Comparison of local intravascular drug-delivery catheter systems

Systemic and local delivery on the photosensitive drug Photofrin polyporphyrin was investigated in normal porcine arteries (n = 192). A macroporous balloon and a novel needle injection catheter were used for local drug delivery and compared with systemic delivery. Fluorescence microscopy combined with digital image analysis was used to quantify the drug-related fluorescence. Systemic delivery showed a maximum in the intima at 4 hours. Application with the porous balloon revealed maximum indicator-related fluorescence intensity in the intima after 5 minutes; delivery with the needle injection catheter resulted in a several-fold enhanced maximum in adventitia after 30 minutes compared with the maximum achieved with either systemic injection or porous balloon application. After 21 days fluorescence was detectable in arteries treated with the new needle injection catheter. Local drug delivery is feasible with either system, but prolonged delivery was achieved only with the needle injection catheter.     

Can corticosteroids be beaten in future asthma therapy?

Despite the enormous therapeutic advance, there is a general trend towards increasing morbidity and mortality due to asthma, which suggests that there is a need for new and improved treatments. The past decade was determined by the so-called "new biology" that identified and cloned almost all receptors and ion channels. This scientific revolution should lead to a more rapid identification of novel targets for major diseases and processes like high throughput screening and combinatorial chemistry should have improved and fastened the development of new drugs. Interestingly, exactly the opposite has happened. With the exception of leukotriene receptor antagonists and some monoclonal antibodies, no new developments have been introduced into asthma therapy during the last decade. The most promising approach is still to find drugs like corticosteroids with multiple functions. However, there is no evidence at the very moment that corticosteroids can be beaten in the next ten years. Therefore, our task is to improve the corticosteroids and make therapy with them even safer. The so-called soft-steroids such as loteprednol and etiprednol belong to the future promising therapeutically effective and safe treatments of allergic disorders.     

Expression of human Kallikrein 14 (KLK14) in breast cancer is associated with higher tumour grades and positive nodal status

Human kallikrein 14 (KLK14) is a steroid hormone-regulated member of the tissue kallikrein family of serine proteases, for which a prognostic and diagnostic value in breast cancer has been suggested. To further characterise the value of KLK14 as a breast tumour marker, we have carefully analysed KLK14 expression in normal breast tissue and breast cancer both on the RNA level by real-time RT-PCR (n = 39), and on the protein level (n = 127) using a KLK14-specific antibody for immunohistochemistry. We correlated KLK14 protein expression data with available clinico-pathological parameters (mean follow-up time was 55 months) including patient prognosis. KLK14 RNA expression as quantified by real-time RT-PCR was significantly more abundant in breast tumours compared to normal breast tissue (P = 0.027), an issue that had not been clarified recently. Concordantly with the RNA data, cytoplasmic KLK14 protein expression was significantly higher in invasive breast carcinomas compared to normal breast tissues (P = 0.003). Furthermore, KLK14 protein expression was associated with higher tumour grade (P = 0.041) and positive nodal status (P = 0.045) but was not significantly associated with shortened disease-free or overall patient survival time in univariate analyses. We conclude that KLK14 is clearly overexpressed in breast cancer in comparison to normal breast tissues and is positively associated with conventional parameters of tumour aggressiveness, but due to a missing association with survival times, the use of KLK14 immunohistochemistry as a prognostic marker in breast cancer is questionable.     

Naïve and central memory T-cell lymphopenia in end-stage renal disease

End-stage renal disease (ESRD) is associated with increased propensity to infections, diminished response to vaccination, impaired cell-mediated immunity, and reduced CD4+/CD8+ T-lymphocyte ratio. Four subsets of CD4+ and CD8+ T cells have been recently identified: na?ve cells (as yet uncommitted), central memory (CM) cells (previously programmed), and CD45RA-positive and CD45RA-negative effector memory (EM) cells (programmed to perform specific effector functions). The effect of ESRD on subpopulations of T lymphocytes is unclear and was studied here. Twenty-one hemodialysis patients and 21 age-matched controls were studied. Pre- and post-dialysis blood samples were obtained and analyzed by three-color flow cytometry. CD4+/CD8+ ratio and the numbers of the na?ve and CM CD4+ and CD8+ T cells were significantly reduced, whereas the numbers of EM CD4+ and CD8+ T cells were unchanged in the ESRD group. The reduction of the na?ve and CM T-cell counts in the ESRD group was associated with increased apoptosis of these cells. Negative correlations were found between severity of azotemia, oxidative stress, and hyperphosphatemia with the number of na?ve T cells. Comparison of diabetic with non-diabetic ESRD patients revealed higher numbers of total CD8+ cells and EM CD8+ T cells in the diabetic group. Dialysis did not significantly change the na?ve and CM CD4+ or CD8+ cell counts, but significantly lowered CD8+ EM cell count. Thus, ESRD results in increased apoptosis and diminished populations of na?ve and CM T lymphocytes. This phenomenon may, in part, contribute to the impaired immune response in this population.     

Dental services for children with mental handicaps: policy changes and parental choices

Dental services for children with mental handicaps are subject to conflicting policies. On the one hand, the community dental service is being asked to move towards a more specialised role and to focus on disadvantaged groups such as people with mental handicaps. On the other hand, policies for community care have stressed that handicapped people are stigmatised by specialised provision and should have access to all the services used by non-handicapped people. A longitudinal study of 162 mentally handicapped children provided an opportunity to assess parents' opinions on this issue. The results showed high levels of contact with the dental services. Most parents were satisfied with the care their children had received, although there was some suggestion of a preference for receiving care from the general dental practitioner service. However, parents whose children were hard to manage tended to prefer the more specialised care provided by the community dental service. The results of the study suggested that there is a continuing role for the community dental service and that general dental practitioners may need support from the community dental service to help them meet the demands of parents whose children have a mental handicap.     

Adenovirus type 35, but not type 5, stimulates NK cell activation via plasmacytoid dendritic cells and TLR9 signaling

In hematopoietic stem cell transplant (HSCT) recipients, disseminated adenoviral infections during the first two months after HSCT can lead to severe complications and fatal outcome. Since NK cells are usually the first lymphocytes to reconstitute after HSCT and have been implicated in the clearance of adenovirus-infected cells, it was investigated whether NK cells are activated by adenovirus in vitro. Exposure of PBMC to human adenovirus type 5 (HAdV5) or HAdV35 resulted in the up-regulation of the activation marker CD69 on NK cells and enhanced the cytolytic activity of NK cells. HAdV5-induced NK cell activation relied on the contribution of T cells as the depletion of T cells from PBMC abolished NK cell activation. In contrast, NK cell activation in response to HAdV35 occurred in the absence of T cells. Plasmacytoid dendritic cells (pDC) were necessary and sufficient to mediate NK cell activation. HAdV35 induced significantly more interferon-α (IFN-α) production by pDC than HAdV5. The increased IFN-α production and NK cell activation correlated with a higher infection efficiency of viruses with the type 35 fiber. The IFN-α response of pDC was enhanced by the presence of NK cells, suggesting a reciprocal interaction between pDC and NK cells. Incubation with a TLR9 antagonist impaired the IFN-α production by pDC as well as NK cell activation, implying that TLR9 signaling is critically involved in the IFN-α response of pDC and NK cell activation after HAdV35 exposure. In conclusion, two human adenovirus serotypes from two different species differ considerably in their capacity to stimulate pDC and NK cells.     

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2(V617F) expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.