Kisspeptins and the placenta: Regulation of trophoblast invasion

The invasion of extravillous trophoblasts into the uterine wall is of crucial importance for placental and fetal development, and its dysregulation has been implicated in a wide spectrum of abnormal pregnancies. Mechanistically, trophoblast invasion strongly resembles the invasion of tumour cells, but differs from it by tight regulation in time and space. This regulation is accomplished by different factors including cytokines and hormones, which are produced by both fetal as well as maternal tissues i.e., placenta and uterus, respectively. Recently, products of the KiSS-1 gene (kisspeptins) have been identified to not only inhibit metastasis in various tumours, but also to repress trophoblast invasion via binding to the G protein-coupled receptor KiSS-1R. In the placenta, expression levels of kisspeptins and their receptor are highest in the first trimester in humans and at day 12.5 in rats, respectively. This coincides with the time when invasiveness peaks and invasion regulation is of central importance. Human kisspeptins are predominantly produced by the syncytiotrophoblast, whereas KiSS-1R is additionally expressed on the invading extravillous trophoblasts indicating a paracrine regulation of extravillous trophoblast invasion by the syncytiotrophoblast. In the structurally different rat placenta both KiSS-1 and its receptor are predominantly expressed by the invasive trophoblast giant cells, thus establishing an autocrine system in the invasion regulation of this trophoblast subpopulation. Amongst all kisspeptins the highly conserved kisspeptin Kp-10 has strongest invasion inhibiting effects suggesting its major role in regulation of trophoblast invasion.     

Verhaltenssucht

Until recently knowledge was limited with respect to clinically relevant excessive reward-seeking behaviour such as pathological gambling, excessive shopping, and excessive working which meet diagnostic criteria of dependent behaviour. To date there is no consistent concept for diagnosis or treatment of excessive reward-seeking behaviour, and its classification is uncertain. However, the high number of subjects seeking treatment emphasises the importance of a clear conceptualisation of the so-called behavioural addictions and their successful treatment. Excessive reward-seeking behaviour may be used to regulate negative emotions. We suggest that, comparable to drug addiction, excessive reward-seeking behaviour can alleviate negative mood states and may be used as an (inadequate) stress coping strategy at the expense of active coping strategies. In the course of a pathological development, behavioural addiction may become the only available behavioural resource to cope with challenging developmental steps or social stress factors such as loneliness or anxiety.     

Trends in suicide rates of the elderly in Austria, 1970-2004: an analysis of changes in terms of age groups, suicide methods and gender

BACKGROUND: Suicides of the elderly (persons aged 65 and older) make up a large proportion of total suicides. Since suicide rates of the elderly are highest in western populations, addressing them as a risk group in prevention plans has been recommended. In order to assess possible approaches to prevention strategies, this study examines high-risk groups of the elderly. METHODS: We examined official statistics on suicides that occurred in Austria between 1970-2004 (18,101 Suicides of the elderly). We analyzed time trends and differences in suicide methods as well as in age groups and both genders of the elderly. RESULTS: Three major high-risk groups were identified: elderly male suicides by firearms; elderly female suicides by poisoning, which occur more often with increasing age; and suicides of both genders by jumping from heights. CONCLUSION: Besides conducting treatment of psychiatric disorders of the elderly, restricting the means to commit suicide may help to prevent it among the elderly. Such specific prevention strategies should be implemented in national suicide prevention plans for the high-risk groups identified in this study.     

Coagulation factor concentrates: past, present, and future

Clotting factor transfusions are vital for people with diseases such as haemophilia. In the 1970s and 1980s, transfusions with pooled plasma led to a devastatingly high number of recipients becoming infected with blood-borne pathogens such as HIV and hepatitis C. This epidemic triggered the development of virus-free factor concentrates through a combination of improved donor selection and screening, effective virucidal technologies, and recombinant protein expression biotechnology. There is now a wide range of recombinant factor concentrates, and an impressive safety record with respect to pathogen transmission. However, remaining therapeutic challenges include the potential threat of transmission of prions and other pathogens, the formation of inhibitory alloantibodies, and the international disparity that exists in product availability due to differences in licensure status as well as prohibitively high costs. In the future, it is likely that bioengineered recombinant proteins that have been modified to enhance pharmacokinetic properties or reduce immunogenicity, or both, will be used increasingly in clinical practice.     

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Abeta protofibrils

The formation of amyloid fibrils is a common biochemical characteristic that occurs in Alzheimer's disease and several other amyloidoses. The unifying structural feature of amyloid fibrils is their specific type of beta-sheet conformation that differentiates these fibrils from the products of normal protein folding reactions. Here we describe the generation of an antibody domain, termed B10, that recognizes an amyloid-specific and conformationally defined epitope. This antibody domain was selected by phage-display from a recombinant library of camelid antibody domains. Surface plasmon resonance, immunoblots, and immunohistochemistry show that this antibody domain distinguishes Abeta amyloid fibrils from disaggregated Abeta peptide as well as from specific Abeta oligomers. The antibody domain possesses functional activity in preventing the formation of mature amyloid fibrils by stabilizing Abeta protofibrils. These data suggest possible applications of B10 in the detection of amyloid fibrils or in the modulation of their formation.     

Seronegative Lyme Neuroborreliosis in a Patient on Treatment for Chronic Lymphatic Leukemia

Abstract We report on a patient who developed seronegative Lyme neuroborreliosis complicating chemotherapy for chronic lymphatic leukemia. After the fifth cycle of chemotherapy (FCR: fludarabine, cyclophosphamide, rituximab and prednisone) the 63-year-old patient developed night sweat, arthralgia in elbows, wrists, proximal interphalangeal joints (PIPs) and strong neuropathic pain in both legs, followed by paresthesia and hypesthesia in the feet, arms and face. Laboratory analysis revealed an elevated C-reactive protein (CRP), a slight elevation of liver enzymes and decreased IgG levels. Cerebrospinal fluid (CSF) analysis showed a lymphomononuclear pleocytosis and an elevation of protein. A broad diagnostic work-up was negative including a negative Borrelia IgG and IgM ELISA. The patient did not remember recent tick bites, but after specific questioning he recollected a transient erythema on his leg developing just before the start of the last cycle of chemotherapy. As the combination of neuropathic pain and arthralgia, the transient erythema and the lymphomononuclear pleocytosis raised the suspicion of Lyme neuroborreliosis, the patient was treated for 3 weeks with ceftriaxone. On therapy all symptoms resolved and CRP normalized. Retrospective PCR analysis of a CSF sample confirmed the clinical diagnosis by detecting Borrelia garinii DNA. This case demonstrates that in immunosuppressed patients borrelial serology may be negative and that additional diagnostic approaches (including tests for direct Borrelia detection) may be needed to demonstrate borrelial infection.