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Background Ongoing changes in cancer care cause an increase in the complexity of cases which is characterized by modern treatment techniques and a higher demand for patient information about the underlying disease and therapeutic options. At the same time, the restructuring of health services and reduced funding have led to the downsizing of hospital care services. These trends strongly influence the workplace environment and are a potential source of stress and burnout among professionals working in radiotherapy. Methods and patients A postal survey was sent to members of the workgroup "Quality of Life" which is part of DEGRO (German Society for Radiooncology). Thus far, 11 departments have answered the survey. 406 (76.1%) out of 534 cancer care workers (23% physicians, 35% radiographers, 31% nurses, 11% physicists) from 8 university hospitals and 3 general hospitals completed the FBAS form (Stress Questionnaire of Physicians and Nurses; 42 items, 7 scales), and a self-designed questionnaire regarding work situation and one question on global job satisfaction. Furthermore, the participants could make voluntary suggestions about how to improve their situation. Results Nurses and physicians showed the highest level of job stress (total score 2.2 and 2.1). The greatest source of job stress (physicians, nurses and radiographers) stemmed from structural conditions (e.g. underpayment, ringing of the telephone) a "stress by compassion" (e.g. "long suffering of patients", "patients will be kept alive using all available resources against the conviction of staff"). In multivariate analyses professional group (p < 0.001), working night shifts (p = 0.001), age group (p = 0.012) and free time compensation (p = 0.024) gained significance for total FBAS score. Global job satisfaction was 4.1 on a 9-point scale (from 1 – very satisfied to 9 – not satisfied). Comparing the total stress scores of the hospitals and job groups we found significant differences in nurses (p = 0.005) and physicists (p = 0.042) and a borderline significance in physicians (p = 0.052). In multivariate analyses "professional group" (p = 0.006) and "vocational experience" (p = 0.036) were associated with job satisfaction (cancer care workers with < 2 years of vocational experience having a higher global job satisfaction). The total FBAS score correlated with job satisfaction (Spearman-Rho = 0.40; p < 0.001). Conclusion Current workplace environments have a negative impact on stress levels and the satisfaction of radiotherapy staff. Identification and removal of the above-mentioned critical points requires various changes which should lead to the reduction of stress.
Mitochondria are essential for respiration and oxidative phosphorylation. Mitochondrial dysfunction due to aging processes is involved in pathologies and pathogenesis of a series of cardiovascular disorders. New results accumulate showing that the enzyme telomerase with its catalytic subunit telomerase reverse transcriptase (TERT) has a beneficial effect on heart functions. The benefit of short-term running of mice for heart function is dependent on TERT expression. TERT can translocate into the mitochondria and mitochondrial TERT (mtTERT) is protective against stress induced stimuli and binds to mitochondrial DNA (mtDNA). Because mtDNA is highly susceptible to damage produced by reactive oxygen species (ROS) which are generated in close proximity to the respiratory chain, the aim of this study was to determine the functions of mtTERT in vivo and in vitro. Therefore, mitochondria from hearts of adult, 2nd generation TERT-deficient mice (TERT -/-) and wt littermates were isolated and state 3 respiration was measured. Strikingly mitochondria from TERT -/- revealed a significantly lower state 3 respiration (TERTwt: 987 +/- 72 pmol/s*mg vs. TERT-/-: 774 +/- 38 pmol/s*mg, p < 0.05, n = 5). These results demonstrated that TERT -/- mice have a so far undiscovered heart phenotype. In contrast mitochondria isolated from liver tissues did not show any differences. To get further insights in the molecular mechanisms, we reduced endogenous TERT levels by shRNA and measured mitochondrial reactive oxygen species (mtROS). mtROS were increased after ablation of TERT (scrambled: 4.98 +/- 1.1% gated vs. shTERT: 2.03 +/- 0.7% gated, p < 0.05, n = 4). We next determined mtDNA deletions, which are caused by mtROS. Semiquantitative realtime PCR of mtDNA deletions revealed that mtTERT protects mtDNA from oxidative damage. To analyze whether mitochondrial integrity is required to protect from apoptosis, vectors with mitochondrially targeted TERT (mitoTERT) and wildtype TERT (wtTERT) were transfected and apoptosis was measured. mitoTERT showed the most prominent protective effect on H2O2 induced apoptosis. In conclusion, mtTERT has a protective role in mitochondria by importantly contributing to mtDNA integrity and thereby enhancing respiration capacity of the heart.
Introduction: Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.
Methods: Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.
Results: A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.
Conclusions: Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.
Background Imatinib mesylate, a selective inhibitor of Abl tyrosine kinase, is efficacious in treating chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL). However, most advanced-phase CML and Ph+ ALL patients relapse on Imatinib therapy. Several mechanisms of refractoriness have been reported, including the activation of the Src-family kinases (SFK). Here, we investigated the biological effect of the new specific dual Src/Abl kinase inhibitor AZD0530 on Ph+ leukaemic cells. Methods Cell lines used included BV173 (CML in myeloid blast crisis), SEM t(4;11), Ba/F3 (IL-3 dependent murine pro B), p185Bcr-Abl infected Ba/F3 cells, p185Bcr-Abl mutant infected Ba/F3 cells, SupB15 (Ph+ ALL) and Imatinib resistant SupB15 (RTSupB15) (Ph+ ALL) cells. Cells were exposed to AZD0530 and Imatinib. Cell proliferation, apoptosis, survival and signalling pathways were assessed by dye exclusion, flow cytometry and Western blotting respectively. Results AZD0530 specifically inhibited the growth of, and induced apoptosis in CML and Ph+ ALL cells in a dose dependent manner, but showed only marginal effects on Ph- ALL cells. Resistance to Imatinib due to the mutation Y253F in p185Bcr-Abl was overcome by AZD0530. Combination of AZD0530 and Imatinib showed an additive inhibitory effect on the proliferation of CML BV173 cells but not on Ph+ ALL SupB15 cells. An ongoing transphosphorylation was demonstrated between SFKs and Bcr-Abl. AZD0530 significantly down-regulated the activation of survival signalling pathways in Ph+ cells, resistant or sensitive to Imatinib, with the exception of the RTSupB15. Conclusion Our results indicate that AZD0530 targets both Src and Bcr-Abl kinase activity and reduces the leukaemic maintenance by Bcr-Abl.
