Lipid phosphate phosphatase 3 enables efficient thymic egress

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance.     

Recovery of a hypothermic drowned child after resuscitation with cardiopulmonary bypass followed by prolonged extracorporeal membrane oxygenation

Drowning is a leading cause of death in children worldwide. However, there is uncertainty about the initiation and the extent of adequate therapeutic interventions after drowning accidents. As prediction of outcome in drowned children remains difficult, initial maximum life support appears to be generally justified. We present the case of a 3-year-old drowned girl in refractory cardiorespiratory arrest who was resuscitated successfully with cardiopulmonary bypass (CPB) followed by extracorporeal membrane oxygenation (ECMO) for 4 days. After a prolonged period in a vegetative state eventually she made an almost complete neurological recovery. We do not have knowledge of any case of drowning reported with a favourable neurological outcome after such a prolonged period of ECMO.     

Detection and classification of focal liver lesions in patients with colorectal cancer: retrospective comparison of diffusion-weighted MR imaging and multi-slice CT

Objectives

To compare the diagnostic performance of diffusion-weighted MR imaging (DWI) with multi-slice CT (MS-CT) in the detection and classification of focal liver lesions in patients with colorectal cancer.

Methods

In a retrospective study 68 patients who underwent DWI at 1.5 T (b-values of 50, 300 and 600 s/mm²) and contrast-enhanced MS-CT were analysed by two radiologists blinded to the clinical results. Imaging results were correlated with intraoperative surgical and ultrasound findings (n = 24), imaging follow-up or PET (n = 44). Sensitivity of DWI and MS-CT in detection of focal liver lesions was compared on a per-lesion and a per-segment basis. Receiver operator-characteristic (ROC) curves to determine the diagnostic performance and the sensitivities of correctly identifying liver metastases on a segmental base were calculated.

Results

For lesion detection, DWI was significantly superior to MS-CT both on a per-lesion (difference in sensitivities for reader 1 and 2 22.65% and 19.06%, p < 0.0001) and a per-segment basis (16.86% and 11.76%, p < 0.0001). Especially lesions smaller than 10 mm were better detected with DWI compared to MS-CT (difference 41.10% and 29.45%, p < 0.0001). ROC-analysis showed superiority for lesions classification (p < 0.0001) of DWI (AUC: 0.949 and 0.951) as compared to MS-CT (AUC: 0.879 and 0.892, p < 0.0001 and p = 0.005). DWI was able to filter out metastatic segments with a higher sensitivity (88.2 and 86.5%) compared to MS-CT (68.0 and 67.4%, p < 0.0001 and p = 0.005, respectively).

Conclusion

Compared to MS-CT DWI is both more sensitive in the detection of liver lesions and more accurate in determining the extent of metastatic disease in patients with colorectal cancer and therefore might help to optimize therapeutic management in those patients.     

Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein,MRP1 to MRP5, BCRP,and BSEP

Inhibition of ABC transporters is a common mechanism underlying drug-drug interactions (DDIs). We determined the inhibitory potential of antifungal drugs currently used for invasive fungal infections on ABC transporters P-glycoprotein (P-gp), MRP1 to MRP5, BCRP, and BSEP in vitro. Membrane vesicles isolated from transporter-overexpressing HEK 293 cells were used to investigate the inhibitory potential of antifungal drugs (250 μM) on transport of model substrates. Concentration-inhibition curves were determined if transport inhibition was >60%. Fifty percent inhibitory concentrations (IC₅₀s) for P-gp and BCRP were both 2 μM for itraconazole, 5 and 12 μM for hydroxyitraconazole, 3 and 6 μM for posaconazole, and 3 and 11 μM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 μM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 μM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 μM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 μM). Despite their wide range of DDIs, azole antifungals exhibit selective inhibition on efflux transporters. Although echinocandins display low potential for clinically relevant DDIs, they demonstrate potent in vitro inhibitory activity. This suggests that inhibition of ABC transporters plays a crucial role in the inexplicable (non-cytochrome P450-mediated) DDIs with antifungal drugs.     

Symptomchecklisten bei Patienten mit chronischen Schmerzen

Symptom checklists, in particular the SCL-90-R, are widely used in screening for psychological distress in patients with chronic pain. A detailed analysis reveals that this may lead to wrong diagnoses in many cases. The problem of using the SCL-90-R in patients with chronic pain is (a) that scale means are elevated due to items asking for pain-associated symptoms and (b) that there is a lack of specificity of the various dimensions of the SCL-90-R. Numerous short forms of the SCL-90-R are compared to the original one and analysed with respect to their applicability in patients with chronic pain. Other screening questionnaires not related to the SCL-90-R were analysed for the same purpose. As a result, the SCL-27, K9, HADS and PHQ are judged to be applicable for screening in patients with chronic pain.