Neuromuscular Blockade with Rocuronium Bromide Increases the Tolerance of Acute Normovolemic Anemia in Anesthetized Pigs

Background: The patient's individual anemia tolerance is pivotal when blood transfusions become necessary, but are not feasible for some reason. To date, the effects of neuromuscular blockade (NMB) on anemia tolerance have not been investigated. Methods: 14 anesthetized and mechanically ventilated pigs were randomly assigned to the Roc group (3.78 mg/kg rocuronium bromide followed by continuous infusion of 1 mg/kg/min, n = 7) or to the Sal group (administration of the corresponding volume of normal saline, n = 7). Subsequently, acute normovolemic anemia was induced by simultaneous exchange of whole blood for a 6% hydroxyethyl starch solution (130/0.4) until a sudden decrease of total body O-2 consumption (VO2) indicated a critical limitation of O-2 transport capacity. The Hb concentration quantified at this time point (Hb(crit)) was the primary end-point of the protocol. Secondary endpoints were parameters of hemodynamics, O-2 transport and tissue oxygenation. Results: Hb(crit) was significantly lower in the Roc group (2.4 +/- 0.5 vs. 3.2 +/- 0.7 g/dl) reflecting increased anemia tolerance. NMB with rocuronium bromide reduced skeletal muscular VO2 and total body O-2 extraction rate. As the cardiac index increased simultaneously, total body VO2 only decreased marginally in the Roc group (change of VO2 relative to baseline -1.7 +/- 0.8 vs. 3.2 +/- 1.9% in the Sal group, p < 0.05). Conclusion: Deep NMB with rocuronium bromide increases the tolerance of acute normovolemic anemia. The underlying mechanism most likely involves a reduction of skeletal muscular VO2. During acellular treatment of an acute blood loss, NMB might play an adjuvant role in situations where profound stages of normovolemic anemia have to be tolerated (e.g. bridging an unexpected blood loss until blood products become available for transfusion). Copyright (C) 2011 S. Karger AG, Base

Role of urothelial cells in BCG immunotherapy for superficial bladder cancer

Intravesical instillation of Bacillus Calmette-Guérin (BCG) is used for the treatment of superficial bladder cancer, both to reduce the recurrence rate of bladder tumour and to diminish the risk of progression. Since its first therapeutic application in 1976, major research efforts have been directed to decipher the exact mechanism of action of the BCG-associated antitumour effect. Bacillus Calmette-Guérin causes an extensive local inflammatory reaction in the bladder wall. Of this, the massive appearance of cytokines in the urine of BCG-treated patients stands out. Activated lymphocytes and macrophages are the most likely sources of these cytokines, but at present other cellular sources such as urothelial tumour cells cannot be ruled out. Bacillus Calmette-Guérin is internalised and processed both by professional antigen-presenting cells and urothelial tumour cells, resulting in an altered gene expression of these cells that accumulates in the presentation of BCG antigens and secretion of particular cytokine

Managing Polyploidy in Ex Situ Conservation Genetics: The Case of the Critically Endangered Adriatic Sturgeon (Acipenser naccarii)

While the current expansion of conservation genetics enables to address more efficiently the management of threatened species, alternative methods for genetic relatedness data analysis in polyploid species are necessary. Within this framework, we present a standardized and simple protocol specifically designed for polyploid species that can facilitate management of genetic diversity, as exemplified by the ex situ conservation program for the tetraploid Adriatic sturgeon Acipenser naccarii. A critically endangered endemic species of the Adriatic Sea tributaries, its persistence is strictly linked to the ex situ conservation of a single captive broodstock currently decimated to about 25 individuals, which represents the last remaining population of Adriatic sturgeon of certain wild origin. The genetic variability of three F1 broodstocks available as future breeders was estimated based on mitochondrial and microsatellite information and compared with the variability of the parental generation. Genetic data showed that the F1 stocks have only retained part of the genetic variation present in the original stock due to the few parent pairs used as founders. This prompts for the urgent improvement of the current F1 stocks by incorporating new founders that better represent the genetic diversity available. Following parental allocation based on band sharing values, we set up a user-friendly tool for selection of candidate breeders according to relatedness between all possible parent-pairs that secures the use of non-related individuals. The approach developed here could also be applied to other endangered tetraploid sturgeon species overexploited for caviar production, particularly in regions lacking proper infrastructure and/or expertise

Novel Protein Kinase Signaling Systems Regulating Lifespan Identified by Small Molecule Library Screening Using Drosophila