Background The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. Methods In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. Results Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. Conclusion Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. Trial registration : ISRCTN66478538
Background The differential diagnosis between follicular thyroid adenoma and minimal invasive follicular thyroid carcinoma is often difficult for several reasons. One major aspect is the lack of typical cytological criteria in well differentiated specimens. New marker molecules, shown by poly- or monoclonal antibodies proved helpful. Methods We performed global gene expression analysis of 12 follicular thyroid tumours (4 follicular adenomas, 4 minimal invasive follicular carcinomas and 4 widely invasive follicular carcinomas), followed by immunohistochemical staining of 149 cases. The specificity of the antibody was validated by western blot analysis Results In gene expression analysis QPRT was detected as differently expressed between follicular thyroid adenoma and follicular thyroid carcinoma. QPRT protein could be detected by immunohistochemistry in 65% of follicular thyroid carcinomas including minimal invasive variant and only 22% of follicular adenomas. Conclusion Consequently, QPRT is a potential new marker for the immunohistochemical screening of follicular thyroid nodules.
Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B2 receptors (B2R). Here we report that C57BL/6.B2R-/- mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R+/+ mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B2R-/- heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-gamma-producing CD4+ and CD8+ T cells in the spleen of B2R-/- and wild-type mice. However, production of IFN-gamma by effector T cells isolated from B2R-/- heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-gamma-producing (CD4+CD44+ and CD8+CD44+) T cells both in the spleen and heart while B2R-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R-/- mice was linked to upregulated secretion of IL-17 and TNF-alpha by antigen-responsive CD4+ T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c+ DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c+ DCs isolated from B2R+/+ spleen, but not by DCs from B2R-/- mice. Notably, adoptive transfer of B2R+/+ CD11c+ DCs (intravenously) into B2R-/- mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed TH17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection. Author Summary: Antibodies and IFN-gamma-producing effector T cells are essential for the immune control of infection by Trypanosoma cruzi, the intracellular protozoa that causes human Chagas disease. Despite the potency of anti-parasite immunity, the parasites are not cleared from their intracellular niches. Instead, a low grade chronic infection prevails, provoking severe immunopathology in the myocardium. Although it is well established that innate sentinel cells sense T. cruzi through receptors for microbial structures, such as Toll-like receptors, it remained unclear whether endogenous inflammatory signals also contribute to the development of adaptive immunity. The present study was motivated by awareness that T. cruzi trypomastigotes (extracellular infective forms) are equipped with proteases that liberate the pro-inflammatory bradykinin peptide from an internal segment of kininogens. Here we demonstrate that splenic dendritic cells (DCs), the antigen-presenting cells that coordinate the adaptive branch of immunity in lymphoid tissues, are potently activated via G-protein-coupled bradykinin B2 receptors (B2R). Analysis of the outcome of infection in B2R-knockout mice revealed that the mutant mice developed a typical susceptible phenotype, owing to impaired development of IFN-gamma-producing effector T cells. Notably, the immune dysfunction of B2R-knockout mice was corrected upon cell transfer of wild-type DCs, thus linking development of protective T cells to DCs' sensing of endogenous danger signals (kinins) released by trypomastigotes.
Die derzeitige Therapie der chronischen Hepatitis C ist komplex und mit zahlreichen Nebenwirkungen assoziiert. Um den Therapieerfolg frühzeitig vorhersagen zu können und die Behandlung individuell zu optimieren, greifen Forscher des Frankfurter Leberzentrums auf mathematische Modellierung zurück. ...
The timing of feedback to early visual cortex in the perception of long-range apparent motion
(2008)
When 2 visual stimuli are presented one after another in different locations, they are often perceived as one, but moving object. Feedback from area human motion complex hMT/V5+ to V1 has been hypothesized to play an important role in this illusory perception of motion. We measured event-related responses to illusory motion stimuli of varying apparent motion (AM) content and retinal location using Electroencephalography. Detectable cortical stimulus processing started around 60-ms poststimulus in area V1. This component was insensitive to AM content and sequential stimulus presentation. Sensitivity to AM content was observed starting around 90 ms post the second stimulus of a sequence and most likely originated in area hMT/V5+. This AM sensitive response was insensitive to retinal stimulus position. The stimulus sequence related response started to be sensitive to retinal stimulus position at a longer latency of 110 ms. We interpret our findings as evidence for feedback from area hMT/V5+ or a related motion processing area to early visual cortices (V1, V2, V3).
Background The successful use of zirconia ceramics in orthopedic surgery led to a demand for dental zirconium-based implant systems. Because of its excellent biomechanical characteristics, biocompatibility, and bright tooth-like color, zirconia (zirconium dioxide, ZrO2) has the potential to become a substitute for titanium as dental implant material. The present study aimed at investigating the osseointegration of zirconia implants with modified ablative surface at an ultrastructural level. Methods A total of 24 zirconia implants with modified ablative surfaces and 24 titanium implants all of similar shape and surface structure were inserted into the tibia of 12 Gottinger minipigs. Block biopsies were harvested 1 week, 4 weeks or 12 weeks (four animals each) after surgery. Scanning electron microscopy (SEM) analysis was performed at the bone implant interface. Results Remarkable bone attachment was already seen after 1 week which increased further to intimate bone contact after 4 weeks, observed on both zirconia and titanium implant surfaces. After 12 weeks, osseointegration without interposition of an interfacial layer was detected. At the ultrastructural level, there was no obvious difference between the osseointegration of zirconia implants with modified ablative surfaces and titanium implants with a similar surface topography. Conclusion The results of this study indicate similar osseointegration of zirconia and titanium implants at the ultrastructural level.
