B-cell activating factor BAFF reflects patients' immunological risk profile after kidney transplantation.

The B-cell activating factor BAFF plays an important role in the development and maturation of B-lymphocytes, which can contribute to the generation of donor-specific antibodies and thus may influence graft function and graft survival. Inconsistent data on the role of BAFF levels after renal transplantation for the formation of donor-specific antibodies and the contribution for allograft rejection exist. The aim of the current study was to determine to what extent the degree of pre-immunization is reflected by each patient's BAFF levels before transplantation and in the follow-up. Furthermore, the impact of BAFF on allograft rejection frequency as well as severity and resulting allograft function over time was analyzed. Additionally, the impact of viral infections on BAFF levels after transplantation - as a potential confounder - was examined. For this purpose, a group of pre-sensitized patients (PRA>0%, (52±24% on average), n=40) was compared with non-sensitized patients (PRA=0%, n=62) and in a subsequent analysis stratification in accordance to the detected BAFF level was performed. Pre-sensitized patients had significantly higher BAFF levels before transplantation and suffered significantly more often from early steroid-resistant, mainly antibody-mediated rejections. A result which was confirmed also in highly sensitized patients with PRA levels >50%. Additionally, in the follow-up patients with either rising BAFF levels over time or BAFF levels above the median also had significantly more often antibody mediated rejections. Additionally, patients with BAFF levels above detected median even displayed impaired creatinine values as well as an induced eGFR slope up to month 48 after transplantation. The occurrence of viral infections (CMV, BKV) was only an additional influencing factor in the absence of concomitant allograft rejections. Therefore, the B-cell proliferation factor BAFF appears not only to reflect the immunological risk profile of patients in the context of kidney transplantation, it may possibly be further developed as a predictor of patients with an increased risk profile for subsequent allograft rejection and impaired allograft function.

Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study.

Tamoxifen treatment for breast cancer increases proliferation of the endometrium, resulting in an enhanced prevalence of endometrial pathologies, including endometrial cancer. An exploratory study was performed to begin to understand the molecular mechanism of tamoxifen action in the endometrium. Gene-expression profiles were generated of endometrial samples of tamoxifen users and compared with matched controls. The pathological classification of samples from both groups included atrophic/inactive endometrium and endometrial polyps. Unsupervised clustering revealed that samples of tamoxifen users were, irrespective of pathological classification, fairly similar and consequently form a subgroup distinct from the matched controls. Using SAM analysis (a statistical method to select genes differentially expressed between groups), 256 differentially expressed genes were selected between the tamoxifen and control groups. Upon comparing these genes with oestrogen-regulated genes, identified under similar circumstances, 95% of the differentially expressed genes turned out to be tamoxifen-specific. Finally, construction of a gene-expression network of the differentially expressed genes revealed that 69 genes centred around five well-known genes: TP53, RELA, MYC, epidermal growth factor receptor and beta-catenin. This could indicate that these well-known genes, and the pathways in which they function, are important for tamoxifen-controlled proliferation of the endometrium.

Specific dose-dependent effects of ethane 1,2-dimethanesulfonate in rat and mouse Leydig cells and non-steroidogenic cells on programmed cell death.

The mechanism by which ethane 1,2-dimethanesulfonate (EDS) selectively kills Leydig cells is poorly understood. To characterize further the cell-specific actions of EDS, we studied biochemical and morphological changes during apoptosis in different Leydig cell and non-steroidogenic cell models. Rat testicular and H540 tumor Leydig cells were killed by 1-2 mM EDS, whereas 20 mM EDS were required for MA-10 cells. This higher concentration of EDS was also necessary for activation of apoptosis in non-steroidogenic Chinese hamster ovary cells, whereas COS-1 monkey kidney cells were resistant. These variable effects of EDS on apoptosis were independent of new protein synthesis and, interestingly, could be delayed by co-incubation with dibutyrl cyclic AMP. Along with cell death, we also observed chromosomal fragmentation and other hallmarks indicative of apoptosis as evidenced by DNA laddering and fluorescent microscopy. Time-lapse photography with a confocal microscope showed that the time of onset, duration and even the sequence of apoptotic events between individual H540 cells was heterogeneous. When the dose of EDS was gradually increased from 2 to 10 mM, the proportion of cells showing normal apoptotic features gradually decreased. Intriguingly, treatment with 10 mM EDS did not result in death for most cells and was marked by an absence of DNA laddering and ultrastructural features of apoptosis and necrosis. However, incubation with 20 mM EDS resulted in necrosis.These results demonstrated that the effects of EDS on cell survival are not specific to Leydig cells, that different cell types have different sensitivities to EDS and that stimulation of the cAMP pathway may mitigate EDS action. The data obtained with H540 cells further revealed that EDS can induce two types of programmed cell death.

