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Kristin T Ansteatt,1 Chanel J Unzicker,1 Marsha L Hurn,1 Oluwaseun O Olaiya,2 Diane J Nugent,3 Michael D Tarantino1 1The Bleeding and Clotting Disorders Institute, Peoria, IL, USA; 2Hematology Oncology, Children’s Mercy Hospital, Kansas City, MO, USA; 3The Center for Inherited Blood Disorders, Santa Ana, CA, USACorrespondence: Michael D TarantinoThe Bleeding and Clotting Disorders Institute, 9128 North Lindbergh Drive, Peoria, IL 61615, USATel +1 309 692-5337Fax +1 309 693-3913Email mtarantino@ilbcdi.orgAbstract: Chronic platelet disorders (CPD), including chronic immune thrombocytopenic purpura (cITP), thrombotic thrombocytopenic purpura (TTP) and platelet function disorders are among the most common bleeding disorders and are associated with morbidity and mortality. The clinical phenotype and complexity of cITP is much like that of hemophilia. In cITP and hemophilia, bleeding is problematic for many, complicating employability, insurability and overall quality-of-life (QoL). While myriad drug therapies are available for cITP and hemophilia, each are variable in their effectiveness, very few (except for clotting factor concentrates for hemophilia) alter the natural history of the disorder and sometimes contribute to specific morbidities and mortality. Like in hemophilia, the management of cITP is not solely based on access to effective treatment but also includes accurate diagnosis and comprehensive care by a multidisciplinary team of specialists trained in the management of bleeding disorders. The model of comprehensive care in Hemophilia Treatment Centers (HTCs) has been recognized as highly effective, improving life expectancy for persons with hemophilia. cITP, and other CPDs, are complex disorders requiring specialized care. However, an integrated care model with a systematic and reliable population-based surveillance program does not exist. Extending the Comprehensive Care model with all its related benefits to the community of persons with cITP is sorely needed. This review will focus on cITP as a prototype chronic platelet disorder that could benefit greatly from the Comprehensive Care model.Keywords: hemophilia, hemorrhage, idiopathic thrombocytopenic purpura, platelet, primary immune thrombocytopenia, thrombocytopenia

Background: Sedation for colonoscopy using intravenous propofol has become standard in many Western countries., Objective: Gender-specific differences have been shown for general anaesthesia in dentistry, but no such data existed for gastrointestinal endoscopy., Design: A prospective observational study., Setting: An academic teaching hospital of Hannover Medical School., Patients: A total of 219 patients (108 women and 111 men) scheduled for colonoscopy., Intervention: Propofol sedation using electroencephalogram monitoring during a constant level of sedation depth (D0 to D2) performed by trained nurses or physicians after a body-weight-adjusted loading dose., Main Outcome Measures: The primary end-point was the presence of gender-specific differences in awakening time (time from end of sedation to eye-opening and complete orientation); secondary outcome parameters analysed were total dose of propofol, sedation-associated complications (bradycardia, hypotension, hypoxaemia and apnoea), patient cooperation and patient satisfaction. Multivariate analysis was performed to correct confounding factors such as age and BMI., Results: Women awakened significantly faster than men, with a time to eye-opening of 7.3 ± 3.7 versus 8.4 ± 3.4 min (P = 0.005) and time until complete orientation of 9.1 ± 3.9 versus 10.4 ± 13.7 min (P = 0.008). The propofol dosage was not significantly different, with some trend towards more propofol per kg body weight in women (3.98 ± 1.81 mg versus 3.72 ± 1.75 mg, P = 0.232)., Conclusion: The effect of gender aspects should be considered when propofol is used as sedation for gastrointestinal endoscopy. That includes adequate dosing for women as well as caution regarding potential overdosing of male patients., Trial Registration: ClinicalTrials.gov (Identifier: NCT02687568).

We have recently shown that approximately half of primary multiple myeloma (MM) samples display constitutive Akt activity, which disposes them for sensitivity to Akt inhibition. The Akt pathway counts among the signaling conduits for oncogenic RAS and activating mutations of K- and N-RAS frequently occur in MM. We therefore analyzed the relation between RAS mutation and Akt dependency in biopsies and CD138-purified cells from MM patients (n = 65) and the function of oncogenic RAS for MM cell survival in a range of MM cell lines with differing RAS status. Whereas RAS mutations do not predict Akt dependency, oncogenic RAS retains an important role for MM cell survival. Knockdown of either K- or N-RAS strongly decreased the viability of MM cells that harbored the respective oncogenic isoform, whereas ablation of wild-type RAS isoforms had little or no effect. Silencing of oncogenic RAS did not affect the Akt pathway, again indicating lack of a direct link. Combined inhibition of RAS and Akt strongly enhanced MM cell death. These data suggest that oncogenic RAS and Akt may independently contribute to MM cell survival. Targeting of both pathways could provide an attractive therapeutic strategy for patients with oncogenic RAS and dysregulated Akt signaling.

Daptomycin is a novel lipopeptide antibiotic agent approved for the treatment of gram-positive life-threatening infections. Here we report, for the first time, the isolation of a highly daptomycin-resistant strain of Corynebacterium jeikeium causing a life-threatening infection in a neutropenic patient undergoing cord blood transplantation for secondary acute myeloid leukemia.

Endothelin (ETB)-receptors mediate anti-apoptotic actions. Lack of functional ETB-receptors leads to increased neuronal apoptosis in the hippocampus. The increased apoptosis must be compensated by other mechanisms, however, as ETB-deficient rats display normal overall brain morphology. To illuminate on brain plasticity in ETB-receptor deficiency, we studied the expression and function of another neuroprotective system, the cannabinoid CB1-receptors, in ETB-deficient hippocampus. We show that CB1 expression in hippocampus increases postnatally in all rats but that the increase in CB1-receptor expression is significantly higher in ETB-deficient compared to wildtype littermates. Neuronal apoptosis decreases during brain maturation but remains on a significantly higher level in the ETB-deficient compared to wildtype dentate. When investigating survival of hippocampal neurons in culture, we found significant protection against hypoxia-induced cell death with CB1-analogs (noladin, (9-tetrahydrocannabinol) only in ETB-deficient neurons. We suggest that CB1-receptor upregulation in the ETB-mutant hippocampus reflects an attempt to compensate for the lack of ETB-receptors.

The potential of erythropoietin (EPO) to reduce hypoxia-induced cell death has been investigated in 5-day-old primary cultures of rat postnatal hippocampal neurons. Application of EPO (100 pM) at the start of hypoxia resulted in a significant reduction of neuronal death (33.0 +/- 7.5% in cells incubated with EPO vs 56.75 +/- 7.3% in non-treated cells; n = 4, p < 0.021). Similiar results were obtained upon application of cycloheximide (CHX; 1 microM) simultaneously with hypoxia (34.75 +/- 5.6% vs 56.75 +/- 7.3% with and without CHX, respectively, n = 4, p < 0.035), indicating that hypoxia-induced neuronal death is an active, protein synthesis-dependent process. Both, EPO and EPO receptor (EPOR) were found to be expressed after hypoxia in hippocampal neurons in vitro and in vivo. These results demonstrate for the first time that EPO can reverse hypoxia-induced neuronal death when applied simultaneously with the hypoxic stimulus.