We here report the complete nucleotide sequence of the 47.9 kb mitochondrial (mt) genome from the obligate aerobic yeast Yarrowia lipolytica. It encodes, all on the same strand, seven subunits of NADH: ubiquinone oxidoreductase (ND1-6, ND4L), apocytochrome b (COB), three subunits of cytochrome oxidase (COX1, 2, 3), three subunits of ATP synthetase (ATP6, 8 and 9), small and large ribosomal RNAs and an incomplete set of tRNAs. The Y. lipolytica mt genome is very similar to the Hansenula wingei mt genome, as judged from blocks of conserved gene order and from sequence homology. The extra DNA in the Y. lipolytica mt genome consists of 17 group 1 introns and stretches of A+Trich sequence, interspersed with potentially transposable GC clusters. The usual mould mt genetic code is used. Interestingly, there is no tRNA able to read CGN (arginine) codons. CGN codons could not be found in exonic open reading frames, whereas they do occur in intronic open reading frames. However, several of the intronic open reading frames have accumulated mutations and must be regarded as pseudogenes. We propose that this may have been triggered by the presence of untranslatable CGN codons. This sequence is available under EMBL Accession No. AJ307410.
Infliximab is a monoclonal antibody directed against TNF-alpha. It has been approved for use in rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis and plaque-type psoriasis. In case reports, positive effects on pustular variants of psoriasis have also been reported. However, paradoxically, manifestation of pustular psoriasis and plaque-type psoriasis has been reported in patients treated with TNF antagonists including infliximab for other indications. Here, we report on 5 patients with chronic plaque-type psoriasis who developed palmoplantar pustulosis during or after discontinuation of infliximab therapy. In two of the five cases, manifestation of palmoplantar pustulosis was not accompanied by worsening of plaque-type psoriasis. Possibly, site-specific factors or a differential contribution of immunological processes modulated by TNF inhibitors to palmoplantar pustulosis and plaque-type psoriasis may have played a role.
Transcriptional activation involves the ordered recruitment of coactivators via direct interactions between distinct binding domains and recognition motifs. The p160/SRC/NCoA coactivator family comprises three members (NCoA-1, -2 and -3), which are organized in multiprotein coactivator complexes. We had identified the PAS-B domain of NCoA-1 as an LXXLL motif binding domain. Here we show that NCoA family members are able to interact with other full-length NCoA proteins via their PAS-B domain and they specifically interact with the CBP-interaction domain (CID/AD1) of NCoA-1. Peptide competition, binding experiments and mutagenesis of LXXLL motifs point at distinct binding motif specificities of the NCoA PAS-B domains. NMR studies of different NCoA-1-PAS-B/LXXLL peptide complexes revealed similar although not identical binding sites for the CID/AD1 and STAT6 transactivation domain LXXLL motifs. In mechanistic studies, we found that overexpression of the PAS-B domain is able to disturb the binding of NCoA-1 to CBP in cells and that a CID/AD1 peptide competes with STAT6 for NCoA-1 in vitro. Moreover, the expression of an endogenous androgen receptor target gene is affected by the overexpression of the NCoA-1 or NCoA-3 PAS-B domains. Our study discloses a new, complementary mechanism for the current model of coactivator recruitment to target gene promoters.
Gene trapping is used to introduce insertional mutations into genes of mouse embryonic stem cells (ESCs). It is performed with gene trap vectors that simultaneously mutate and report the expression of the endogenous gene at the site of insertion and provide a DNA tag for rapid identification of the disrupted gene. Gene traps have been employed worldwide to assemble libraries of mouse ESC lines harboring mutations in single genes, which can be used to make mutant mice. However, most of the employed gene trap vectors require gene expression for reporting a gene trap event and therefore genes that are poorly expressed may be under-represented in the existing libraries. To address this problem, we have developed a novel class of gene trap vectors that can induce gene expression at insertion sites, thereby bypassing the problem of intrinsic poor expression. We show here that the insertion of the osteopontin enhancer into several conventional gene trap vectors significantly increases the gene trapping efficiency in high-throughput screens and facilitates the recovery of poorly expressed genes.
Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ~18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions.
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.
While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21ras and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21ras -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyper-activation of the ERK pathway relative to wild-type cells. RNAi knock down (KD) of SKAP-55 in T-cell lines also showed an increase in p21ras activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21ras activating exchange factor RasGRP1 in the process. Firstly, SKAP-55 bound to RasGRP1 via its C-terminus, while secondly, the loss of binding abrogated SKAP-55 inhibition of ERK and ELK activation. Thirdly, SKAP-55−/− primary T-cells showed an increased presence of RasGRP1 in the trans-Golgi network (TGN) following TCR activation, the site where p21ras becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21ras-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion.
Background: Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from ß-cell autoimmunity.
Methods: We investigated the role of the -2221Msp(C/T) and -23HphI(A/T) polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317), Addison´s disease (AD, n = 107) or Hashimoto´s thyroiditis (HT, n = 61)], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62) as well as in healthy controls (HC, n = 275).
Results: T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T) and "AA" -23HphI(A/T) polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively). The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC.
Conclusion: We demonstrate that the allele "C" of the -2221Msp(C/T) and "A" -23HphI(A/T) insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II.
