Die Bedeutung der Arbeit beim vorzeitigen Ausscheiden aus dem Arbeitsleben

Since the mid-1990s, many German companies have used the part-time retirement scheme (Altersteilzeit) as an opportunity to release older workers. This was often consistent with the interests of the workers themselves. This paper explores whether workers who participate in this early retirement scheme would like to continue to work. A survey of all the workers in one company who participated in the part-time retirement scheme revealed that those already retired would more often like to continue working than employees who are still awaiting retirement. To a greater extent, early retirees would also like to return to work with shorter working hours or for a time-limited project. Results are explained with the affective forecasting bias that is based on the psychological decision theory and economic utility theory – the future utility of an action cannot be anticipated. The “reflective thinking” approach moreover invites the conclusion that the diverging interest of the two groups in continued employment may be due to the different stage of practical knowledge about the situation in (pre-)retirement.     

Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-[3H]emopamil.

(-)-Emopamil ((S)-emopamil, (2S)-2-isopropyl-5-(methylphenethylamino)- 2-phenylvaleronitrile hydrochloride) is a Ca(2+)-antagonistic phenylalkylamine which also blocks serotonin (5-HT2) receptors and has antiischemic properties. The (-)-[3H]emopamil tissue distribution profile of specific binding is in striking contrast to that observed for (+)-[3H]PN 200-110 or (-)-[3H]desmethoxyverapamil: (-)-[3H]emopamil labels membrane fractions from guinea-pig liver much greater than adrenal gland greater than kidney approximately lung approximately ductus deferens approximately brain approximately skeletal muscle. Binding to liver membrane was saturable (KD = 12.8 nM, Bmax = 35 pmol/mg of protein), stereoselective, reversible (K-1 = 0.22 min-1 at 25 degrees C) and inhibited by tetraethylammonium (IC50: 1.8 mM) greater than Li+ (IC50: 12.5 mM) approximately Na+ (IC50: 13.6 mM) and [NH4+] (IC50: 79.3 mM) but not by Rb+, Cs+ or K+. The high-affinity liver membrane binding sites have a pharmacological profile that is distinct from the phenylalkylamine receptor domain of the voltage-dependent L-type Ca2+ channel. Similar sites exist in brain and other tissues, albeit with a lower density. Amiodarone, butoprozine and amiloride derivatives bind with high affinity whereas 1,4-dihydropyridines do not interact at all. It is suggested that the novel phenylalkylamine site is linked to a sodium-dependent carrier or transport system.     

Metabolism and toxicity of thioacetamide and thioacetamide s-oxide in rat hepatocytes

The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrolobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects, TA requires oxidative bioactivation, leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO(2)), which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 h. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology, and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [(14)C]-TASO is inhibited by unlabeled TA, which acts as a "cold-trap" for [(14)C]-TA and prevents its reoxidation to [(14)C]-TASO. This in turn increases the net consumption of [(14)C]-TASO despite the fact that its oxidation to TASO(2) is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA, may help explain phenomena previously interpreted as "saturation toxicokinetics" in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification.     

Leukostase und Tumorlyse

The occurrence of hyperleukocytosis (leukocytes >?100.000/μl) is associated with complications such as leukostasis, tumor lysis and consumption coagulopathy in patients with acute leukemia much more often than in patients with chronic malignant hematological diseases. To manage these situations may be complex as organ failure is often imminent or manifest, infectious complications arise and indications for induction chemotherapy are usually urgent. Prophylaxis and therapy of the tumor lysis syndrome consists of hydration, lowering of uric acid and the management of electrolyte disturbances. Leukostasis requires immediate reduction of the leukocyte count by leukapheresis, administration of hydroxycarbamide and, ultimately, by causative and specific treatment of the underlying disease itself. In patients with curable diseases or favorable long-term prognosis, transfer to the intensive care unit must be evaluated early in the course of impending organ dysfunction, especially in cases of acute respiratory failure.     

Influence of prothrombin complex concentrates on plasma coagulation in critically ill patients

Objective: To evaluate thrombogenicity of prothrombin complex concentrates (PCCs) in critically ill patients.¶Design: Prospective clinical study.¶Setting: Medical intensive care unit at a university hospital.¶Patients: 16 consecutive patients suffering from acquired deficiencies of coagulation factors and with either overt bleeding from any site or a planned invasive procedure.¶Interventions: 2000 factor IX units of PCCs intravenously.¶Measurements and results: Prothrombin time (PT), activated partial prothrombin time, fibrinogen, platelet count, plasma levels of coagulation factors II, V, VII, VIII, IX, X, antithrombin, protein C, thrombin-antithrombin complex (TAT), prothrombin fragment F₁₊₂, and the fibrin degradation product D-dimer were measured prior to and 1, 3, and 24 h after administration of PCCs. PT as well as coagulation factors II, VII, IX, and X, TAT, and F₁₊₂ showed a significant increase after administration of PCCs. All other parameters remained unchanged.¶Conclusions: Administration of PCCs induces thrombin generation. No evidence for induction of disseminated intravascular coagulation in biochemical terms could be found. When rapid correction of acquired coagulation factor disturbances is warranted, the use of PCCs seems reasonable, but the elevated risk of intravascular thrombus formation should be kept in mind.     

Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway

An extract of the plant Coleus forskohlii has been used for centuries in Ayurvedic medicine to treat various diseases such as hypothyroidism, heart disease, and respiratory disorders. Additionally, complex herbal mixtures containing this extract are gaining popularity in United States for their putative "fat-burning" properties. The active ingredient in C. forskohlii extract is the diterpene compound forskolin. Forskolin is a widely used biochemical tool that activates adenyl cyclase, thereby increasing intracellular concentration of cAMP and thus activating the protein kinase A (PKA) signal transduction pathway. We show herein that both forskolin and its nonadenyl cyclase-activating analog 1,9 dideoxyforskolin induce CYP3A gene expression in primary hepatocytes by functioning as agonists of the pregnane X receptor (PXR). We show that activation of PKA signaling potentiates PXR-mediated induction of CYP3A gene expression in cultured hepatocytes and increases the strength of PXR-coactivator protein-protein interaction in cell-based assays. Kinase assays show that PXR can serve as a substrate for catalytically active PKA in vitro. Our data provide important insights into the molecular mechanism of both the PKA-dependent and -independent effects of forskolin on the expression of drug-metabolizing enzymes in liver. Finally, our data suggest that herbal therapy with C. forskohlii extract should be approached cautiously due to the potential for herb-drug interactions in patients on combination therapy.     

Extracorporeal membrane oxygenation in adult patients with hematologic malignancies and severe acute respiratory failure

Introduction

Acute respiratory failure (ARF) is the main reason for intensive care unit (ICU) admissions in patients with hematologic malignancies (HMs). We report the first series of adult patients with ARF and HMs treated with extracorporeal membrane oxygenation (ECMO).

Methods

This is a retrospective cohort study of 14 patients with HMs (aggressive non-Hodgkin lymphoma (NHL) n = 5; highly aggressive NHL, that is acute lymphoblastic leukemia or Burkitt lymphoma, n = 5; Hodgkin lymphoma, n = 2; acute myeloid leukemia, n = 1; multiple myeloma, n = 1) receiving ECMO support because of ARF (all data as medians and interquartile ranges; age, 32 years (22 to 51 years); simplified acute physiology score II (SAPS II): 51 (42 to 65)). Etiology of ARF was pneumonia (n = 10), thoracic manifestation of NHL (n = 2), sepsis of nonpulmonary origin (n = 1), and transfusion-related acute lung injury (n = 1). Diagnosis of HM was established during ECMO in four patients, and five first received (immuno-) chemotherapy on ECMO.

Results

Before ECMO, the PaO₂/FiO₂ ratio was 60 (53 to 65), (3.3 to 3.7). Three patients received venoarterial ECMO because of acute circulatory failure in addition to ARF; all other patients received venovenous ECMO. All patients needed vasopressors, and five needed hemofiltration. Thrombocytopenia occurred in all patients (lowest platelet count was 20 (11 to 21) G/L). Five major bleeding events were noted. ECMO duration was 8.5 (4 to 16) days. ICU and hospital survival was 50%. All survivors were alive at follow-up (36 (10 to 58) months); five patients were in complete remission, one in partial remission, and one had relapsed.

Conclusions

ECMO therapy is feasible in selected patients with HMs and ARF and can be associated with long-term disease-free survival.     

The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease

BACKGROUND: We investigated the influence of 2 common Toll-like receptor 4 (TLR4) polymorphisms on susceptibility and disease characteristics of Crohn's disease (CD). METHODS: Genomic DNA from 204 patients with CD and 199 unrelated controls was analyzed for the presence of 2 single nucleotide polymorphisms in the TLR4 gene, resulting in the amino acid substitutions Asp299Gly and Thr399Ile. In addition, the carrier status for the 3 common CD-associated CARD15/NOD2 gene mutations, Arg702Trp, Gly908Arg, and 1007fs, was determined. The frequency of the different genotypes was compared, and a detailed genotype-phenotype correlation was performed. RESULTS: An almost 2-fold increase in the frequency of the TLR4 Asp299Gly phenotype was observed in patients with CD (14.2%) compared with healthy controls (7.5%, P = 0.038, odds ratio = 2.03). The prevalence of a stricturing phenotype was increased in patients heterozygous for 1 of the TLR4 polymorphisms studied (Asp299Gly, 34.5%; Thr399Ile, 36.7%) compared with patients with wild-type TLR4 (17.1% and 16.7%; P = 0.04 and 0.02, respectively). The presence of the Asp299Gly polymorphism in the absence of CARD15/NOD2 mutations was a particularly strong predictor of the stricturing disease phenotype that was present in 47.4% of the patients with Asp299Gly+/NOD2- compared with 10.1% of the patients with the Asp299Gly-/NOD2+ status (P = 0.0009; P = 0.0004 for Thr399Ile+/NOD2- versus Thr399Ile-/NOD2+). In contrast, there was a trend toward a higher prevalence of the penetrating phenotype in the TLR4-/NOD2+ group (71.6%) compared with the TLR4+/NOD2- group (47.4%, P = 0.059). CONCLUSIONS: The TLR4 Asp299Gly polymorphism is a risk factor for CD. TLR4 and CARD15/NOD2 mutations may contribute to distinct disease phenotypes.