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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.
Background: Models of isolated and perfused kidneys are used to study the effects of drugs, hazardous or toxic substances on renal functions. Since physiological and morphological parameters of small laboratory animal kidneys are difficult to compare to human renal parameters, porcine kidney perfusion models have been developed to simulate closer conditions to the human situation, but exact values of renal parameters for different collection and perfusion conditions have not been reported so far. If the organs could be used out of regular slaughtering processes animal experiments may be avoided.
Methods: To assess renal perfusion quality, we analyzed different perfusion settings in a standardized model of porcine kidney hemoperfusion with organs collected in the operating theatre (OP: groups A-D) or in a public abattoir (SLA: group E) and compared the data to in vivo measurements in living animals (CON). Experimental groups had defined preservation periods (0, 2 and 24 hrs), one with additional albumin in the perfusate (C) for edema reduction.
Results: Varying perfusion settings resulted in different functional values (mean +/- SD): blood flow (RBF [ml/min*100 g]: (A) 339.9 +/- 61.1; (C) 244.5 +/- 53.5; (D) 92.8 +/- 25.8; (E) 153.8 +/- 41.5); glomerular filtration (GFR [ml/min*100 g]: (CON) 76.1 +/- 6.2; (A) 59.2 +/- 13.9; (C) 25.0 +/- 10.6; (D) 1.6 +/- 1.3; (E) 16.3 +/- 8.2); fractional sodium reabsorption (RFNa [%] (CON) 99.8 +/- 0.1; (A) 82.3 +/- 8.1; (C) 86.8 +/- 10.3; (D) 38.4 +/- 24.5; (E) 88.7 +/- 5.8). Additionally the tubular coupling-ratio of Na-reabsorption/O2-consumption was determined (TNa/O2-cons [mmol-Na/mmol- O2] (CON) 30.1; (A) 42.0, (C) 80.6; (D) 17.4; (E) 23.8), exhibiting OP and SLA organs with comparable results.
Conclusion: In the present study functional values for isolated kidneys with different perfusion settings were determined to assess organ perfusion quality. It can be summarized that the hemoperfused porcine kidney can serve as a biological model with acceptable approximation to in vivo renal physiology, also if the organs originate from usual slaughtering processes.
Background During gram-negative sepsis, lipopolysaccharide (LPS) induces tissue factor expression on monocytes. The resulting disseminated intravascular coagulation leads to tissue ischemia and worsens the prognosis of septic patients. There are indications, that fever reduces the mortality of sepsis, the effect on tissue factor activity on monocytes is unknown. Therefore, we investigated whether heat shock modulates LPS-induced tissue factor activity in human blood. Methods Whole blood samples and leukocyte suspensions, respectively, from healthy probands (n = 12) were incubated with LPS for 2 hours under heat shock conditions (43°C) or control conditions (37°C), respectively. Subsequent to further 3 hours of incubation at 37°C the clotting time, a measure of tissue factor expression, was determined. Cell integrity was verified by trypan blue exclusion test and FACS analysis. Results Incubation of whole blood samples with LPS for 5 hours at normothermia resulted in a significant shortening of clotting time from 357 ± 108 sec to 82 ± 8 sec compared to samples incubated without LPS (n = 12; p < 0.05). This LPS effect was mediated by tissue factor, as inhibition with active site-inhibited factor VIIa (ASIS) abolished the effect of LPS on clotting time. Blockade of protein synthesis using cycloheximide demonstrated that LPS exerted its procoagulatory effect via an induction of tissue factor expression. Upon heat shock treatment, the LPS effect was blunted: clotting times were 312 ± 66 s in absence of LPS and 277 ± 65 s in presence of LPS (n = 8; p > 0.05). Similarly, heat shock treatment of leukocyte suspensions abolished the LPS-induced tissue factor activity. Clotting time was 73 ± 31 s, when cells were treated with LPS (100 ng/mL) under normothermic conditions, and 301 ± 118 s, when treated with LPS (100 ng/mL) and heat shock (n = 8, p < 0.05). Control experiments excluded cell damage as a potential cause of the observed heat shock effect. Conclusion Heat shock treatment inhibits LPS-induced tissue factor activity in human whole blood samples and isolated leukocytes.
The pathogenic spirochete Leptospira interrogans disseminates throughout its hosts via the bloodstream, then invades and colonizes a variety of host tissues. Infectious leptospires are resistant to killing by their hosts' alternative pathway of complement-mediated killing, and interact with various host extracellular matrix (ECM) components. The LenA outer surface protein (formerly called LfhA and Lsa24) was previously shown to bind the host ECM component laminin and the complement regulators factor H and factor H-related protein-1. We now demonstrate that infectious L. interrogans contain five additional paralogs of lenA, which we designated lenB, lenC, lenD, lenE and lenF. All six genes encode domains predicted to bear structural and functional similarities with mammalian endostatins. Sequence analyses of genes from seven infectious L. interrogans serovars indicated development of sequence diversity through recombination and intragenic duplication. LenB was found to bind human factor H, and all of the newly-described Len proteins bound laminin. In addition, LenB, LenC, LenD, LenE and LenF all exhibited affinities for fibronectin, a distinct host extracellular matrix protein. These characteristics suggest that Len proteins together facilitate invasion and colonization of host tissues, and protect against host immune responses during mammalian infection.
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.
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.« ...