Introduction To investigate the predictive value of clinical and biological markers for a pathological complete remission after a preoperative dose-dense regimen of doxorubicin and docetaxel, with or without tamoxifen, in primary operable breast cancer. Methods Patients with a histologically confirmed diagnosis of previously untreated, operable, and measurable primary breast cancer (tumour (T), nodes (N) and metastases (M) score: T2-3(>= 3 cm) N0-2 M0) were treated in a prospectively randomised trial with four cycles of dose-dense (bi-weekly) doxorubicin and docetaxel (ddAT) chemotherapy, with or without tamoxifen, prior to surgery. Clinical and pathological parameters (menopausal status, clinical tumour size and nodal status, grade, and clinical response after two cycles) and a panel of biomarkers (oestrogen and progesterone receptors, Ki-67, human epidermal growth factor receptor 2 (HER2), p53, bcl-2, all detected by immunohistochemistry) were correlated with the detection of a pathological complete response (pCR). Results A pCR was observed in 9.7% in 248 patients randomised in the study and in 8.6% in the subset of 196 patients with available tumour tissue. Clinically negative axillary lymph nodes, poor tumour differentiation, negative oestrogen receptor status, negative progesterone receptor status, and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic regression model, whereas in a multivariate analysis only the clinical nodal status and hormonal receptor status provided significantly independent information. Backward stepwise logistic regression revealed a response after two cycles, with hormone receptor status and lymph-node status as significant predictors. Patients with a low percentage of cells stained positive for Ki-67 showed a better response when treated with tamoxifen, whereas patients with a high percentage of Ki-67 positive cells did not have an additional benefit when treated with tamoxifen. Tumours overexpressing HER2 showed a similar response to that in HER2-negative patients when treated without tamoxifen, but when HER2-positive tumours were treated with tamoxifen, no pCR was observed. Conclusion Reliable prediction of a pathological complete response after preoperative chemotherapy is not possible with clinical and biological factors routinely determined before start of treatment. The response after two cycles of chemotherapy is a strong but dependent predictor. The only independent factor in this subset of patients was bcl-2. Trial registration number NCT00543829
Background This study was carried out to compare the HRQoL of patients in general practice with differing chronic diseases with the HRQoL of patients without chronic conditions, to evaluate the HRQoL of general practice patients in Germany compared with the HRQoL of the general population, and to explore the influence of different chronic diseases on patients HRQoL, independently of the effects of multiple confounding variables. Methods A cross-sectional questionnaire survey including the SF-36, the EQ-5D and demographic questions was conducted in 20 general practices in Germany. 1009 consecutive patients aged 15–89 participated. The SF-36 scale scores of general practice patients with differing chronic diseases were compared with those of patients without chronic conditions. Differences in the SF-36 scale/summary scores and proportions in the EQ-5D dimensions between patients and the general population were analyzed. Independent effects of chronic conditions and demographic variables on the HRQoL were analyzed using multivariable linear regression and polynomial regression models. Results The HRQoL for general practice patients with differing chronic diseases tended to show more physical than mental health impairments compared with the reference group of patients without. Patients in general practice in Germany had considerably lower SF-36 scores than the general population (P < 0.001 for all) and showed significantly higher proportions of problems in all EQ-5D dimensions except for the self-care dimension (P < 0.001 for all). The mean EQ VAS for general practice patients was lower than that for the general population (69.2 versus 77.4, P < 0.001). The HRQoL for general practice patients in Germany seemed to be more strongly affected by diseases like depression, back pain, OA of the knee, and cancer than by hypertension and diabetes. Conclusion General practice patients with differing chronic diseases in Germany had impaired quality of life, especially in terms of physical health. The independent impacts on the HRQoL were different depending on the type of chronic disease. Findings from this study might help health professionals to concern more influential diseases in primary care from the patient´s perspective.
Objectives To examine the dose-response relationship between cumulative exposure to kneeling and squatting as well as to lifting and carrying of loads and symptomatic knee osteoarthritis (OA) in a population-based case-control study. Methods In five orthopedic clinics and five practices we recruited 295 male patients aged 25 to 70 with radiographically confirmed knee osteoarthritis associated with chronic complaints. A total of 327 male control subjects were recruited. Data were gathered in a structured personal interview. To calculate cumulative exposure, the self-reported duration of kneeling and squatting as well as the duration of lifting and carrying of loads were summed up over the entire working life. Results The results of our study support a dose-response relationship between kneeling/squatting and symptomatic knee osteoarthritis. For a cumulative exposure to kneeling and squatting > 10.800 hours, the risk of having radiographically confirmed knee osteoarthritis as measured by the odds ratio (adjusted for age, region, weight, jogging/athletics, and lifting or carrying of loads) is 2.4 (95% CI 1.1-5.0) compared to unexposed subjects. Lifting and carrying of loads is significantly associated with knee osteoarthritis independent of kneeling or similar activities. Conclusions As the knee osteoarthritis risk is strongly elevated in occupations that involve both kneeling/squatting and heavy lifting/carrying, preventive efforts should particularly focus on these "high-risk occupations".
Background The EGF receptor has been shown to internalize via clathrin-independent endocytosis (CIE) in a ligand concentration dependent manner. From a modeling point of view, this resembles an ultrasensitive response, which is the ability of signaling networks to suppress a response for low input values and to increase to a pre-defined level for inputs exceeding a certain threshold. Several mechanisms to generate this behaviour have been described theoretically, the underlying assumptions of which, however, have not been experimentally demonstrated for the EGF receptor internalization network. Results Here, we present a mathematical model of receptor sorting into alternative pathways that explains the EGF-concentration dependent response of CIE. The described mechanism involves a saturation effect of the dominant clathrin-dependent endocytosis pathway and implies distinct steady-states into which the system is forced for low vs high EGF stimulations. The model is minimal since no experimentally unjustified reactions or parameter assumptions are imposed. We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached. Further, we describe extensibility of the model to more than two pathways which might play a role in contexts other than receptor internalization. Conclusions Our main result is that a scenario where different endocytosis routes consume the same form of receptor corroborates the observation of a clear-cut, stimulus dependent sorting. This is especially important since a receptor modification discriminating between the pathways has not been found. The model is not restricted to EGF receptor internalization and might account for ultrasensitivity in other cellular contexts.
Background Medical students come into contact with infectious diseases early on their career. Immunity against vaccine-preventable diseases is therefore vital for both medical students and the patients with whom they come into contact. Methods The purpose of this study was to compare the medical history and serological status of selected vaccine-preventable diseases of medical students in Germany. Results The overall correlation between medical history statements and serological findings among the 150 students studied was 86.7 %, 66.7 %, 78 % and 93.3 % for measles, mumps, rubella and varicella, conditional on sufficient immunity being achieved after one vaccination. Conclusions Although 81.2 % of the students medical history data correlated with serological findings, significant gaps in immunity were found. Our findings indicate that medical history alone is not a reliable screening tool for immunity against the vaccine-preventable diseases studied.
