Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.     

Characterization of CSOC 882, a novel immortalized ovarian cancer cell line expressing EGFR, HER2, and activated AKT

OBJECTIVE: Only a small number of comprehensively characterized immortalized ovarian cancer cell lines are available for laboratory studies on ovarian cancer. We describe a new ovarian cancer cell line that arose from primary culture of a stage IC, grade III ovarian carcinoma, designated CSOC 882. METHODS: We characterized CSOC 882 by karyotyping, growth modeling, immunohistochemical staining, immunoblotting, drug sensitivity testing, and xenografting in nude mice. RESULTS: CSOC 882 possessed an abnormal tetraploid karyotype including loss of one copy of chromosomes 2, 17, 19, and 21, and deletion of 8p21. Growth of CSOC 882 was best modeled using the logistic growth equation revealing an average doubling time of 31 h. CSOC 882 cells expressed vimentin, cytokeratin, p53, BRCA1, EGF receptor, HER2, androgen receptor, estrogen receptor alpha, and progesterone receptor, while no evidence of estrogen receptor beta or factor VIII was observed. Some but not all CSOC 882 cells were positive for CA125 reflecting the primary tumor, which had patchy CA125 staining. Drug sensitivity assays demonstrated that CSOC 882 was more sensitive to cisplatin and carboplatin than SKOV3 and HCC1937 while CSOC 882 and SKOV3 were both sensitive to paclitaxel unlike HCC1937. CSOC 882 xenografts retained the original characteristics of vimentin, cytokeratin, and factor VIII labeling. CONCLUSIONS: CSOC 882 is an immortalized cell line that has survived more than 130 passages in culture and retained molecular features of the primary tumor from which it was derived. Compared to the most common ovarian carcinoma cell lines, CSOC 882 is a unique resource for genetic and cellular research on ovarian cancer.     

Mesenchymal stem cells induce endothelial activation via paracine mechanisms.

Mesenchymal stem cells (MSCs) are bone marrow-derived, pluripotent cells that possess the ability to transdifferentiate into various mesenchymal tissues such as bone, endothelium, and (heart) muscle. Therefore, these cells may provide a therapeutic tool, especially for the treatment of myocardial infarction. The interaction of the MSCs with the endothelial barrier and their ability to ultimately leave blood vessels after application are crucial in this context. In this study, the authors focused on the soluble factors produced by MSCs and their effect on the intracellular signal transduction of endothelial cells. The authors performed immunohistochemical measurements on human umbilical vein endothelial cells (HUVECs) treated with conditioned stem cell medium and took measurements of the intracellular nitric oxide (NO) levels and calcium changes. After application of conditioned stem cell medium, the authors detected an increase in endothelial NO synthase (eNOS) activity by translocation (Ca(2+)) and by phosphorylation (increase of pAKT and peNOS1177). Additionally, the authors observed an upregulation of pERK within the same time. The phosphorylated eNOS forms are linked to these findings and the increase of intracellular NO in the DAF measurements. Moreover, conditioned medium also increased intracellular calcium levels in endothelial cells. Concluding, the authors postulate that MSCs emit soluble factors that alter the NO and calcium levels of endothelial cells and may be important for facilitate crossing the endothelial barrier.     

Infection of honey bees with acute bee paralysis virus does not trigger humoral or cellular immune responses

We have studied the responses of honey bees at different life stages (Apis mellifera) to controlled infection with acute bee paralysis virus and have identified the haemolymph of infected larvae and adult worker bees as the compartment where massive propagation of ABPV occurs. Insects respond with a broad spectrum of induced innate immune reactions to bacterial infections, whereas defence mechanisms based on RNA interference play a major role in antiviral immunity. In this study, we have determined that honey bee larvae and adult workers do not produce a humoral immune reaction upon artificial infection with ABPV, in contrast to control individuals challenged with Escherichia coli. ABPV-infected bees produced neither elevated levels of specific antimicrobial peptides (AMPs), such as hymenoptaecin and defensin, nor any general antimicrobial activity, as revealed by inhibition-zone assays. Additionally, adult bees did not generate melanised nodules upon ABPV infection, an important cellular immune function activated by bacteria and viruses in some insects. Challenge of bees with both ABPV and E. coli showed that innate humoral and cellular immune reactions are induced in mixed infections, albeit at a reduced level.     