Medium to long-term results with the cementless threaded Acetabular Munich II type cup.

Compared to pressfit cups, little information exists about the results of screwed cups in hip arthroplasty. 51 cementless or hybrid (cemented stem) primary total hip replacements with a cementless corundium blasted titaniumn alloy threaded Aesculap Munich II type cup were examined with a mean follow up of 7.9 years. 23 of the patients were male and 28 patients were female. From these cups 22 were implanted on the right side and 29 on the left. The results were compared to 53 patients (28 male, 25 female, 29 right side, 24 left side) with the threaded Aesculap Munich I type cup, that has a smooth surface and a direct contact of bone with the polyethylene inlay. The mean follow up ws 10.2 years. The early and medium to long-term clinical and radiographic results show an encouraging improvement of the Merle d'Aubigné Score of the type II cup compared to the type I cup. Two of the Aesculap type Munich II cups had to be revised; four showed radiologic signs of loosening. In conclusion, the threaded Aesculap cup type Munich II seems to be a decisive advance in the development of threaded acetabular hip cups. The intermediate results exceed those from smooth-surface screwed rings and compare favourably with those from cemented cups and with those from cementless press-fit metal-backed cups.

The Traveling Shutter Wave analyses non-linear compliance during mechanical ventilation.

Mechanical ventilation is an important, often life-saving component of modern intensive care medicine. However, it may further aggravate pulmonary pathology by endinspiratory overdistension of the alveoli or by their endexpiratory collapse. To prevent both the ventilator may be adjusted based on the slope of the pressure-volume curve, named as compliance, which is often determined by a stepwise inflation of the lungs. This maneuver gained no widespread clinical acceptance because of being cumbersome and invasive. Therefore, we developed a modification of the well known interrupter technique - the Traveling Shutter Wave. A wave of short-term (300 ms) occlusions "travels" over the tidal volume range. Differential compliance is calculated by division of volume and pressure differences between two adjacent occlusion maneuvers. The technique is well suited for the clinical setting because the ventilatory pattern does not need to be changed. This manuscript describes the realization of the Traveling Shutter Wave as well as its application in two patients.

A Data-Driven Approach to Hue-Preserving Color-Blending.

Color mapping and semitransparent layering play an important role in many visualization scenarios, such as information visualization and volume rendering. The combination of color and transparency is still dominated by standard alpha-compositing using the Porter-Duff over operator which can result in false colors with deceiving impact on the visualization. Other more advanced methods have also been proposed, but the problem is still far from being solved. Here we present an alternative to these existing methods specifically devised to avoid false colors and preserve visual depth ordering. Our approach is data driven and follows the recently formulated knowledge-assisted visualization (KAV) paradigm. Preference data, that have been gathered in web-based user surveys, are used to train a support-vector machine model for automatically predicting an optimized hue-preserving blending. We have applied the resulting model to both volume rendering and a specific information visualization technique, illustrative parallel coordinate plots. Comparative renderings show a significant improvement over previous approaches in the sense that false colors are completely removed and important properties such as depth ordering and blending vividness are better preserved. Due to the generality of the defined data-driven blending operator, it can be easily integrated also into other visualization frameworks.

Expression cloning and characterization of a novel sodium-dicarboxylate cotransporter from winter flounder kidney.

A cDNA coding for a Na+-dicarboxylate cotransporter, fNaDC-3, from winter flounder (Pseudopleuronectes americanus) kidney was isolated by functional expression in Xenopus laevis oocytes. The fNaDC-3 cDNA is 2384 nucleotides long and encodes a protein of 601 amino acids with a calculated molecular mass of 66.4 kDa. Secondary structure analysis predicts at least eight membrane-spanning domains. Transport of succinate by fNaDC-3 was sodium-dependent, could be inhibited by lithium, and evoked an inward current. The apparent affinity constant (Km) of fNaDC-3 for succinate of 30 microM resembles that of Na+-dicarboxylate transport in the basolateral membrane of mammalian renal proximal tubules. The substrates specific for the basolateral transporter, 2,3-dimethylsuccinate and cis-aconitate, not only inhibited succinate uptake but also evoked inward currents, proving that they are transported by fNaDC-3. Succinate transport via fNaDC-3 decreased by lowering pH, as did citrate transport, although much more moderately. These characteristics suggest that fNaDC-3 is a new type of Na+-dicarboxylate transporter that most likely corresponds to the Na+-dicarboxylate cotransporter in the basolateral membrane of mammalian renal proximal tubules.