Background The inhibitor telaprevir (VX-950) of the hepatitis C virus (HCV) protease NS3-4A has been tested in a recent phase 1b clinical trial in patients infected with HCV genotype 1. This trial revealed residue mutations that confer varying degrees of drug resistance. In particular, two protease positions with the mutations V36A/G/L/M and T54A/S were associated with low to medium levels of drug resistance during viral breakthrough, together with only an intermediate reduction of viral replication fitness. These mutations are located in the protein interior and far away from the ligand binding pocket. Results Based on the available experimental structures of NS3-4A, we analyze the binding mode of different ligands. We also investigate the binding mode of VX-950 by protein-ligand docking. A network of non-covalent interactions between amino acids of the protease structure and the interacting ligands is analyzed to discover possible mechanisms of drug resistance. We describe the potential impact of V36 and T54 mutants on the side chain and backbone conformations and on the non-covalent residue interactions. We propose possible explanations for their effects on the antiviral efficacy of drugs and viral fitness. Molecular dynamics simulations of T54A/S mutants and rotamer analysis of V36A/G/L/M side chains support our interpretations. Experimental data using an HCV V36G replicon assay corroborate our findings. Conclusion T54 mutants are expected to interfere with the catalytic triad and with the ligand binding site of the protease. Thus, the T54 mutants are assumed to affect the viral replication efficacy to a larger degree than V36 mutants. Mutations at V36 and/or T54 result in impaired interaction of the protease residues with the VX-950 cyclopropyl group, which explains the development of viral breakthrough variants.
Viele Patienten, die zum Radiologen geschickt werden, um eine Röntgenaufnahme ihrer Lunge machen zu lassen, fragen besorgt: Aber die Röntgenstrahlen sind doch schädlich, muss das denn wirklich sein? Solche Einwände kommen selbst von langjährigen Rauchern und Menschen, die ansonsten bereit sind, gesundheitliche Gefährdungen auf sich zu nehmen. Bald könnte es jedoch eine Alternative zur Röntgenuntersuchung der Lunge geben. In der Abteilung Pneumologie des Universitätsklinikums Frankfurt wird derzeit ein Verfahren zur bildhaften Darstellung der Lunge erprobt, das sich an den Luftschwingungen in der Lunge orientiert und ganz auf Röntgenstrahlen verzichtet.
Psychische Störungen überschreiten alle Grenzen – es gibt sie in allen Kulturen, zu allen Zeiten, in allen soziodemografischen Schichten und in jedem Lebensalter. Sie sind häufige Themen sowohl in Talkshows, Fernsehserien und Illustrierten als auch in Literatur, Theater und bildender Kunst. Jeden können sie treffen, und beinahe jeder kennt zumindest eine Person, die an einer klinisch bedeutsamen psychischen Störung leidet. Zu deren Behandlung und Erforschung sowie zur Ausbildung von Psychologischen Psychotherapeuten wurde 1999 am Fachbereich Psychologie und Sportwissenschaften der Universität Frankfurt die Verhaltenstherapie-Ambulanz eingerichtet. Primäres Ziel der universitären Ambulanz ist dabei, die Forschung und Lehre des Fachs »Klinische Psychologie und Psychotherapie « mit der praktischen therapeutischen Arbeit an Klienten zusammenzuführen, um damit die Verbindung aus Forschung, Lehre, Ausbildung und Praxis herzustellen.
Background: The evaluation of local mental health care remains difficult. For this reason systematic development of appropriate services is barely possible.
Methods: We examined involuntary hospitalization in the city of Frankfurt/Main with regard to diagnoses, socio-demographic data, complementary psychosocial outpatient care, and circumstances of hospitalization. There are four psychiatric clinics, each serving a catchment area of more than 165.000 inhabitants. These clinics are responsible for all psychiatric in-patient treatments regardless of the admission modus. During a one year period, 677 patients were involuntarily hospitalized. Statistical analyses were performed subsequent to pooling the data.
Results: During a period of one year, 103 out of 100.000 inhabitants of Frankfurt/Main were admitted involuntarily. The rate of involuntary admissions related to all admissions was 10.98 percent. Any complementary psychosocial care was missing in more than 70 percent of patients admitted involuntarily. Only about 10 percent of patients were examined by a physician before reaching the hospital and in disappointing 1.3 percent the municipal mental health service had been consulted prior to involuntarily admission.
Conclusion: Our results show that a systematic improvement of precautionary complementary psychosocial care for risk patients is needed as well as the obligation of psychiatric emergency consultation before involuntary hospitalization.
Background The arterial in line application of the leukocyte inhibition module (LIM) in the cardiopulmonary bypass (CPB) limits overshooting leukocyte activity during cardiac surgery. We now studied in a porcine model whether LIM may have beneficial effects on cardiac function after CPB. Methods German landrace pigs underwent CPB (60 min myocardial ischemia; 30 min reperfusion)without (group I; n=6) or with LIM (group II; n=6). The cardiac indices (CI) and cardiac function were analyzed pre and post CPB with a Swan-Ganz catheter and the cardiac function analyzer. Neutrophil labeling with technetium, scintigraphy, and histological analyses were done to track activated neutrophils within the organs. Results LIM prevented CPB-associated increase of neutrophil counts in peripheral blood. In group I, the CI significantly declined post CPB (post: 3.26 +/- 0.31; pre: 4.05 +/- 0.45 l/min/m2; p<0.01). In group II, the CI was only slightly reduced (post: 3.86 +/- 0.49; pre 4.21 +/- 1.32 l/min/m2; p=0.23). Post CPB, the intergroup difference showed significantly higher CI values in the LIM group (p<0.05) which was in conjunction with higher pre-load independent endsystolic pressure volume relationship (ESPVR) values (group I: 1.57 +/- 0.18; group II: 1.93 +/- 0.16; p<0.001). Moreover, the systemic vascular resistance and pulmonary vascular resistance were lower in the LIM group. LIM appeared to accelerate the sequestration of hyperactivated neutrophils in the spleen and to reduce neutrophil infiltration of heart and lung. Conclusions Our data provide strong evidence that LIM improves perioperative hemodynamics and cardiac function after CPB by limiting neutrophil activity and inducing accelerated sequestration of neutrophils in the spleen.