Poster presentation: Light is the main phase-adjusting stimulus of the circadian clock located in the suprachiasmatic nucleus (SCN). A candidate pathway transmitting photic information at the postsynaptic site in the SCN is the extracellular signal-regulated kinase (ERK 1/2) which has been previously shown to be an essential element in the photoentrainment of the circadian rhythm. An upstream activator of the ERK signalling route is the small intracellular GTPase Ras. Here we observed that endogenous Ras activity in the SCN was subjected to rhythmic changes, reaching maximum levels at the late subjective day and minimum levels at the late subjective night (CT22). In order to investigate if Ras would modulate the circadian cycle, we used transgenic mice expressing constitutively activated Val-12 Ha-Ras selectively in neurons (synRas mice). In these mice Ras activity was also cycling during the circadian rhythm yet, Ras activities were up-regulated at each time point measured. We investigated if this change in Ras activity translates into a behavioral phenotype by monitoring free-running activity rhythms under conditions of constant darkness. SynRas mice exhibited circadian rhythms in locomotor activities similar to WT mice. However, when challenged by applying a 15 minutes light pulse at CT22 to promote phase advance shifts, synRas mice were completely non-responsive. As a first step towards the possible intracellular mechanism of this behavioral change we analyzed ERK1/2 activities in more details: We found a 1,7-fold increase of circadian peak levels of ERK 1/2 activities at CT10 and CT14 in synRas mice, while at minimum levels (CT18, CT22) no differences were found between ERK1/2 activities of WT and synRas mice. In WT animals the 15 minutes light pulse at CT22 resulted in rapid up regulations of Ras, ERK1/2 and CREB activities as described previously by others. However, in correlation with the lack of a behavioral response, ERK1/2 but not Ras and CREB activities remained unchanged in synRas mice, suggesting that Ras-dependent and Ras-independent pathways may co-exist to regulate ERK1/2 and behavioral phase shifts in response to the acute light treatment. Next we investigated the length "tau" of the locomotor activity rhythm during constant darkness and found a slight shortening by about 10 minutes in synRas mice as compared to the WT littermates. Recently, "tau" has been discussed to be modulated by the interaction between glycogen synthase 3beta (GSK3beta) and a clock gene product (Per 2) that is involved in the determination of circadian phase durations. We describe here a down-regulation of GSK3beta phosphorylation in synRas mice as a possible mechanism of "tau" shortening. Taken together, cycling of Ras activity at elevated levels in the SCN during the circadian rhythm results in a distinct pattern of behavioral phenotype changes correlating with de-regulated ERK1/2 or GSK3beta activities.
Aims: To analyze the relationship between exposure to chlorinated and aromatic organic solvents and malignant lymphoma in a multi-centre, population-based case-control study.
Methods: Male and female patients with malignant lymphoma (n=710) between 18 and 80 years of age were prospectively recruited in six study regions in Germany (Ludwigshafen /Upper Palatinate, Heidelberg/ Rhine-Neckar-County, Wurzburg/ Lower Frankonia, Hamburg, Bielefeld/ Gutersloh, and Munich). For each newly recruited lymphoma case, a gender, region and age-matched (+/- 1 year of birth) population control was drawn from the population registers. In a structured personal interview, we elicited a complete occupational history, including every occupational period that lasted at least one year. On the basis of job task-specific supplementary questionnaires, a trained occupational physician assessed the exposure to chlorinated hydrocarbons (trichloroethylene, tetrachloroethylene, dichloromethane, carbon tetrachloride) and aromatic hydrocarbons (benzene, toluene, xylene, styrene). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression analysis, adjusted for smoking (in pack years) and alcohol consumption. To increase the statistical power, patients with specific lymphoma subentities were additionally compared with the entire control group using unconditional logistic regression analysis.
Results: We observed a statistically significant association between high exposure to chlorinated hydrocarbons and malignant lymphoma (Odds ratio = 2.1; 95% confidence interval 1.1-4.3). In the analysis of lymphoma subentities, a pronounced risk elevation was found for follicular lymphoma and marginal zone lymphoma. When specific substances were considered, the association between trichloroethylene and malignant lymphoma was of borderline statistical significance. Aromatic hydrocarbons were not significantly associated with the lymphoma diagnosis.
Conclusions: In accordance with the literature, this data point to a potential etiologic role of chlorinated hydrocarbons (particularly trichloroethylene) and malignant lymphoma. Chlorinated hydrocarbons might affect specific lymphoma subentities differentially. Our study does not support a strong association between aromatic hydrocarbons (benzene, toluene, xylene, or styrene) and the diagnosis of a malignant lymphoma.
Poster presentation: The transcription factor NF-kappaB plays a central role in the development and maintenance of the central nervous system and its constitutive activation in neurons has been repeatedly reported. Previous work from our laboratories (poster presentation: Compartimentalized NF-kappaB activity in the axon initial segment) had revealed an intriguing clustering of activated IKKalpha/beta and other downstream elements of an activated NF-kappaB cascade (phospho-IkappaBalpha, phospho-p65(Ser536)) in the axon initial segment (AIS). Accumulation of certain voltage-gated sodium channels (Na(v)1.2), M-type potassium channels (KCNQ2) as well as cytoskeletal anchoring proteins (AnkyrinG) characterise the AIS. However, it is not yet clear how AIS-localized IKK gets activated and whether this can be connected to the constitutive activation of NF-kappaB. Long-term blockade of sodium channels with tetrodotoxin, potassium-channels with linopirdine or NMDA-receptors with MK-801 did not elicit any change upon the constitutive activation of the pathway. Strikingly, the occurrence of phosphorylated IkappaBalpha was even unaltered by 24 h of incubation with protein synthesis inhibitors. Others have reported that impairment of NF-kappaB inhibits neuritogenesis. In this line we observed that the early initiation of IkappaBalpha phosphorylation was susceptible to inhibition of IKK in DIV1–2 neurons. We therefore aim to identify the interaction partners of the activated IKK complex in the AIS. Proteomic methods such as co-immunoprecipitation analyses and mass-spectrometry will help us to identify the key players in the initiation of constitutive IKK phosphorylation and activation in neurons.