Using the galactomannan antigen assay in the diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation

Invasive aspergillosis (IA) is the most common life-threatening infections after hematopoietic stem cell transplant (HSCT). The serum galactomannan (GM) is recognized as an indirect mycological criteria for an early diagnosis of IA. Starting January 2011, we implementing in Fundeni Clinical Institute, Bucharest, for the first time in Romania, the detection of GM antigen (Platelia Aspergillus EIA, Bio-Rad). In 2011, patients undergoing HSCT were screened with the galactomannan ELISA; we performed a retrospective chart review of 162 SCT patients who underwent galactomannan testing. Thirteen of the patients (8.02%) had at least one positive galactomannan ELISA, and four had multiple positive tests. When calculated in reference to a proved or probable diagnosis of aspergillosis, the galactomannan ELISA had a sensitivity of 0.857 and a specificity of 0.913. The positive predictive value was 0.46, and the negative predictive value was 0.993. The Platelia Aspergillus galactomannan antigenemia assay may assist physicians in making an early diagnosis of IA, in correlation with clinical and radiological criteria. The test has a high sensitivity and specificity and a very good negative predictive value. We found the screening of GM ELISA to be a highly specific diagnostic tool in detecting IA manifested in patients undergoing HSCT.     

Effects of Preoperative Short Term Use of Atorvastatin on Endothelial Progenitor Cells after Coronary Surgery: A Randomized, Controlled Trial

Objectives

We investigated the effects of short-term use of atorvastatin on CD34+/VEGF-R2+/CD133+/CD45- endothelial progenitor cell (EPC) count after on-pump coronary artery bypass surgery (CABG).

Methods

Between Feb-2010 and May-2010, we randomly assigned, in a placebo-controlled, double-blind study, 60 consecutive patients who underwent isolated, first-time CABG to receive either 14-day atorvastatin (40 mg/day) or placebo preoperatively. Urgent CABG and recent myocardial infarction were excluded. EPCs were quantified (cells/μl) by flow cytometric phenotyping obtained from venous blood samples collected preoperatively (T₁), 6-hours (T₂), and on the 5th day postoperatively (T₃). Levels of markers of inflammation and serum cardiac troponin I were also measured preoperatively and daily until day-5 after surgery.

Results

There were no differences in baseline risk factors including cholesterol profiles, and EuroSCORES between the groups. The composite primary end-point, favored statin group with higher amount of circulating, early EPC count (cells/μl) at all time points compared with placebo (T₁, 2.30?±?0.02 versus 1.58?±?0.03, p?2, 5.00?±?0.06 versus 2.19?±?0.06, p?3, 3.03?±?0.08 versus 1.78?±?0.02, p?1, 0.8?±?0.1 versus 2.2?±?1.5, p?2, 72.9?±?3.2 versus 96.0?±?3.6, p?3, 4.3?±?1.2 versus 11.4?±?4.1, p?p?=?0.02).

Conclusions

Short-term atorvastatin use increases circulating early EPCs both pre- and post-operatively and is associated with better preservation of sinus rhythm and reduced hsCRP levels. (ClinicalTrials.gov number, NCT01096875)     

Loss of NKG2D in murine NK cells leads to increased perforin production upon long-term stimulation with IL-2

NK cells are innate lymphocytes responsible for lysis of pathogen-infected and transformed cells. One of the major activating receptors required for target cell recognition is the NK group 2D (NKG2D) receptor. Numerous reports show the necessity of NKG2D for effective tumor immune surveillance. Further studies identified NKG2D as a key element allowing tumor immune escape. We here use a mouse model with restricted deletion of NKG2D in mature NKp46⁺ cells (NKG2D^ΔNK). NKG2D^ΔNK NK cells develop normally, have an unaltered IFN-γ production but kill tumor cell lines expressing NKG2D ligands (NKG2DLs) less efficiently. However, upon long-term stimulation with IL-2, NKG2D-deficient NK cells show increased levels of the lytic molecule perforin. Thus, our findings demonstrate a dual function of NKG2D for NK cell cytotoxicity; while NKG2D is a crucial trigger for cytotoxicity of tumor cells expressing activating ligands it is also capable to limit perforin production in IL-2 activated NK cells.     

Flt3 signaling-dependent dendritic cells protect against atherosclerosis

Early events in atherosclerosis occur in the aortic intima and involve monocytes that become macrophages. We looked for these cells in the steady state adult mouse aorta, and surprisingly, we found a dominance of dendritic cells (DCs) in the intima. In contrast to aortic adventitial macrophages, CD11c(+)MHC II(hi) DCs were poorly phagocytic but were immune stimulatory. DCs were of two types primarily: classical Flt3-Flt3L signaling-dependent, CD103(+)CD11b(-) DCs and macrophage-colony stimulating factor (M-CSF)-dependent, CD14(+)CD11b(+)DC-SIGN(+) monocyte-derived DCs. Both types expanded during atherosclerosis. By crossing Flt3(-/-) to Ldlr(-/-) atherosclerosis-prone mice, we developed a selective and marked deficiency of classical CD103(+) aortic DCs, and they were associated with exacerbated atherosclerosis without alterations in blood lipids. Concomitantly, the Flt3(-/-)Ldlr(-/-) mice had fewer Foxp3(+) Treg cells and increased inflammatory cytokine mRNAs in the aorta. Therefore, functional DCs are dominant in normal aortic intima and, in contrast to macrophages, CD103(+) classical DCs are associated with atherosclerosis protection.