Background: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. Methods/Design: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific selfmanagement, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guidelineoriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NTproBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. Discussion: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. Trial registration: Current Controlled Trials ISRCTN30822978.
Keine Bevölkerungsgruppe wächst so schnell wie die Gruppe der über 80-jährigen, 2050 werden es in Deutschland voraussichtlich zehn Millionen Menschen sein. Ganz ähnlich wie in vielen anderen Ländern auf allen Kontinenten, mit Ausnahme von Afrika. Aber ist die Medizin auf diese unausweichliche Entwicklung vorbereitet? »Noch nicht,« sagt Privatdozent Dr. Rupert Püllen, Altersmediziner und Chefarzt der Medizinisch-Geriatrischen Klinik der Frankfurter Diakonie- Kliniken. »Die Geriatrie führt unter den vielfältigen medizinischen Fachdisziplinen noch immer ein Schattendasein. Es mangelt an ausgebildeten Altersmedizinern ebenso wie an verlässlichen wissenschaftlichen Daten, aus denen sich evidenzbasierte Behandlungsstrategien für diese Altersgruppe ableiten lassen.« ...
Das Altenpflegeheim ist für die Heimbewohner einerseits ihr Zuhause, andererseits wird es aber von vielen alten Menschen als der erzwungene Daueraufenthalt bis zum Lebensende empfunden. Dies ruft in den Beziehungen zwischen Heimbewohnern, ihren Angehörigen und den Pflegenden oftmals Spannungen hervor, die das zentrale Recht der Bewohnerinnen und Bewohner, aber auch das zentrale Anliegen der Pflegenden tangieren: die Erhaltung und Förderung der Selbstbestimmtheit des alten Menschen. Viele der betroffenen Heimbewohner sind vor allem aufgrund von Demenzerkrankungen unterschiedlicher Genese nicht mehr einwilligungsfähig. Dennoch äußern sie durch Gestik und Mimik in recht differenzierter Weise ihre Freude, ihre Vorlieben, ihre Ängste und ihren Unwillen. So zeigen sie oftmals, ob sie einer therapeutischen oder pflegerischen Maßnahme zustimmen oder sie ablehnen. Diese außerordentlich schwer zu interpretierenden Willensäußerungen sind zweifellos eine erhebliche Herausforderung, die nur in Kooperation aller Beteiligten gelöst werden kann.
Im Jahr 1906 beschrieb Alois Alzheimer (1864 – 1915) erstmals krankhafte Eiweißablagerungen im Gehirn einer Patientin, bei der er einige Jahre zuvor eine Demenz diagnostiziert hatte. Diese Ablagerungen machte er für den geistigen Abbau verantwortlich. Über die zugrunde liegenden biologischen Ursachen der Krankheit (»Ätiologie«) konnte der Frankfurter Arzt jedoch nur Vermutungen anstellen. Inzwischen weiß man, dass die Gene mit darüber entscheiden, ob jemand im Alter an Alzheimer-Demenz (AD) erkrankt. Bei der seltener auftretenden familiären Form der AD sind die verantwortlichen Gene inzwischen bekannt. Doch auch bei der häufigeren sporadischen Form der Krankheit konnten verschiedene Arbeitsgruppen, einschließlich unserer eigenen, inzwischen einige »Risiko-Gene« identifizieren. Eine Erkrankung des Gehirns Aufbauend auf den Befunden von Alois Alzheimer beschäftigten sich in der zweiten Hälfte des 20. Jahrhunderts immer mehr Forschergruppen mit der Alzheimer-Krankheit. ...
Was passiert auf molekularer Ebene, wenn der Körper altert? Eine Antwort darauf lautet: Es häufen sich irreparable Schäden an Zellen, an Zellbestandteilen wie den Organellen, der DNA oder Eiweißen und anderen Molekülen. DassFehler passieren, ist unvermeidlich, denn jeder Stoffwechselvorgang birgt eine gewisse Störanfälligkeit in sich. Ein junger Organismus ist dank ausgefeilter Reparatursysteme in der Lage, Fehler zu korrigieren. Nimmt diese Fähigkeit mit dem Altern ab, so treten zwei Arten von Problemen mit besonders weitreichenden Folgen auf: Fehler bei der Replikation (dem Kopieren) der DNA und molekulare Schäden, die freie Radikale anrichten. So können Defekte der DNA einerseits die Entstehung von Tumoren verursachen, andererseits aber auch Alterungsprozesse beschleunigen.
Viele Menschen befürchten, die Medizin kenne am Lebensende keine Grenzen. Wie können Bürger in Fragen ihres eigenen Todes selbst bestimmen? Seit im Frühjahr zwei sehr verschiedene Gesetzentwürfe vorgelegt worden sind, wird in der Öffentlichkeit noch lebhafter darüber diskutiert, wie der Umgang mit Patientenverfügungen geregelt werden soll. Brauchen wir überhaupt Patientenverfügungen, in denen versucht wird, verschiedene Eventualitäten gedanklich vorwegzunehmen? Der Medizinethiker Stephan Sahm bezweifelt dies. Denn diese Dokumente erweisen sich als ein unzugängliches Instrument. Alternativen sind notwendig. Dazu zählen die »Natürliche Stellvertreterschaft durch Angehörige«, die Vorsorgevollmacht und der »Umfassende Vorsorgeplan«. Dabei handelt es sich um eine Strategie, die an den veränderten Bedürfnissen des Patienten ausgerichtet ist. Denn Sahm hat bei seinen empirischen Studien festgestellt, dass sich Blickwinkel und Vorstellungen deutlich verändern, ob man sich nun als Gesunder oder als Kranker mit diesem Thema beschäftigt.