Protein kinase signaling cascades control most aspects of cellular function. The ATP binding domains of signaling protein kinases are the targets of most available inhibitors. These domains are highly conserved from mammals to flies. Herein we describe screening of a library of small molecule inhibitors of protein kinases for their ability to increase Drosophila lifespan. We developed an assay system which allowed screening using the small amounts of materials normally present in commercial chemical libraries. The studies identified 17 inhibitors, the majority of which targeted tyrosine kinases associated with the epidermal growth factor receptor (EGFR), platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) receptors, G-protein coupled receptor (GPCR), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the insulin and insulin-like growth factor (IGFI) receptors. Comparison of the protein kinase signaling effects of the inhibitors in vitro defined a consensus intracellular signaling profile which included decreased signaling by p38MAPK (p38), c-Jun N-terminal kinase (JNK) and protein kinase C (PKC). If confirmed, many of these kinases will be novel additions to the signaling cascades known to regulate metazoan longevity

Perception of Vibrotactile Cues in Musical Performance

We suggest that studies on active touch psychophysics are needed to inform the design of haptic musical interfaces and better understand the relevance of haptic cues in musical performance. Following a review of the previous literature on vibrotactile perception in musical performance, two recent experiments are reported. The first experiment investigated how active finger-pressing forces affect vibration perception, finding significant effects of vibration type and force level on perceptual thresholds. Moreover, the measured thresholds were considerably lower than those reported in the literature, possibly due to the concurrent effect of large (unconstrained) finger contact areas, active pressing forces, and long-duration stimuli. The second experiment assessed the validity of these findings in a real musical context by studying the detection of vibrotactile cues at the keyboard of a grand and an upright piano. Sensitivity to key vibrations in fact not only was highest at the lower octaves and gradually decreased toward higher pitches; it was also significant for stimuli having spectral peaks of acceleration similar to those of the first experiment, i.e., below the standard sensitivity thresholds measured for sinusoidal vibrations under passive touch conditions

Genotype-dependent lifespan effects in peptone deprived Caenorhabditis elegans

Dietary restriction appears to act as a general non-genetic mechanism that can robustly prolong lifespan. There have however been reports in many systems of cases where restricted food intake either shortens, or does not affect, lifespan. Here we analyze lifespan and the effect of food restriction via deprived peptone levels on lifespan in wild isolates and introgression lines (ILs) of the nematode Caenorhabditis elegans. These analyses identify genetic variation in lifespan, in the effect of this variation in diet on lifespan and also in the likelihood of maternal, matricidal, hatching. Importantly, in the wild isolates and the ILs, we identify genotypes in which peptone deprivation mediated dietary restriction reduces lifespan. We also identify, in recombinant inbred lines, a locus that affects maternal hatching, a phenotype closely linked to dietary restriction in C. elegans. These results indicate that peptone deprivation mediated dietary restriction affects lifespan in C. elegans in a genotype-dependent manner, reducing lifespan in some genotypes. This may operate by a mechanism similar to dietary restriction

Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial

BACKGROUND: Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-beta, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma. METHODS: We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks. RESULTS: A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0-12 months), and the median overall survival was 4.4 months (range: 0-22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients. CONCLUSIONS: Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable

Murine Leukemia Virus Spreading in Mice Impaired in the Biogenesis of Secretory Lysosomes and Ca2+-Regulated Exocytosis

Retroviruses have been observed to bud intracellularly into multivesicular bodies (MVB), in addition to the plasma membrane. Release from MVB is thought to occur by Ca(2+)-regulated fusion with the plasma membrane.To address the role of the MVB pathway in replication of the murine leukemia virus (MLV) we took advantage of mouse models for the Hermansky-Pudlak syndrome (HPS) and Griscelli syndrome. In humans, these disorders are characterized by hypopigmentation and immunological alterations that are caused by defects in the biogenesis and trafficking of MVBs and other lysosome related organelles. Neonatal mice for these disease models lacking functional AP-3, Rab27A and BLOC factors were infected with Moloney MLV and the spread of virus into bone marrow, spleen and thymus was monitored. We found a moderate reduction in MLV infection levels in most mutant mice, which differed by less than two-fold compared to wild-type mice. In vitro, MLV release form bone-marrow derived macrophages was slightly enhanced. Finally, we found no evidence for a Ca(2+)-regulated release pathway in vitro. Furthermore, MLV replication was only moderately affected in mice lacking Synaptotagmin VII, a Ca(2+)-sensor regulating lysosome fusion with the plasma membrane.Given that MLV spreading in mice depends on multiple rounds of replication even moderate reduction of virus release at the cellular level would accumulate and lead to a significant effect over time. Thus our in vivo and in vitro data collectively argue against an essential role for a MVB- and secretory lysosome-mediated pathway in the egress of MLV