High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest.

INTRODUCTION: After cardiac arrest due to acute coronary syndromes (ACS) therapeutic hypothermia (HT) is the standard care to reduce neurologic damage. Additionally, the concomitant medical treatment with aspirin and a P2Y12 receptor inhibitor like clopidogrel (Cl), prasugrel (Pr) or ticagrelor (Ti) is mandatory. The platelet inhibitory effect of these drugs under hypothermia remains unclear. METHODS: 164 patients with ACS were prospectively enrolled in this study. 84 patients were treated with HT, 80 patients were under normothermia (NT). All patients were treated with aspirin and one of the P2Y12 receptor inhibitors Cl, Pr or Ti. 24h after the initial loading dose the platelet reactivity index (PRI/VASP-index) was determined to achieve the platelet inhibitory effect. RESULTS: In the HT-group the PRI/VASP-index was significantly higher compared to the NT-group (54.86%±25.1 vs. 28.98%±22.8; p<0.001). In patients under HT receiving Cl, the platelet inhibition was most markedly reduced (HT vs. NT: 66.39%±19.1 vs. 33.36%±22.1; p<0.001) compared to Pr (HT vs. NT: 37.6%±25.0 vs. 27.04%±25.5; p=0.143) and Ti (HT vs. NT: 41.5%±21.0 vs. 17.83%±14.5; p=0.009). The rate of non-responder defined as PRI/VASP-index>50% was increased in HT compared to NT (60.7% vs. 22.5%; p<0.001) with the highest rates in the group receiving Cl (CL: 82% vs. 26%, p<0.001; Pr: 32% vs. 23%; n.s.; Ti: 30% vs. 8%, n.s.). CONCLUSION: The platelet inhibitory effect in patients treated with HT after cardiac arrest is significantly reduced. This effect was most marked with the use of Cl. The new P2Y12-inhibitors Pr and Ti improved platelet inhibition in HT, but could not completely prevent non-responsiveness.

Regulation of glucose-6-phosphatase gene expression by insulin and metformin.

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.

Recursive neural network rule extraction for data with mixed attributes.

In this paper, we present a recursive algorithm for extracting classification rules from feedforward neural networks (NNs) that have been trained on data sets having both discrete and continuous attributes. The novelty of this algorithm lies in the conditions of the extracted rules: the rule conditions involving discrete attributes are disjoint from those involving continuous attributes. The algorithm starts by first generating rules with discrete attributes only to explain the classification process of the NN. If the accuracy of a rule with only discrete attributes is not satisfactory, the algorithm refines this rule by recursively generating more rules with discrete attributes not already present in the rule condition, or by generating a hyperplane involving only the continuous attributes. We show that for three real-life credit scoring data sets, the algorithm generates rules that are not only more accurate but also more comprehensible than those generated by other NN rule extraction methods.

[Perspectives in the vocational rehabilitation of the mentally ill and disabled--an overview of the current status and problems in the region of Westphalia]. / Perspektiven der Arbeitsrehabilitation psychisch Kranker und Behinderter--ein Uberblick über den Stand und die Probleme im Landesteil Westfalen.

The number of persons suffering from chronic mental disease but living outside the psychiatric hospital in the community, is rising, resulting in an increasing demand for facilities for occupation, occupational therapy and rehabilitation and for paid employment. The past few years have seen a distinct increase in the number of sheltered workplaces for the mentally ill. This development has also led to qualitative differentiation in the offers. In the region of Westphalia there are currently some 940 work places in special departments for the mentally handicapped at workshops for the disabled. Self-help enterprises and those offering opportunities for persons living on social benefits or pensions to supplement their income currently offer some 470 workplaces for the mentally ill, ten psychiatric hospitals are giving their former patients an opportunity to take part in occupational therapy as outpatients. Considerable differences are to be registered with regard to the offers of work, the forms of organization, the tasks involved and the types of supervision. Finally, a specialized psychosocial service has been established within the past four years by the head welfare office of the Landschaftsverband Westfalen-Lippe; this service is designed for the care of the mentally ill at their work place. Like many developments in social psychiatry, the differentiation of occupational rehabilitation has resulted from practical experience. Empirical findings on the indication for and efficiency of individual measures are virtually non-existent. A prospective five-year study is planned to investigate further results.