Blutproben und Gewebe von Familien mit erblich bedingten degenerativen Erkrankungen wie Parkinson sind ein zentrales Forschungsobjekt der neu eingerichteten Forschungsprofessur »Molekulare Neurogenetik« innerhalb der Neurologischen Klinik der Universität Frankfurt. Sind die verantwortlichen Mutationen identifiziert, werden sie im Hirngewebe von Mäusen künstlich erzeugt. Aus der Untersuchung der krankhaften Veränderungen lassen sich Diagnostik und Therapie weiter entwickeln. Als bisherigen Höhepunkt unserer Forschungstätigkeit haben wir in einigen Parkinson- Familien als Krankheitsursache den Funktionsverlust eines Eiweißes namens PINK1 in den Mitochondrien nachgewiesen. Aufgrund dieser Beobachtung lässt sich oxidativer Stress als auslösender Schritt im Krankheitsgeschehen interpretieren. Experimentelle Therapien mit anti-oxidativen Medikamenten sind in Zellkultur getestet worden und sollen künftig auch im Mausmodell zum Einsatz kommen.
Mit meisterhafter Präzision und einem zuverlässigen Gespür für das Außergewöhnliche seines Falles beschrieb Alois Alzheimer vor über 100 Jahren erstmals die feingeweblichen (histologischen) Veränderungen derjenigen Krankheit, die später seinen Namen tragen sollte. Gleichwohl konnte Alzheimer mithilfe des Mikroskops und der damals modernsten Färbetechniken nur wenig über den Zusammenhang zwischen den zu Lebzeiten des Patienten beobachteten Krankheitssymptomen und spezifischen Gehirnveränderungen aussagen. Heute ist zwar der histologische Befund noch immer für die zuverlässige Sicherung der Diagnose Morbus Alzheimer notwendig, aber moderne Schnittbild- sowie elektrophysiologische Verfahren erlauben es erstmals, neuroanatomische und neurofunktionelle Veränderungen zu Lebzeiten der Patienten zu erfassen. Neben ihrem unverzichtbaren Einsatz in der Ausschlussdiagnostik anderer schwerwiegender Gehirnerkrankungen wie Blutungen, Schlaganfälle und Tumore eröffnen diese Verfahren der klinischen Psychiatrie aufregende neue Forschungsperspektiven.
Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1–S126, 2006; or http://www.psoriasis-leitlinie.de).
Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous.
Poster presentation Background Single nucleotide polymorphisms (SNPs) of the TNF gene at positions -238 and -308 have earlier been associated with psoriasis vulgaris and psoriatic arthritis (PsA). However, a strong linkage disequilibrium at the chromosomal region 6p21 renders the interpretation of these findings difficult since also other risk factors for psoriasis (PSORS1) than SNPs of the TNF gene have bee mapped to that particular region. Therefore, in this study several SNPs of the TNF gene and of its neighbouring lymphotoxin alpha (LTA) gene were analysed independently and dependently on carrying the PSORS1 risk allele. Methods SNPs in the promoter of the TNF gene (-238G/A, -308G/A, -857C/T, -1031T/C), and one SNP of the LTA gene (+252A/G), of the TNLFRSF1A gene (+36A/G) and of the TNLFRSF1B gene (+676T/G), respectively, were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The tryptophan–tryptophan–cysteine–cysteine haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used to estimate the genetic impact of the PSORS1 risk allele. Results Whereas an earlier-described association of allele TNF*-238A with psoriasis could be confirmed, our study revealed that this association was completely dependent on concomitant carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint manifestations, strong association with the allele TNF*-857T was detected (OR = 1.956; P value corrected for multiple testing, Pcorr = 0.0025) also in patients negative for the PSORS1 risk allele. Conclusion Our results indicate genetic differences between psoriasis vulgaris patients with and without joint manifestation. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect linkage disequilibrium with PSORS1, TNF*-857T may represent a risk factor for PsA independent of PSORS1. A potential pathophysiologic relevance of the elucidated genetic association is further suggested by previously reported experimental evidence for a functional impact of the respective TNF polymorphism on TNFalpha expression levels.
Antiaging ist en vogue. Viele Menschen nutzen diesen Begriff, verstehen darunter jedoch ganz unterschiedliche Dinge. Das Spektrum reicht von Gymnastik für ältere Menschen bis hin zu Maßnahmen der plastischen Chirurgie im Sinne einer »Schönheitschirurgie «, von sinnvollen und richtigen Angeboten bis hin zu Dingen, deren Nähe zur Scharlatanerie aus Sicht der Schulmedizin nicht zu verkennen ist. Dieser Artikel soll einen Überblick geben über die Aspekte des Antiaging, die einer Betrachtung aus Sicht der wissenschaftlich orientierten Medizin zugänglich sind.
cGMP- and cAMP-dependent protein kinases (cGK and cAK) mediate the inhibitory effects of endothelium-derived messenger molecules nitric oxide and prostacyclin on platelets. To understand the mechanisms involved in platelet inhibition we searched for new substrates of cGK and cAK. We identified Rap1GAP2, the only GTPase-activating protein of Rap1 in platelets. Rap1 is a guanine-nucleotide binding protein that controls integrin activity, platelet adhesion and aggregation. Rap1GAP2 is required to turn over Rap1-GTP to Rap1-GDP resulting in the inactivation of integrins and reduced cellular adhesion. Using phospho-specific antibodies we demonstrate phosphorylation of endogenous Rap1GAP2 on serine 7 by cGK and cAK in intact platelets. Yeast-two-hybrid screening revealed an interaction of the phosphoserine/-threonine binding adapter protein 14-3-3 with Rap1GAP2, and we mapped the 14-3-3 binding site to the N-terminus of Rap1GAP2 close to the cGK/cAK phosphorylation site. We could show that 14-3-3 binding to Rap1GAP2 requires phosphorylation of serine 9. Platelet activation by ADP and thrombin treatment induces Rap1GAP2 serine 9 phosphorylation and enhances the attachment of 14-3-3 to Rap1GAP2. In contrast, phosphorylation of serine 7 by cGK/cAK leads to the detachment of 14-3-3. Furthermore, Rap1GAP2 serine 7 phosphorylation correlates with the inhibition of Rap1-GTP formation by cGMP and cAMP in platelets. Cell adhesion experiments provide additional evidence that Rap1GAP2 is activated by the detachment of 14-3-3. Point mutants of Rap1GAP2 deficient in 14-3-3 binding inhibit Rap1-mediated cell adhesion significantly stronger than a Rap1GAP2 mutant that binds 14-3-3 constitutively. Our findings define a novel regulatory mechanism that might contribute to both platelet activation and endothelial inhibition of platelet adhesion and aggregation.
