Preeclampsia (PE), Hemolysis Elevated Liver Enzymes and Low Platelets (HELLP)-syndrome, and intrauterine growth restriction (IUGR) are associated with abnormal placentation. In early pregnancy, placental cytotrophoblasts fuse and form multinuclear syncytiotrophoblasts. The envelope gene of the human endogenous retrovirus-W, Syncytin, is a key factor for mediating cell-cell fusion of cytotrophoblasts. This study investigated clinical parameters of PE and HELLP-associated IUGR and analyzed the cell-cell fusion index and beta-human chorionic gonadotropin (beta-hCG) secretion of cytotrophoblasts isolated and cultured from placentas of these patients. In addition, we performed absolute quantitation of Syncytin and determined the apoptosis rate in both cultured cytotrophoblasts and placental tissues. Cultured cytotrophoblasts from PE and HELLP-associated IUGR correlated with a pronounced lower cell-cell fusion index, 1.8- and 3.6-fold; less nuclei per syncytiotrophoblast, 1.4- and 2.0-fold; a significantly decreased beta-hCG secretion, 4.3- and 17.2-fold and a reduction of Syncytin gene expression, 8.1 (P = 0.019) and 222.7-fold (P = 0.011) compared with controls, respectively. In contrast, a significantly 2.3-fold higher apoptosis rate was observed in cultured PE/IUGR cytotrophoblasts (P = 0.043). Importantly, Syncytin gene expression in primary placental tissues of PE/IUGR was 5.4-fold lower (P = 0.047) and in HELLP/IUGR 10.6-fold lower (P = 0.019) along with a 1.8- and 1.9-fold significant increase in the apoptosis rate compared with controls, respectively. Low Syncytin expression in both cultured cytotrophoblasts and primary tissues from pathological placentas supports an intrinsic placenta-specific deregulation of cell-cell fusion in the formation of syncytiotrophoblasts leading to increased apoptosis. These processes could contribute to the development and severity of PE and HELLP-associated IUGR.

Following brain injury, S100B is released from damaged astrocytes but also yields repair mechanisms. We measured S100B in the cerebrospinal fluid (CSF) and serum (Cobas e411 electrochemiluminescence assay, Roche) longitudinally in a large cohort of patients treated with a ventricular drainage following traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Statistical analysis was performed with SPSS software applying the Mann-Whitney rank sum test or chi-test where appropriate. S100B in CSF and serum was significantly increased following TBI (n = 71) and SAH (n = 185) for at least one week following injury. High S100B levels in CSF and serum were inconsistent associated with outcome. The passage of S100B from CSF to blood (100∗serumS100B/CSFS100B) was significantly decreased although the albumin quotient suggested an “open” blood-CSF barrier. Events possibly interfering with the BBB did not affect the S100B passage (P = .591). In conclusion, we could not confirm S100B measurements to reliably predict outcome, and a compromised blood-CSF barrier did not affect the passage of S100B from CSF to serum.

BackgroundCancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.MethodsCytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data.ResultsThe in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5μmol/l (= 9944ng/ml), Nevirapine 239μmol/l (= 63786ng/ml), Etravirine 89.0μmol/l (= 38740ng/ml), Lersivirine 543μmol/l (= 168523ng/ml), Delavirdine 171μmol/l (= 78072ng/ml), Rilpivirine 24.4μmol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162–15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856–8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.ConclusionAll studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.

High S100B serum levels are considered to reflect brain injury severity. However, the dynamics of S100B passage from the cerebral compartment into the blood remain unclear. We examined the temporal profile of S100B release into the cerebrospinal fluid (CSF) and blood in acute brain injury.In patients treated with ventricular drainage (subarachnoid hemorrhage, SAH, n = 23; traumatic brain injury, TBI, n = 19), we measured S100B levels in the serum and CSF. The Glasgow Coma Score (GCS) was assessed daily. Statistical analysis was performed by the Mann-Whitney rank sum test for group differences and by the Pearson correlation.In normal controls (n = 6), S100B levels in the serum (0.05 +/- 0.01 microg/L) comprised around 10% of the CSF concentration (0.66 +/- 0.08 microg/L). Following brain injury, S100B levels were significantly increased in the serum (p < 0.05 in SAH day 2-5, TBI day 1-8) and excessively increased in the CSF (p < 0.05 in SAH and TBI day 1-10). For the individual patient, there was no consistent correlation between S100B levels in serum or CSF and GCS. We therefore calculated the ratio of S100B serum/CSF. Following brain injury, the S100B passage from the CSF to the blood was significantly impaired. Further, higher ratios were correlated with better neurological function (p = 0.002).Because stimulated active S100B release may serve as a repair mechanism, a higher S100B serum/CSF ratio may contribute to neurological recovery.