Bypassing of DNA lesions by damage-tolerant DNA polymerases depends on the interaction of these enzymes with the monoubiquitylated form of the replicative clamp protein, PCNA. We have analyzed the contributions of ubiquitin and PCNA binding to damage bypass and damage-induced mutagenesis in Polymerase {eta} (encoded by RAD30) from the budding yeast Saccharomyces cerevisiae. We report here that a ubiquitin-binding domain provides enhanced affinity for the ubiquitylated form of PCNA and is essential for in vivo function of the polymerase, but only in conjunction with a basal affinity for the unmodified clamp, mediated by a conserved PCNA interaction motif. We show that enhancement of the interaction and function in damage tolerance does not depend on the ubiquitin attachment site within PCNA. Like its mammalian homolog, budding yeast Polymerase {eta} itself is ubiquitylated in a manner dependent on its ubiquitin-binding domain.
Der Morbus Parkinson tritt in der Regel sporadisch auf und ist nach dem Morbus Alzheimer die häufigste degenerative Erkrankung des menschlichen Nervensystems. Sie ist bei nicht-menschlichen Wirbeltieren unbekannt und befällt außer dem Nervensystem keine anderen Organe. Wie bei vielen anderen Krankheiten auch erkennt der Kliniker nur die späten und bereits Symptome verursachenden Stadien des Morbus Parkinson. Spezielle Fehlfunktionen der Motorik, wie Hypokinese, Rigor, Ruhetremor weisen zwar auf die Erkrankung hin, können jedoch unter dem Bild eines »Parkinsonismus« auch bei anderen Krankheiten auftreten. Kennzeichnend dagegen ist ein eigenartiger pathologischer Prozess, der sich durch die Entwicklung von Einschlusskörpern in Nervenzellen auszeichnet. Der Prozess beschränkt sich auf wenige empfängliche Nervenzelltypen im zentralen, peripheren und enterischen Nervensystem. Die Einschlusskörper entwickeln sich nicht spontan und erscheinen auch nicht regelmäßig im Verlauf der Alterung des Nervensystems, selbst bei über Hundertjährigen nicht. Man hat also Grund, sie als pathologische Bildungen zu betrachten, auch wenn sie anfänglich in nur geringer Dichte im Nervengewebe auftreten. Die frühen symptomfreien Stadien der Krankheit lassen sich erst nach dem Tod der Patienten nachweisen. Wesentliche Kriterien für die Stellung einer postmortalen Diagnose sind die Einschlusskörper. Wie sie sich entwickeln und in den verschiedenen Stadien der Krankheit im Nervensystem ausbreiten, beschreiben Prof. Dr. Heiko Braak und Dr. Dr. Kelly Del Tredici.
Mathematische Methoden in der Biologie haben sich in den vergangenen 25 Jahren zunehmend etabliert. Etwa in den Bereichen der Entwicklung von Organen und Organismen sind große Anstrengungen in der Mathematik unternommen worden, die grundlegenden Mechanismen der Entwicklung aufzudecken. Der einfache Gedanke, auf dem diese Methode aufbaut, ist ein reduktionistischer: Man verwendet einen minimalen Satz von in der Biologie beobachteten Wechselwirkungen – etwa zwischen den Zellen, die das betrachtete Gewebe aufbauen –, übersetzt sie in ein mathematisches System von dynamischen Gleichungen, löst diese auf dem Computer und prüft, ob sich in der Lösung die erwartete Struktur zeigt. Wenn dies allein aufgrund experimenteller Daten aus der Biologie nicht möglich ist, ergibt sich der größte Nutzen der mathematischen Beschreibung: Dann sind neue Hypothesen im mathematischen Modell notwendig, um das reale System beschreiben zu können. Damit sagen die Theoretiker Zusammenhänge voraus, die aus der Biologie alleine nicht ableitbar sind. Diese können durch neue gezielte Experimente verifiziert werden. Ein ähnlicher Ansatz wurde in jüngerer Zeit von unserer Gruppe am Frankfurter Instute for Advanced Studies (FIAS) in der Immunologie verwendet.
Im Altenheim gehören Psychopharmaka ganz selbstverständlich zum Pflegealltag. Damit daraus keine gefährliche Routine entsteht, hat ein Team aus Gerontopsychiatern, Medizinethikern und Juristen der Johann Wolfgang Goethe-Universität ein Frankfurter Pflegeheim auf dessen Wunsch hin unter die Lupe genommen. Ihr Maßnahmenkatalog gibt allen beteiligten Personen und Institutionen und sogar der Politik Hinweise, wie mehr Achtsamkeit im Umgang mit diesen Medikamenten erreicht werden kann. Es geht nämlich keineswegs darum, Psychopharmaka generell zu verteufeln. In manchen Fällen bemängeln die Fachleute, dass notwendige Antidementiva oder Antidepressiva nicht verschrieben wurden, in anderen wurden dagegen Doppelmedikation und oft zu lange Therapiedauer gerügt. Die Wissenschaftler entwickeln über 70 Handlungsempfehlungen, mit denen die Versorgung optimiert und somit die Lebensqualität der Bewohner erhöht werden kann.
Anderer Fehler sind gute Lehrer « – so lautet ein nur wenig bekanntes altes deutsches Sprichwort. Für medizinische Fehler galt das die längste Zeit nicht: entweder totgeschwiegen oder als »Kunstfehler « in das Licht der Öffentlichkeit gezerrt, entzogen sich ärztliche Fehler einer systematischen Analyse. Damit hat die Medizin lange eine wichtige Chance vertan. Am Institut für Allgemeinmedizin der Universität Frankfurt beschäftigt sich seit einigen Jahren ein Team unter Leitung von Prof. Dr. Ferdinand Gerlach intensiv mit der Fehlerforschung. ...